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Linking epigenetic signature and metabolic phenotype in IDH mutant and IDH wildtype diffuse glioma
(2020)
Aims: Changes in metabolism are known to contribute to tumour phenotypes. If and how metabolic alterations in brain tumours contribute to patient outcome is still poorly understood. Epigenetics impact metabolism and mitochondrial function. The aim of this study is a characterisation of metabolic features in molecular subgroups of isocitrate dehydrogenase mutant (IDHmut) and isocitrate dehydrogenase wildtype (IDHwt) gliomas. Methods: We employed DNA methylation pattern analyses with a special focus on metabolic genes, large-scale metabolism panel immunohistochemistry (IHC), qPCR-based determination of mitochondrial DNA copy number and immune cell content using IHC and deconvolution of DNA methylation data. We analysed molecularly characterised gliomas (n = 57) for in depth DNA methylation, a cohort of primary and recurrent gliomas (n = 22) for mitochondrial copy number and validated these results in a large glioma cohort (n = 293). Finally, we investigated the potential of metabolic markers in Bevacizumab (Bev)-treated gliomas (n = 29). Results: DNA methylation patterns of metabolic genes successfully distinguished the molecular subtypes of IDHmut and IDHwt gliomas. Promoter methylation of lactate dehydrogenase A negatively correlated with protein expression and was associated with IDHmut gliomas. Mitochondrial DNA copy number was increased in IDHmut tumours and did not change in recurrent tumours. Hierarchical clustering based on metabolism panel IHC revealed distinct subclasses of IDHmut and IDHwt gliomas with an impact on patient outcome. Further quantification of these markers allowed for the prediction of survival under anti-angiogenic therapy. Conclusion: A mitochondrial signature was associated with increased survival in all analyses, which could indicate tumour subgroups with specific metabolic vulnerabilities.
Simple Summary: Targeted therapies are of growing interest to physicians in cancer treatment. These drugs target specific genes and proteins involved in the growth and survival of cancer cells. Brain tumor therapy is complicated by the fact that not all drugs can penetrate the blood brain barrier and reach their target. We explored the non-invasive method, Magnetic Resonance Spectroscopy, for monitoring drug penetration and its effects in live animals bearing brain tumors. We were able to show the presence of the investigated drug in mouse brains and its on-target activity.
Abstract: Background: BAY1436032 is a fluorine-containing inhibitor of the R132X-mutant isocitrate dehydrogenase (mIDH1). It inhibits the mIDH1-mediated production of 2-hydroxyglutarate (2-HG) in glioma cells. We investigated brain penetration of BAY1436032 and its effects using 1H/19F-Magnetic Resonance Spectroscopy (MRS). Methods: 19F-Nuclear Magnetic Resonance (NMR) Spectroscopy was conducted on serum samples from patients treated with BAY1436032 (NCT02746081 trial) in order to analyze 19F spectroscopic signal patterns and concentration-time dynamics of protein-bound inhibitor to facilitate their identification in vivo MRS experiments. Hereafter, 30 mice were implanted with three glioma cell lines (LNT-229, LNT-229 IDH1-R132H, GL261). Mice bearing the IDH-mutated glioma cells received 5 days of treatment with BAY1436032 between baseline and follow-up 1H/19F-MRS scan. All other animals underwent a single scan after BAY1436032 administration. Mouse brains were analyzed by liquid chromatography-mass spectrometry (LC-MS/MS). Results: Evaluation of 1H-MRS data showed a decrease in 2-HG/total creatinine (tCr) ratios from the baseline to post-treatment scans in the mIDH1 murine model. Whole brain concentration of BAY1436032, as determined by 19F-MRS, was similar to total brain tissue concentration determined by Liquid Chromatography with tandem mass spectrometry (LC-MS/MS), with a signal loss due to protein binding. Intratumoral drug concentration, as determined by LC-MS/MS, was not statistically different in models with or without R132X-mutant IDH1 expression. Conclusions: Non-invasive monitoring of mIDH1 inhibition by BAY1436032 in mIDH1 gliomas is feasible.
The production of light neutral mesons in AA collisions probes the physics of the Quark-Gluon Plasma (QGP), which is formed in heavy-ion collisions at the LHC. More specifically, the centrality dependent neutral meson spectra in AA collisions compared to its spectra in minimum-bias pp collisions, scaled with the number of hard collisions, provides information on the energy loss of partons traversing the QGP. The measurement allows to test with high precision the predictions of theoretical model calculations. In addition, the decay of the π0 and η mesons are the dominant back- grounds for all direct photon measurements. Therefore, pushing the limits of the precision of neutral meson production is key to learning about the temperature and space-time evolution of the QGP.
In the ALICE experiment neutral mesons can be detected via their decay into two photons. The latter can be reconstructed using the two calorimeters EMCal and PHOS or via conversions in the detector material. The excellent momentum resolution of the conversion photons down to very low pT and the high reconstruction efficiency and triggering capability of calorimeters at high pT, allow us to measure the pT dependent invariant yield of light neutral mesons over a wide kinematic range.
Combining state-of-the-art reconstruction techniques with the high statistics delivered by the LHC in Run 2 gives us the opportunity to enhance the precision of our measurements. In these proceedings, new ALICE run 2 preliminary results for neutral meson production in pp and Pb–Pb collisions at LHC energies are presented.
Nature affects human well-being in multiple ways. However, the association between species diversity and human well-being at larger spatial scales remains largely unexplored. Here, we examine the relationship between species diversity and human well-being at the continental scale, while controlling for other known drivers of well-being. We related socio-economic data from more than 26,000 European citizens across 26 countries with macroecological data on species diversity and nature characteristics for Europe. Human well-being was measured as self-reported life-satisfaction and species diversity as the species richness of several taxonomic groups (e.g. birds, mammals and trees). Our results show that bird species richness is positively associated with life-satisfaction across Europe. We found a relatively strong relationship, indicating that the effect of bird species richness on life-satisfaction may be of similar magnitude to that of income. We discuss two, non-exclusive pathways for this relationship: the direct multisensory experience of birds, and beneficial landscape properties which promote both bird diversity and people's well-being. Based on these results, this study argues that management actions for the protection of birds and the landscapes that support them would benefit humans. We suggest that political and societal decision-making should consider the critical role of species diversity for human well-being.
Introduction: Recommendations for venous thromboembolism and deep venous thrombosis (DVT) prophylaxis using graduated compression stockings (GCS) is historically based and has been critically examined in current publications. Existing guidelines are inconclusive as to recommend the general use of GCS.
Patients/Methods: 24 273 in-patients (general surgery and orthopedic patients) undergoing surgery between 2006 and 2016 were included in a retrospectively analysis from a single center. From January 2006 to January 2011 perioperative GCS was employed additionally to drug prophylaxis and from February 2011 to March 2016 patients received drug prophylaxis alone. According to german guidelines all patients received venous thromboembolism prophylaxis with weight-adapted LMWH. Risk stratification (low risk, moderate risk, high risk) was based on the guideline of the American College of Chest Physicians. Data analysis was performed before and after propensity matching (PM). The defined primary endpoint was the incidence of symptomatic or fatal pulmonary embolism (PE). A secondary endpoint was the incidence of deep venous thromboembolism (DVT).
Results: After risk stratification (low risk n = 16 483; moderate risk n = 4464; high risk n = 3326) a total of 24 273 patient were analyzed. Before to PM the relative risk for the occurrence of a PE or DVT was not increased by abstaining from GCS. After PM two groups of 11 312 patients each, one with and one without GCS application, were formed. When comparing the two groups, the relative risk (RR) for the occurrence of a pulmonary embolism was: Low Risk 0.99 [CI95% 0.998–1.000]; Moderate Risk 0.999 [CI95% 0.95–1.003]; High Risk 0.996 [CI95% 0.992–1.000] (p > 0.05). The incidence of PE in the total group LMWH alone was 0.1% (n = 16). In the total group using LMWH + GCS, the incidence was 0.3% (n = 29). RR after PM was 0.999 [CI95% 0.998–1.00].
Conclusion: In comparison to prior studies with only small numbers of patients our trial shows in a large group of patients with moderate and high risk developing VTE we can support the view that abstaining from GCS-use does not increase the incidence of symptomatic or fatal PE and symptomatic DVT.
Over the last 15 years the Diagnostic Center of Acute Leukemia (DCAL) at the Frankfurt University has diagnosed and elucidated the Mixed Lineage Leukemia (MLL) recombinome with >100 MLL fusion partners. When analyzing all these different events, balanced chromosomal translocations were found to comprise the majority of these cases (~70%), while other types of genetic rearrangements (3-way-translocations, spliced fusions, 11q inversions, interstitial deletions or insertion of chromosomal fragments into other chromosomes) account for about 30%. In nearly all those complex cases, functional fusion proteins can be produced by transcription, splicing and translation. With a few exceptions (10 out of 102 fusion genes which were per se out-of-frame), all these genetic rearrangements produced a direct MLL fusion gene, and in 94% of cases an additional reciprocal fusion gene. So far, 114 patients (out of 2454 = ~5%) have been diagnosed only with the reciprocal fusion allele, displaying no MLL-X allele. The fact that so many MLL rearrangements bear at least two fusion alleles, but also our findings that several direct MLL fusions were either out-of-frame fusions or missing, raises the question about the function and importance of reciprocal MLL fusions. Recent findings also demonstrate the presence of reciprocal MLL fusions in sarcoma patients. Here, we want to discuss the role of reciprocal MLL fusion proteins for leukemogenesis and beyond.
Two-person neuroscience (2 PN) is a recently introduced conceptual and methodological framework used to investigate the neural basis of human social interaction from simultaneous neuroimaging of two or more subjects (hyperscanning). In this study, we adopted a 2 PN approach and a multiple-brain connectivity model to investigate the neural basis of a form of cooperation called joint action. We hypothesized different intra-brain and inter-brain connectivity patterns when comparing the interpersonal properties of joint action with non-interpersonal conditions, with a focus on co-representation, a core ability at the basis of cooperation. 32 subjects were enrolled in dual-EEG recordings during a computerized joint action task including three conditions: one in which the dyad jointly acted to pursue a common goal (joint), one in which each subject interacted with the PC (PC), and one in which each subject performed the task individually (Solo).
A combination of multiple-brain connectivity estimation and specific indices derived from graph theory allowed to compare interpersonal with non-interpersonal conditions in four different frequency bands. Our results indicate that all the indices were modulated by the interaction, and returned a significantly stronger integration of multiple-subject networks in the joint vs. PC and Solo conditions. A subsequent classification analysis showed that features based on multiple-brain indices led to a better discrimination between social and non-social conditions with respect to single-subject indices. Taken together, our results suggest that multiple-brain connectivity can provide a deeper insight into the understanding of the neural basis of cooperation in humans.
Inhibitors against the NS3-4A protease of hepatitis C virus (HCV) have proven to be useful drugs in the treatment of HCV infection. Although variants have been identified with mutations that confer resistance to these inhibitors, the mutations do not restore replicative fitness and no secondary mutations that rescue fitness have been found. To gain insight into the molecular mechanisms underlying the lack of fitness compensation, we screened known resistance mutations in infectious HCV cell culture with different genomic backgrounds. We observed that the Q41R mutation of NS3-4A efficiently rescues the replicative fitness in cell culture for virus variants containing mutations at NS3-Asp168. To understand how the Q41R mutation rescues activity, we performed protease activity assays complemented by molecular dynamics simulations, which showed that protease-peptide interactions far outside the targeted peptide cleavage sites mediate substrate recognition by NS3-4A and support protease cleavage kinetics. These interactions shed new light on the mechanisms by which NS3-4A cleaves its substrates, viral polyproteins and a prime cellular antiviral adaptor protein, the mitochondrial antiviral signaling protein MAVS. Peptide binding is mediated by an extended hydrogen-bond network in NS3-4A that was effectively optimized for protease-MAVS binding in Asp168 variants with rescued replicative fitness from NS3-Q41R. In the protease harboring NS3-Q41R, the N-terminal cleavage products of MAVS retained high affinity to the active site, rendering the protease susceptible for potential product inhibition. Our findings reveal delicately balanced protease-peptide interactions in viral replication and immune escape that likely restrict the protease adaptive capability and narrow the virus evolutionary space.
Highlights
• Explanation of mobility design and its practical, aesthetic and emblematic effects on travel behaviour.
• Review of recent studies on mobility design elements and the promotion of non-motorised travel.
• Discussion of research gaps and methodological challenges of data collection and comparability.
Abstract
To promote non-motorised travel, many travel behaviour studies acknowledge the importance of the built environment to modal choice, for example with its density or mix of uses. From a mobility design theory perspective, however, objects and environments affect human perceptions, assessments and behaviour in at least three different ways: by their practical, aesthetic and emblematic functions. This review of existing evidence will argue that travel behaviour research has so far mainly focused on the practical function of the built environment. For that purpose, we systematically identified 56 relevant studies on the impacts of the built environment on non-motorised travel behaviour in the Web of Science database. The focus of research on the practical design function primary involves land use distribution, street network connectivity and the presence of walking and cycling facilities. Only a small number of papers address the aesthetic and emblematic functions. These show that the perceived attractiveness of an environment and evoked feelings of traffic safety increase the likelihood of walking and cycling. However, from a mobility design perspective, the results of the review indicate a gap regarding comprehensive research on the effects of the aesthetic and emblematic functions of the built environment. Further research involving these functions might contribute to a better understanding of how to promote non-motorised travel more effectively. Moreover, limitations related to survey techniques, regional distribution and the comparability of results were identified.
This research examines the impact of online display advertising and paid search advertising relative to offline advertising on firm performance and firm value. Using proprietary data on annualized advertising expenditures for 1651 firms spanning seven years, we document that both display advertising and paid search advertising exhibit positive effects on firm performance (measured by sales) and firm value (measured by Tobin's q). Paid search advertising has a more positive effect on sales than offline advertising, consistent with paid search being closest to the actual purchase decision and having enhanced targeting abilities. Display advertising exhibits a relatively more positive effect on Tobin's q than offline advertising, consistent with its long-term effects. The findings suggest heterogeneous economic benefits across different types of advertising, with direct implications for managers in analyzing advertising effectiveness and external stakeholders in assessing firm performance.
The US Treasury recently permitted deferred longevity income annuities to be included in pension plan menus as a default payout solution, yet little research has investigated whether more people should convert some of the $18 trillion they hold in employer-based defined contribution plans into lifelong income streams. We investigate this innovation using a calibrated lifecycle consumption and portfolio choice model embodying realistic institutional considerations. Our welfare analysis shows that defaulting a modest portion of retirees’ 401(k) assets (over a threshold) is an attractive way to enhance retirement security, enhancing welfare by up to 20% of retiree plan accruals.
In this paper a new method of experimental data analysis, the Particle-Set Identification method, is presented. The method allows to reconstruct moments of multiplicity distribution of identified particles. The difficulty the method copes with is due to incomplete particle identification – a particle mass is frequently determined with a resolution which does not allow for a unique determination of the particle type. Within this method the moments of order k are calculated from mean multiplicities of k-particle sets of a given type. The Particle-Set Identification method remains valid even in the case of correlations between mass measurements for different particles. This distinguishes it from the Identity method introduced by us previously to solve the problem of incomplete particle identification in studies of particle fluctuations.
Deubiquitinases (DUBs) are vital for the regulation of ubiquitin signals, and both catalytic activity of and target recruitment by DUBs need to be tightly controlled. Here, we identify asparagine hydroxylation as a novel posttranslational modification involved in the regulation of Cezanne (also known as OTU domain–containing protein 7B (OTUD7B)), a DUB that controls key cellular functions and signaling pathways. We demonstrate that Cezanne is a substrate for factor inhibiting HIF1 (FIH1)- and oxygen-dependent asparagine hydroxylation. We found that FIH1 modifies Asn35 within the uncharacterized N-terminal ubiquitin-associated (UBA)-like domain of Cezanne (UBACez), which lacks conserved UBA domain properties. We show that UBACez binds Lys11-, Lys48-, Lys63-, and Met1-linked ubiquitin chains in vitro, establishing UBACez as a functional ubiquitin-binding domain. Our findings also reveal that the interaction of UBACez with ubiquitin is mediated via a noncanonical surface and that hydroxylation of Asn35 inhibits ubiquitin binding. Recently, it has been suggested that Cezanne recruitment to specific target proteins depends on UBACez. Our results indicate that UBACez can indeed fulfill this role as regulatory domain by binding various ubiquitin chain types. They also uncover that this interaction with ubiquitin, and thus with modified substrates, can be modulated by oxygen-dependent asparagine hydroxylation, suggesting that Cezanne is regulated by oxygen levels.
Hypoxia inhibits ferritinophagy, increases mitochondrial ferritin, and protects from ferroptosis
(2020)
Highlights
• Hypoxia decreases NCOA4 transcription in primary human macrophages.
• NCOA4 mRNA is a target of miR-6862-5p.
• Lowering NCOA4 increases FTMT abundance under hypoxia.
• FTMT and FTH protect from ferroptosis.
• Tumor cells lack the hypoxic decrease of NCOA4 and fail to stabilize FTMT.
Abstract
Cellular iron, at the physiological level, is essential to maintain several metabolic pathways, while an excess of free iron may cause oxidative damage and/or provoke cell death. Consequently, iron homeostasis has to be tightly controlled. Under hypoxia these regulatory mechanisms for human macrophages are not well understood. Hypoxic primary human macrophages reduced intracellular free iron and increased ferritin expression, including mitochondrial ferritin (FTMT), to store iron. In parallel, nuclear receptor coactivator 4 (NCOA4), a master regulator of ferritinophagy, decreased and was proven to directly regulate FTMT expression. Reduced NCOA4 expression resulted from a lower rate of hypoxic NCOA4 transcription combined with a micro RNA 6862-5p-dependent degradation of NCOA4 mRNA, the latter being regulated by c-jun N-terminal kinase (JNK). Pharmacological inhibition of JNK under hypoxia increased NCOA4 and prevented FTMT induction. FTMT and ferritin heavy chain (FTH) cooperated to protect macrophages from RSL-3-induced ferroptosis under hypoxia as this form of cell death is linked to iron metabolism. In contrast, in HT1080 fibrosarcome cells, which are sensitive to ferroptosis, NCOA4 and FTMT are not regulated. Our study helps to understand mechanisms of hypoxic FTMT regulation and to link ferritinophagy and macrophage sensitivity to ferroptosis.
Highlights
• PUR, PVC and PLA microplastics affect life-history parameters of Daphnia magna.
• Natural kaolin particles are less toxic than microplastics.
• Microplastic toxicity is material-specific, e.g. PVC is most toxic on reproduction.
• In case of PVC, plastic chemicals are the main driver of microplastic toxicity.
• PLA bioplastics are similarly toxic as conventional plastics.
Abstract
Given the ubiquitous presence of microplastics in aquatic environments, an evaluation of their toxicity is essential. Microplastics are a heterogeneous set of materials that differ not only in particle properties, like size and shape, but also in chemical composition, including polymers, additives and side products. Thus far, it remains unknown whether the plastic chemicals or the particle itself are the driving factor for microplastic toxicity. To address this question, we exposed Daphnia magna for 21 days to irregular polyvinyl chloride (PVC), polyurethane (PUR) and polylactic acid (PLA) microplastics as well as to natural kaolin particles in high concentrations (10, 50, 100, 500 mg/L, ≤ 59 μm) and different exposure scenarios, including microplastics and microplastics without extractable chemicals as well as the extracted and migrating chemicals alone. All three microplastic types negatively affected the life-history of D. magna. However, this toxicity depended on the endpoint and the material. While PVC had the largest effect on reproduction, PLA reduced survival most effectively. The latter indicates that bio-based and biodegradable plastics can be as toxic as their conventional counterparts. The natural particle kaolin was less toxic than microplastics when comparing numerical concentrations. Importantly, the contribution of plastic chemicals to the toxicity was also plastic type-specific. While we can attribute effects of PVC to the chemicals used in the material, effects of PUR and PLA plastics were induced by the mere particle. Our study demonstrates that plastic chemicals can drive microplastic toxicity. This highlights the importance of considering the individual chemical composition of plastics when assessing their environmental risks. Our results suggest that less studied polymer types, like PVC and PUR, as well as bioplastics are of particular toxicological relevance and should get a higher priority in ecotoxicological studies.
Decline in physical activity in the weeks preceding sustained ventricular arrhythmia in women
(2020)
Background: Heightened risk of cardiac arrest following physical exertion has been reported. Among patients with an implantable defibrillator, an appropriate shock for sustained ventricular arrhythmia was preceded by a retrospective self-report of engaging in mild-to-moderate physical activity. Previous studies evaluating the relationship between activity and sudden cardiac arrest lacked an objective measure of physical activity and women were often underrepresented.
Objective: To determine the relationship between physical activity, recorded by accelerometer in a wearable cardioverter-defibrillator (WCD), and sustained ventricular arrhythmia among female patients.
Methods: A dataset of female adult patients prescribed a WCD for a diagnosis of myocardial infarction or dilated cardiomyopathy was compiled from a commercial database. Curve estimation, to include linear and nonlinear interpolation, was applied to physical activity as a function of time (days before arrhythmia).
Results: Among women who received an appropriate WCD shock for sustained ventricular arrhythmia (N = 120), a quadratic relationship between time and activity was present prior to shock. Physical activity increased starting at the beginning of the 30-day period up until day -16 (16 days before the ventricular arrhythmia) when activity begins to decline.
Conclusion: For patients who received treatment for sustained ventricular arrhythmia, a decline in physical activity was found during the 2 weeks preceding the arrhythmic event. Device monitoring for a sustained decline in physical activity may be useful to identify patients at near-term risk of a cardiac arrest.
Entorhinal-retrosplenial circuits for allocentric-egocentric transformation of boundary coding
(2020)
Spatial navigation requires landmark coding from two perspectives, relying on viewpoint-invariant and self-referenced representations. The brain encodes information within each reference frame but their interactions and functional dependency remains unclear. Here we investigate the relationship between neurons in the rat's retrosplenial cortex (RSC) and entorhinal cortex (MEC) that increase firing near boundaries of space. Border cells in RSC specifically encode walls, but not objects, and are sensitive to the animal’s direction to nearby borders. These egocentric representations are generated independent of visual or whisker sensation but are affected by inputs from MEC that contains allocentric spatial cells. Pharmaco- and optogenetic inhibition of MEC led to a disruption of border coding in RSC, but not vice versa, indicating allocentric-to-egocentric transformation. Finally, RSC border cells fire prospective to the animal’s next motion, unlike those in MEC, revealing the MEC-RSC pathway as an extended border coding circuit that implements coordinate transformation to guide navigation behavior.
Aim: To assess volumetric tissue changes at peri‐implantitis sites following combined surgical therapy of peri‐implantitis over a 6‐month follow‐up period.
Materials and Methods: Twenty patients (n = 28 implants) diagnosed with peri‐implantitis underwent access flap surgery, implantoplasty at supracrestally or bucally exposed implant surfaces and augmentation at intra‐bony components using a natural bone mineral and application of a native collagen membrane during clinical routine treatments. The peri‐implant region of interest (ROI) was intra‐orally scanned pre‐operatively (S0), and after 1 (S1) and 6 (S2) months following surgical therapy. Digital files were converted to standard tessellation language (STL) format for superimposition and assessment of peri‐implant volumetric variations between time points. The change in thickness was assessed at a standardized ROI, subdivided into three equidistant sections (i.e. marginal, medial and apical). Peri‐implant soft tissue contour area (STCA) (mm2) and its corresponding contraction rates (%) were also assessed.
Results: Peri‐implant tissues revealed a mean thickness change (loss) of −0.11 and −0.28 mm at 1 and 6 months. S0 to S1 volumetric variations pointed to a thickness change of −0.46, 0.08 and 0.4 mm at marginal, medial and apical regions, respectively. S0 to S2 analysis exhibited corresponding thickness changes of −0.61, −0.25 and −0.09 mm, respectively. The thickness differences between the areas were statistically significant at both time periods. The mean peri‐implant STCA totalled to 189.2, 175 and 158.9 mm2 at S0, S1 and S2, showing a significant STCA contraction rate of 7.9% from S0 to S1 and of 18.5% from S0 to S2. Linear regression analysis revealed a significant association between the pre‐operative width of keratinized mucosa (KM) and STCA contraction rate.
Conclusions: The peri‐implant mucosa undergoes considerable volumetric changes after combined surgical therapy. However, tissue contraction appears to be influenced by the width of KM.
In resource-limited or point-of-care settings, rapid diagnostic tests (RDTs), that aim to simultaneously detect HIV antibodies and p24 capsid (p24CA) antigen with high sensitivity, can pose important alternatives to screen for early infections. We evaluated the performance of the antibody and antigen components of the old and novel version of the Determine™ HIV-1/2 Ag/Ab Combo RDTs in parallel to quantifications in a fourth-generation antigen/antibody immunoassay (4G-EIA), p24CA antigen immunoassay (p24CA-EIA), immunoblots, and nucleic acid quantification. We included plasma samples of acute, treatment-naïve HIV-1 infections (Fiebig stages I–VI, subtypes A1, B, C, F, CRF02_AG, CRF02_AE, URF) or chronic HIV-1 and HIV-2 infections. The tests’ antigen component was evaluated also for a panel of subtype B HIV-1 transmitted/founder (T/F) viruses, HIV-2 strains and HIV-2 primary isolates. Furthermore, we assessed the analytical sensitivity of the RDTs to detect p24CA using a highly purified HIV-1NL4-3 p24CA standard. We found that 77% of plasma samples from acutely infected, immunoblot-negative HIV-1 patients in Fiebig stages II–III were identified by the new RDT, while only 25% scored positive in the old RDT. Both RDTs reacted to all samples from chronically HIV-1-infected and acutely HIV-1-infected patients with positive immunoblots. All specimens from chronically infected HIV-2 patients scored positive in the new RDT. Of note, the sensitivity of the RDTs to detect recombinant p24CA from a subtype B virus ranged between 50 and 200 pg/mL, mirrored also by the detection of HIV-1 T/F viruses only at antigen concentrations tenfold higher than suggested by the manufacturer. The RTD failed to recognize any of the HIV-2 viruses tested. Our results indicate that the new version of the Determine™ HIV-1/2 Ag/Ab Combo displays an increased sensitivity to detect HIV-1 p24CA-positive, immunoblot-negative plasma samples compared to the precursor version. The sensitivity of 4G-EIA and p24CA-EIA to detect the major structural HIV antigen, and thus to diagnose acute infections prior to seroconversion, is still superior.
When a visual stimulus is repeated, average neuronal responses typically decrease, yet they might maintain or even increase their impact through increased synchronization. Previous work has found that many repetitions of a grating lead to increasing gamma-band synchronization. Here we show in awake macaque area V1 that both, repetition-related reductions in firing rate and increases in gamma are specific to the repeated stimulus. These effects showed some persistence on the timescale of minutes. Further, gamma increases were specific to the presented stimulus location. Importantly, repetition effects on gamma and on firing rates generalized to natural images. These findings suggest that gamma-band synchronization subserves the adaptive processing of repeated stimulus encounters, both for generating efficient stimulus responses and possibly for memory formation.
Mitochondria have a central role in regulating a range of cellular activities and host responses upon bacterial infection. Multiple pathogens affect mitochondria dynamics and functions to influence their intracellular survival or evade host immunity. On the other side, major host responses elicited against infections are directly dependent on mitochondrial functions, thus placing mitochondria centrally in maintaining homeostasis upon infection. In this review, we summarize how different bacteria and viruses impact morphological and functional changes in host mitochondria and how this manipulation can influence microbial pathogenesis as well as the host cell metabolism and immune responses.
In this proceeding, we review our recent work using deep convolutional neural network (CNN) to identify the nature of the QCD transition in a hybrid modeling of heavy-ion collisions. Within this hybrid model, a viscous hydrodynamic model is coupled with a hadronic cascade “after-burner”. As a binary classification setup, we employ two different types of equations of state (EoS) of the hot medium in the hydrodynamic evolution. The resulting final-state pion spectra in the transverse momentum and azimuthal angle plane are fed to the neural network as the input data in order to distinguish different EoS. To probe the effects of the fluctuations in the event-by-event spectra, we explore different scenarios for the input data and make a comparison in a systematic way. We observe a clear hierarchy in the predictive power when the network is fed with the event-by-event, cascade-coarse-grained and event-fine-averaged spectra. The carefully-trained neural network can extract high-level features from pion spectra to identify the nature of the QCD transition in a realistic simulation scenario.
Previous studies reported on the safety and applicability of mesenchymal stem/stromal cells (MSCs) to ameliorate pulmonary inflammation in acute respiratory distress syndrome (ARDS). Thus, multiple clinical trials assessing the potential of MSCs for COVID-19 treatment are underway. Yet, as SARS-inducing coronaviruses infect stem/progenitor cells, it is unclear whether MSCs could be infected by SARS-CoV-2 upon transplantation to COVID-19 patients. We found that MSCs from bone marrow, amniotic fluid, and adipose tissue carry angiotensin-converting enzyme 2 and transmembrane protease serine subtype 2 at low levels on the cell surface under steady-state and inflammatory conditions. We did not observe SARS-CoV-2 infection or replication in MSCs at steady state under inflammatory conditions, or in direct contact with SARS-CoV-2-infected Caco-2 cells. Further, indoleamine 2,3-dioxygenase 1 production in MSCs was not impaired in the presence of SARS-CoV-2. We show that MSCs are resistant to SARS-CoV-2 infection and retain their immunomodulation potential, supporting their potential applicability for COVID-19 treatment.
Knowledge of consumers' willingness to pay (WTP) is a prerequisite to profitable price-setting. To gauge consumers' WTP, practitioners often rely on a direct single question approach in which consumers are asked to explicitly state their WTP for a product. Despite its popularity among practitioners, this approach has been found to suffer from hypothetical bias. In this paper, we propose a rigorous method that improves the accuracy of the direct single question approach. Specifically, we systematically assess the hypothetical biases associated with the direct single question approach and explore ways to de-bias it. Our results show that by using the de-biasing procedures we propose, we can generate a de-biased direct single question approach that is accurate enough to be useful for managerial decision-making. We validate this approach with two studies in this paper.
The striking similarities that have been observed between high-multiplicity proton-proton (pp) collisions and heavy-ion collisions can be explored through multiplicity-differential measurements of identified hadrons in pp collisions. With these measurements, it is possible to study mechanisms such as collective flow that determine the shapes of hadron transverse momentum (pT) spectra, to search for possible modifications of the yields of short-lived hadronic resonances due to scattering effects in an extended hadron-gas phase, and to investigate different explanations provided by phenomenological models for enhancement of strangeness production with increasing multiplicity. In this paper, these topics are addressed through measurements of the K∗(892)0 and φ(1020) mesons at midrapidity in pp collisions at √s = 13 TeV as a function of the charged-particle multiplicity. The results include the pT spectra, pT-integrated yields, mean transverse momenta, and the ratios of the yields of these resonances to those of longer-lived hadrons. Comparisons with results from other collision systems and energies, as well as predictions from phenomenological models, are also discussed.
The inclusive J/ψ meson production in Pb–Pb collisions at a center-of-mass energy per nucleon–nucleon collision of sNN=5.02 TeV at midrapidity (|y|<0.9) is reported by the ALICE Collaboration. The measurements are performed in the dielectron decay channel, as a function of event centrality and J/ψ transverse momentum pT, down to pT=0. The J/ψ mean transverse momentum 〈pT〉 and rAA ratio, defined as 〈pT2〉PbPb/〈pT2〉pp, are evaluated. Both observables show a centrality dependence decreasing towards central (head-on) collisions. The J/ψ nuclear modification factor RAA exhibits a strong pT dependence with a large suppression at high pT and an increase to unity for decreasing pT. When integrating over the measured momentum range pT<10 GeV/c, the J/ψ RAA shows a weak centrality dependence. Each measurement is compared with results at lower center-of-mass energies and with ALICE measurements at forward rapidity, as well as to theory calculations. All reported features of the J/ψ production at low pT are consistent with a dominant contribution to the J/ψ yield originating from charm quark (re)combination.
This paper presents the first measurements of the charge independent (CI) and charge dependent (CD) two-particle transverse momentum correlators GCI 2 and GCD 2 in Pb–Pb collisions at √sNN = 2.76 TeV by the ALICE collaboration. The two-particle transverse momentum correlator G2 was introduced as a measure of the momentum current transfer between neighboring system cells. The correlators are measured as a function of pair separation in pseudorapidity (Δη) and azimuth (Δφ) and as a function of collision centrality. From peripheral to central collisions, the correlator GCI 2 exhibits a longitudinal broadening while undergoing a monotonic azimuthal narrowing. By contrast, GCD 2 exhibits a narrowing along both dimensions. These features are not reproduced by models such as HIJING and AMPT. However, the observed narrowing of the correlators from peripheral to central collisions is expected to result from the stronger transverse flow profiles produced in more central collisions and the longitudinal broadening is predicted to be sensitive to momentum currents and the shear viscosity per unit of entropy density η/s of the matter produced in the collisions. The observed broadening is found to be consistent with the hypothesized lower bound of η/s and is in qualitative agreement with values obtained from anisotropic flow measurements.
This Letter presents the first direct investigation of the p–0 interaction, using the femtoscopy technique in high-multiplicity pp collisions at √s = 13 TeV measured by the ALICE detector. The 0 is reconstructed via the decay channel to Λγ, and the subsequent decay of Λ to pπ−. The photon is detected via the conversion in material to e+e− pairs exploiting the capability of the ALICE detector to measure electrons at low transverse momenta. The measured p–0 correlation indicates a shallow strong interaction. The comparison of the data to several theoretical predictions obtained employing the Correlation Analysis Tool using the Schrödinger Equation (CATS) and the Lednický–Lyuboshits approach shows that the current experimental precision does not yet allow to discriminate between different models, as it is the case for the available scattering and hypernuclei data. Nevertheless, the p–0 correlation function is found to be sensitive to the strong interaction, and driven by the interplay of the different spin and isospin channels. This pioneering study demonstrates the feasibility of a femtoscopic measurement in the p–0 channel and with the expected larger data samples in LHC Run 3 and Run 4, the p–0 interaction will be constrained with high precision.
Multiplicity dependence of light (anti-)nuclei production in p–Pb collisions at √sNN =5.02 TeV
(2020)
The measurement of the deuteron and anti-deuteron production in the rapidity range −1 < y < 0 as a function of transverse momentum and event multiplicity in p–Pb collisions at √sNN = 5.02 TeV is presented. (Anti-)deuterons are identified via their specific energy loss dE/dx and via their time-offlight. Their production in p–Pb collisions is compared to pp and Pb–Pb collisions and is discussed within the context of thermal and coalescence models. The ratio of integrated yields of deuterons to protons (d/p) shows a significant increase as a function of the charged-particle multiplicity of the event starting from values similar to those observed in pp collisions at low multiplicities and approaching those observed in Pb–Pb collisions at high multiplicities. The mean transverse particle momenta are extracted from the deuteron spectra and the values are similar to those obtained for p and particles. Thus, deuteron spectra do not follow mass ordering. This behaviour is in contrast to the trend observed for non-composite particles in p–Pb collisions. In addition, the production of the rare 3He and 3He nuclei has been studied. The spectrum corresponding to all non-single diffractive p-Pb collisions is obtained in the rapidity window −1 < y < 0 and the pT-integrated yield dN/dy is extracted. It is found that the yields of protons, deuterons, and 3He, normalised by the spin degeneracy factor, follow an exponential decrease with mass number.
The ALICE collaboration at the CERN LHC reports novel measurements of jet substructure in pp collisions at √s = 7 TeV and central Pb–Pb collisions at √sNN = 2.76 TeV. Jet substructure of track-based jets is explored via iterative declustering and grooming techniques. We present the measurement of the momentum sharing of two-prong substructure exposed via grooming, the zg, and its dependence on the opening angle, in both pp and Pb–Pb collisions. We also present the measurement of the distribution of the number of branches obtained in the iterative declustering of the jet, which is interpreted as the number of its hard splittings. In Pb–Pb collisions, we observe a suppression of symmetric splittings at large opening angles and an enhancement of splittings at small opening angles relative to pp collisions, with no significant modification of the number of splittings. The results are compared to predictions from various Monte Carlo event generators to test the role of important concepts in the evolution of the jet in the medium such as colour coherence.
ϒ production in p–Pb interactions is studied at the centre-of-mass energy per nucleon–nucleon collision √sNN = 8.16 TeV with the ALICE detector at the CERN LHC. The measurement is performed reconstructing bottomonium resonances via their dimuon decay channel, in the centre-of-mass rapidity intervals 2.03 < ycms < 3.53 and −4.46 < ycms < −2.96, down to zero transverse momentum. In this work, results on the ϒ(1S) production cross section as a function of rapidity and transverse momentum are presented. The corresponding nuclear modification factor shows a suppression of the ϒ(1S) yields with respect to pp collisions, both at forward and backward rapidity. This suppression is stronger in the low transverse momentum region and shows no significant dependence on the centrality of the interactions. Furthermore, the ϒ(2S) nuclear modification factor is evaluated, suggesting a suppression similar to that of the ϒ(1S). A first measurement of the ϒ(3S) has also been performed. Finally, results are compared with previous ALICE measurements in p–Pb collisions at √sNN = 5.02 TeV and with theoretical calculations.
Measurement of groomed jet substructure observables in p+p collisions at √s = 200 GeV with STAR
(2020)
In this letter, measurements of the shared momentum fraction (zg) and the groomed jet radius (Rg), as defined in the SoftDrop algorithm, are reported in p+p collisions at √s = 200 GeV collected by the STAR experiment. These substructure observables are differentially measured for jets of varying resolution parameters from R = 0.2 − 0.6 in the transverse momentum range 15 < pT,jet < 60 GeV/c. These studies show that, in the pT,jet range accessible at √s = 200 GeV and with increasing jet resolution parameter and jet transverse momentum, the zg distribution asymptotically converges to the DGLAP splitting kernel for a quark radiating a gluon. The groomed jet radius measurements reflect a momentum-dependent narrowing of the jet structure for jets of a given resolution parameter, i.e., the larger the pT,jet, the narrower the first splitting. For the first time, these fully corrected measurements are compared to Monte Carlo generators with leading order QCD matrix elements and leading log in the parton shower, and to state-of-the-art theoretical calculations at next-to-leading-log accuracy. We observe that PYTHIA 6 with parameters tuned to reproduce RHIC measurements is able to quantitatively describe data, whereas PYTHIA 8 and HERWIG 7, tuned to reproduce LHC data, are unable to provide a simultaneous description of both zg and Rg, resulting in opportunities for fine parameter tuning of these models for p+p collisions at RHIC energies. We also find that the theoretical calculations without non-perturbative corrections are able to qualitatively describe the trend in data for jets of large resolution parameters at high pT,jet, but fail at small jet resolution parameters and low jet transverse momenta.
We report on the measurement of the size of the particle-emitting source from two-baryon correlations with ALICE in high-multiplicity pp collisions at √s = 13 TeV. The source radius is studied with low relative momentum p–p, p–p, p–, and p– pairs as a function of the pair transverse mass mT considering for the first time in a quantitative way the effect of strong resonance decays. After correcting for this effect, the radii extracted for pairs of different particle species agree. This indicates that protons, antiprotons, s, and s originate from the same source. Within the measured mT range (1.1–2.2) GeV/c2 the invariant radius of this common source varies between 1.3 and 0.85 fm. These results provide a precise reference for studies of the strong hadron–hadron interactions and for the investigation of collective properties in small colliding systems.
Multiplicity dependence of inclusive J/ψ production at midrapidity in pp collisions at √s = 13 TeV
(2020)
Measurements of the inclusive J/ψ yield as a function of charged-particle pseudorapidity density dNch/dη in pp collisions at √s = 13 TeV with ALICE at the LHC are reported. The J/ψ meson yield is measured at midrapidity (|y| < 0.9) in the dielectron channel, for events selected based on the charged-particle multiplicity at midrapidity (|η| < 1) and at forward rapidity (−3.7 < η < −1.7 and 2.8 < η < 5.1); both observables are normalized to their corresponding averages in minimum bias events. The increase of the normalized J/ψ yield with normalized dNch/dη is significantly stronger than linear and dependent on the transverse momentum. The data are compared to theoretical predictions, which describe the observed trends well, albeit not always quantitatively.
Investigation of the linear and mode-coupled flow harmonics in Au+Au collisions at √sNN = 200 GeV
(2020)
Flow harmonics (vn) of the Fourier expansion for the azimuthal distributions of hadrons are commonly employed to quantify the azimuthal anisotropy of particle production relative to the collision symmetry planes. While lower order Fourier coefficients (v2 and v3) are more directly related to the corresponding eccentricities of the initial state, the higher-order flow harmonics (vn>3) can be induced by a modecoupled response to the lower-order anisotropies, in addition to a linear response to the same-order anisotropies. These higher-order flow harmonics and their linear and mode-coupled contributions can be used to more precisely constrain the initial conditions and the transport properties of the medium in theoretical models. The multiparticle azimuthal cumulant method is used to measure the linear and mode-coupled contributions in the higher-order anisotropic flow, the mode-coupled response coefficients, and the correlations of the event plane angles for charged particles as functions of centrality and transverse momentum in Au+Au collisions at nucleon-nucleon center-of-mass energy √sN N= 200 GeV. The results are compared to similar LHC measurements as well as to several viscous hydrodynamic calculations with varying initial conditions.
Monoterpenes and their monoterpenoid derivatives form a subclass of terpene(oid)s. They are widely used in medicines/pharmaceuticals, as flavor and fragrance compounds, or in agriculture and are also considered as future biofuels. However, for many of these substances, the extraction from natural sources poses challenges such as occurring at low concentrations in their raw material or because the natural sources are diminishing. Furthermore, many of the structurally more complex terpenoids cannot be chemically synthesized in an economic way. Therefore, microbial production provides an attractive alternative, taking advantage of the often distinct regio- and stereoselectivity of enzymatic reactions. However, monoterpenes and monoterpenoids are challenging products for industrial biotechnology processes due to their pronounced cytotoxicity, which complicates the production in microorganisms compared to longer-chain terpenes (sesquiterpenes, diterpenes, etc.).
The aim of this thesis was to generate a biotechnological complement to fossil-resources-based chemical processes for industrial monoterpenoid production. Therefore, a starting point for the further development of a microbial cell factory based on the microbe Pseudomonas putida KT2440 was aimed to be created. This production organism should be able to conduct a whole- cell biocatalysis to selectively oxyfunctionalize monoterpene hydrocarbons using renewable industrial by-products and waste streams as raw material for monoterpenoid production (Figure 1). As a model substance, the production of (-)-menthol should be addressed due to its industrial significance. (-)-Menthol is one of the world’s most widely-used flavor and fragrance compounds by volume as well as a medical component, having an annual production volume of over 30,000 tons. An approach for (-)-menthol production from renewable resources could be a biotechnological(-chemical) two-step conversion (Figure 1), starting from (+)-limonene, a by-product of the citrus fruit processing industry.
The thesis project was divided into three parts. In the first part, enzymes (limonene-3- hydroxylases) were to be identified that can convert (+)-limonene into the precursor of (-)-menthol, (+)-trans-isopiperitenol. To counteract product toxicity, in the second part, the tolerance of the intended production organism P. putida KT2440 towards monoterpenes and their monoterpenoid derivatives should be increased. Finally, in the third part, the identified hydroxylase enzymes would be expressed in the improved P. putida KT2440 strain to create a whole-cell biocatalyst for the first reaction step of a two-step (-)-menthol production, starting from (+)-limonene.
To achieve these objectives, different genetic/molecular biology and analytical methods were applied. In this way, two cytochrome P450 monooxygenase enzymes from the fungi Aureobasidium pullulans and Hormonema carpetanum could be identified and functionally expressed in Pichia pastoris, which can catalyze the intended hydroxylation reaction on (+) limonene with high stereo- and regioselectivity. A further characterization of the enzyme from A. pullulans showed that apart from (+) limonene the protein can also hydroxylate ( ) limonene, - and -pinene, as well as 3-carene.
Furthermore, within this thesis, mechanisms of microbial monoterpenoid resistance of P. putida could be identified. It was shown that the different monoterpenes and monoterpenoids tested have very different toxicity levels and that mainly the Ttg efflux pumps of P. putida GS1 are responsible for the tolerance to many of these compounds. Based on these results, a P. putida KT2440 strain with increased resistance to various monoterpenoids, including isopiperitenol, could then be generated, which can be used as a host organism for the further development of monoterpenoid-producing cell factories.
While within the scope of this work the heterologous expression of the fungal gene in prokaryotic cells in a functional form could not be realized despite different approaches, the identified enzymes, the monoterpenoid-tolerant P. putida strain and a plasmid developed for heterologous gene expression in P. putida provide a starting point for the further design of a microbial cell factory for biotechnological monoterpenoid production.
The miRNA biogenesis is tightly regulated to avoid dysfunction and consequent disease development. Here, we describe modulation of miRNA processing as a novel noncanonical function of the 5-lipoxygenase (5-LO) enzyme in monocytic cells. In differentiated Mono Mac 6 (MM6) cells, we found an in situ interaction of 5-LO with Dicer, a key enzyme in miRNA biogenesis. RNA sequencing of small noncoding RNAs revealed a functional impact, knockout of 5-LO altered the expression profile of several miRNAs. Effects of 5-LO could be observed at two levels. qPCR analyses thus indicated that (a) 5-LO promotes the transcription of the evolutionarily conserved miR-99b/let-7e/miR-125a cluster and (b) the 5-LO-Dicer interaction downregulates the processing of pre-let-7e, resulting in an increase in miR-125a and miR-99b levels by 5-LO without concomitant changes in let-7e levels in differentiated MM6 cells. Our observations suggest that 5-LO regulates the miRNA profile by modulating the Dicer-mediated processing of distinct pre-miRNAs. 5-LO inhibits the formation of let-7e which is a well-known inducer of cell differentiation, but promotes the generation of miR-99b and miR-125a known to induce cell proliferation and the maintenance of leukemic stem cell functions.
"Wie kann ich die Čechen differenzieren? In städtische u. ländliche (Machar u. Brezina)?" fragte Hugo von Hofmannsthal unsicher Hermann Bahr, als er den Editionsplan für die "Österreichische Bibliothek" konzipierte. Die Frage mag, was die tschechische Literatur betrifft, etwas naiv erscheinen, sie zeigt jedoch, dass Hofmannsthal zumindest von zwei markanten Vertretern der frühen tschechischen literarischen Moderne eine gewisse Kenntnis besaß. Der Dichter und Feuilletonist Josef Svatopluk Machar (1864–1942) lebte seit 1889 in Wien. Bahr hatte ihn im Juli 1892 kennengelernt und bei der Gründung der Wochenschrift "Die Zeit" mit ihm zusammengearbeitet, und auch nach Bahrs Rückzug von dieser Zeitschrift 1899 fungierte Machar als wichtiges Verbindungsglied zu tschechischen Schriftstellern und Politikern einschließlich T. G. Masaryks. In der deutsch-österreichischen Presse zu Beginn des 20. Jahrhunderts auf Machars Namen zu stoßen, war nicht schwer. Öfters wurden seine Konflikte mit der katholischen Kirche erwähnt, die er mit seinen Feuilletons, Gedichten und Vorträgen provozierte. Zudem war er zum meistübersetzten tschechischen Dichter avanciert. Grund hierfür waren nicht nur die Qualität seines Werkes und seine wachsende Popularität bei tschechischen Lesern - derlei tschechische Schriftsteller ließen sich mehrere finden. Der Hauptgrund bestand vielmehr darin, dass er in Wien lebte und etliche seiner dortigen Freunde ihn übersetzt hatten. Einer von ihnen war Emil Saudek, der Hofmannsthal auf den zweiten der oben genannten tschechischen Dichter, den Symbolisten Otokar Březina, aufmerksam machte. Dieser bislang wenig bekannte Umstand soll im Folgenden beleuchtet werden.
Der hier edierte und übersetzte Text ist Teil einer Sammelrezension ("Poésie"), in der Teodor de Wyzewa 1887 im Februar-Heft der "Revue indépendante" neue Lyrikbände bespricht.
Sie sind ihm Anlass eines grundsätzlichen Nachdenkens über Symbolismus, insofern dieser als eine neue Schreibweise der Lyrik im Gespräch ist und, so Wyzewa, es der Klärung des Symbolbegriffs bedarf, auf den der 1887 bereits geläufige Name der neuen Bewegung verweist.
Im Blickpunkt der Arbeit steht die Historiografie der Unternehmungen Friedrich I. Barbarossas 1154-1158 in der Lombardei. Während der hochgebildete Bischof Otto von Freising ein reges Forschungsinteresse darstellt, sind seine beiden Zeitgenossen, die eigenständige Berichte über die Ereignisse verfassten, in der Forschung weitestgehend unberücksichtigt geblieben. Durch einen Vergleich der 'Gesta' Bischofs Otto von Freising, des 'Libellus' des Lodesen Otto Morena und der 'Narratio' eines anonymen Schreibers aus Mailand zeigt diese Arbeit die Absichten der Autoren auf und fragt, inwieweit die sich widersprechenden Schilderungen als "alternativen Fakten" aufgefasst werden können.
Nach einem Abriss über den Begriff der "alternativen Fakten", dem im Zuge der Präsidentschaft von Donald Trump Aufmerksamkeit zuteilwurde und der hier als unbewusst oder bewusst erfolgte Verformung verstanden wird, der neuzeitlichen Rezeption Barbarossas sowie einer zeitlichen und räumlichen Einordnung werden die "Ausgangslagen" der Autoren betrachtet. Die Entstehung der 'Gesta' und ihr Verhältnis zu Ottos erstem Werk sind umstritten. Es zeigt sich, dass die Positionen Ottos von Freising und Otto Morenas kaiserfreundliche, diejenige des Mailänders Autors eine kaiserfeindliche Absicht erwarten lassen.
Eine kleinteilige Betrachtung der Vorworte/Prologe der Werke offenbart die selbst geäußerten Absichten. Die Anlehnung der 'Gesta' Ottos von Freising an einen durch oder im Auftrag Barbarossas verfassten Tatenbericht sowie seine Lobpreisungen des Kaisers stellen eine Färbung der Darstellung in Aussicht. Auch bei Otto Morena zeigt sich eine starke Verbundenheit zum Kaiser, die Zweifel an der Neutralität seines Werkes aufkommen lassen muss. Der anonyme Autor aus Mailand bekennt ausdrücklich, zum Nutzen der Nachwelt zu schreiben und reiht die Zerstörung Mailands 1162 als Endpunkt einer weitzurückreichenden Opfernarrative ein. Auch wenn ausdrückliche Ausfälle gegen den Kaiser unterbleiben, sind starke Zweifel an einer neutralen Darstellung angezeigt.
Die Beschäftigung mit den Ereignissen des Jahres 1154 zeigt "alternative" Darstellungen: Die Darstellung Ottos von Freising hält sich an die kaiserliche Vorlage und ist im Sinne des Kaisers gehalten, was sich auch bei Otto Morena zeigt, der darüber hinaus die Rolle Lodis betont. Die Mailänder "Gegendarstellung" hingegen lastet negative Ereignisse ausschließlich Barbarossa an.
Otto von Freising betont die lange geplante Kaiserkrönung in Rom und den Feldzug gegen die Normannen als Ausgangspunkt des ersten Italienzuges. Otto Morena legt den Beginn des Disputs zwischen Barbarossa und den Mailändern auf die Versammlung des Hofes in Konstanz, wo Klagen zweier Lodesen Anlass zu Friedrichs erstem Italienzug gegeben hätten. Der Anonymus aus Mailand wirft Barbarossa vor, mit dem Ziel der militärischen Unterwerfung aufgebrochen zu sein.
Otto von Freising übernahm die Darstellung Barbarossas von einem Bestechungsversuch der Mailänder, deren Konsuln anschließend seinen Zug durch verödete Landschaften geführt hätten, was auch Otto Morena zu berichten weiß. Der Mailänder Schreiber verschweigt dies und erzählt stattdessen von Misshandlungen der Mailänder durch das königliche Gefolge. Die Erstürmung der Burg Rosate stilisiert er als unbegründeten Gewaltakt, während die Schreiber aus Lodi und Freising rechtfertigend argumentieren.
Die unabhängig überlieferte 'Conventio', die 1158 nach der Belagerung Mailands zwischen der Stadt und dem Kaiser geschlossen wurde, beinhaltete neben Strafbestimmungen die Anerkennung der Hoheit des Kaisers unter Wahrung der kommunalen Herrschaftsform. Während Otto Morena ihre Bestimmungen nur höchst unvollständig wiedergab, sodass der Schluss naheliegt, dass er sie nicht kannte, lieferte der Mailänder Anonymus durch gezielte Auslassungen und Verfälschung ihrer Bestimmungen erneut "alternative Fakten" und erweckte den Anschein einer Rückkehr zu den "kaiserfernen" Jahren vor Barbarossa.
Bei genauer Betrachtung der auf dem Hoftag von Roncaglia 1158 festgestellten 'lex omnis iurisdictio' wird deutlich, dass diese entgegen der bisherigen Forschungsmeinung keinen Bruch der 'Conventio' darstellte. Eine Konfrontation der Darstellungen der Ereignisse im Januar 1159 in Mailand mit dem Augenzeugenberichts Vinzenz' von Prag zeigt, dass Otto Morena erneut nur knapp berichtet. Der Anonymus hingegen liefert eine "alternative" Darstellung, nach der die Gesandten des Kaisers gekommen waren, um das Recht zu brechen. Diese Tendenziösität wird auch bei der Einnahme der Burg Trezzo deutlich, über die ein Bericht von Ottos einstigem Kaplan Rahewin vorliegt.
Die Darstellungen offenbaren, dass ihre Autoren ihre Texte gezielt einzusetzen gedachten und so zu Produzenten "alternativen Fakten" wurden. Für den Historiker zeigt sich einmal mehr die Wichtigkeit einer quellenkritischen Arbeitsweise, wie sie Johannes Fried in seiner "Memorik" eindrucksvoll vertrat.
Radar technology in the millimeter-wave frequency band offers many interesting features for wind park surveillance, such as structural monitoring of rotor blades or the detection of bats and birds in the vicinity of wind turbines (WTs). Currently, the majority of WTs are affected by shutdown algorithms to minimize animal fatalities via direct collision with the rotor blades or barotrauma effects. The presence of rain is an important parameter in the definition of those algorithms together with wind speed, temperature, time of the day, and season of the year. A Ka-band frequency-modulated continuous-wave radar (33.4-36.0 GHz) installed at the tower of a 2-MW WT was used during a field study. We have observed characteristic rain-induced patterns, based on the range-Doppler algorithm. To better understand those signatures, we have developed a laboratory experiment and implemented a numerical modeling framework. Experimental and numerical results for rain detection and classification are presented and discussed here. Based on this article, a bat- and bird-friendly adaptive WT control can be developed for improved WT efficiency in periods of rain and, at the same time, reduced animal mortality.
Unresolved inflammation maintained by release of danger‐associated molecular patterns, particularly high‐mobility group box‐1 (HMGB1), is crucial for hepatocellular carcinoma (HCC) pathogenesis. To further characterize interactions between leucocytes and necrotic cancerous tissue, a cellular model of necroinflammation was studied in which murine Raw 264.7 macrophages or primary splenocytes were exposed to necrotic lysates (N‐lys) of murine hepatoma cells or primary hepatocytes. In comparison to those derived from primary hepatocytes, N‐lys from hepatoma cells were highly active—inducing in macrophages efficient expression of inflammatory cytokines like C‐X‐C motif ligand‐2 , tumor necrosis factor‐α, interleukin (IL)‐6 and IL‐23‐p19. This activity associated with higher levels of HMGB1 in hepatoma cells and was curbed by pharmacological blockage of the receptor for advanced glycation end product (RAGE)/HMGB1 axis or the mitogen‐activated protein kinases ERK1/2 pathway. Analysis of murine splenocytes furthermore demonstrated that N‐lys did not comprise of functionally relevant amounts of TLR4 agonists. Finally, N‐lys derived from hepatoma cells supported inflammatory splenic Th17 and Th1 polarization as detected by IL‐17, IL‐22 or interferon‐γ production. Altogether, a straightforward applicable model was established which allows for biochemical characterization of immunoregulation by HCC necrosis in cell culture. Data presented indicate a remarkably inflammatory capacity of necrotic hepatoma cells that, at least partly, depends on the RAGE/HMGB1 axis and may shape immunological properties of the HCC microenvironment.
Cryo-electron tomography combined with subtomogram averaging (StA) has yielded high-resolution structures of macromolecules in their native context. However, high-resolution StA is not commonplace due to beam-induced sample drift, images with poor signal-to-noise ratios (SNR), challenges in CTF correction, and limited particle number. Here we address these issues by collecting tilt series with a higher electron dose at the zero-degree tilt. Particles of interest are then located within reconstructed tomograms, processed by conventional StA, and then re-extracted from the high-dose images in 2D. Single particle analysis tools are then applied to refine the 2D particle alignment and generate a reconstruction. Use of our hybrid StA (hStA) workflow improved the resolution for tobacco mosaic virus from 7.2 to 4.4 Å and for the ion channel RyR1 in crowded native membranes from 12.9 to 9.1 Å. These resolution gains make hStA a promising approach for other StA projects aimed at achieving subnanometer resolution.
The blood-brain barrier (BBB) protects the brain microenvironment from external damage. It is formed by endothelial cells (ECs) lining the brain vessels, expressing tight junctions and having reduced transcytosis, resulting in a very low paracellular and transcellular passage of substances, respectively (low permeability). The specific BBB phenotype is maintained by Wnt molecules secreted by astrocytes (ACs) that bind to receptors in ECs, and start a molecular cascade that leads to β-catenin translocating to the nucleus and activating the transcription of BBB genes.
An increasing number of studies report BBB dysfunction in Alzheimer’s disease (AD), although the topic is currently under debate. AD is a neurodegenerative condition characterized by brain depositions of Aβ aggregates and Tau neurofibrillary tangles. The aetiology of AD is unknown, although round 5% of all AD cases have a genetic origin. Mutations in APP or PSEN1/2 can lead to Aβ over-production and accumulation, causing familiar AD. There is no cure for AD, as all clinical trials failed during the past years. Consequently, I studied the role of the BBB in AD, aiming to investigate if a BBB dysfunction occurs in AD, and to identify by transcriptomic analysis novel gene regulations happening at the BBB in AD. The final objective was to evaluate the potential of identified BBB genes as therapeutical target.
I used transgenic mice expressing the human APP mutations Swiss, Dutch and Iowa under the control of the neuronal promoter Thy1 (Thy1-APPSwDI) as AD model. In this AD mouse model, I could detect Aβ deposits and memory loss by immunofluorescence (IF) and behavioural tests. Importantly, I identified an increase of BBB permeability to 3-4 kDa dextrans in 6 months, 9-12 months, and 18 months or older AD mice compared to age-matched control wild types (WT), indicating BBB dysfunction in AD mice.
In order to study the BBB transcriptional changes in AD, I sequenced the RNA from 6 and 18 months old AD and WT mouse brain microvessels (MBMVs), as well as of FACS-sorted ECs, mural cells (MuCs), ACs, and microglia (MG) in collaboration with GenXPro, a company specialized in 3’ RNA sequencing. Currently, no transcriptomic datasets of ECs and MuCs are publicly available, suggesting that this is the first study sequencing those cell types in the context of AD.
The analysis of sequencing data from MBMVs and ECs revealed a Wnt/β-catenin repression, and an increase of inflammatory genes like Ccl3 in ECs, that could explain the BBB dysfunction observed in AD mice. Furthermore, the sequencing data from MuCs identified a set of 11 genes strongly regulated in both 6 and 18 month AD groups. Three of those 11 genes are known to be involved in inflammatory processes, demonstrating that inflammation affects and plays an important role in MuCs and ECs during AD.
Thanks to published sequencing data, some up-regulated MG genes in AD are well known and recognized, such as Trem2 and Apoe. Those genes were found in the FACS-sorted MG data as well, validating the AD model and with it, the other novel sequenced datasets. Importantly, one of the most strongly AD-regulated genes in MBMV and MG samples was Dkk2, a member of the Dickkopf family of secreted proteins known to be involved in Wnt signalling modulation. Importantly, a dual luciferase reporter assay proved that Dkk2 is a Wnt inhibitor. A preliminary immunohistochemistry examination of DKK2 in human brain autopsy tissue from an AD patient and age-matched control revealed a stronger DKK2 immunoreactivity in the AD brain.
In order to answer the question whether a rescue of BBB function would ameliorate AD symptoms, I made use of a tamoxifen-inducible transgenic mouse line to activate the Wnt/β-catenin pathway specifically in ECs, leading to a gain of function (GOF) condition (Cdh5-CreERT2+/–/Ctnnb1(Ex3)fl/fl). This mouse line was then crossed with the AD line, creating AD/GOF and AD/control groups.
AD/GOF mice performed better in a Y-Maze memory test than AD/controls when the Wnt/β-catenin pathway was induced before AD onset, indicating a protective effect. Moreover, the finding implies that shielding BBB functioning in AD further protects the brain from AD toxic effects, suggesting an important role of brain vasculature in AD and its potential as therapeutic target.
Recurrent cortical network dynamics plays a crucial role for sequential information processing in the brain. While the theoretical framework of reservoir computing provides a conceptual basis for the understanding of recurrent neural computation, it often requires manual adjustments of global network parameters, in particular of the spectral radius of the recurrent synaptic weight matrix. Being a mathematical and relatively complex quantity, the spectral radius is not readily accessible to biological neural networks, which generally adhere to the principle that information about the network state should either be encoded in local intrinsic dynamical quantities (e.g. membrane potentials), or transmitted via synaptic connectivity. We present two synaptic scaling rules for echo state networks that solely rely on locally accessible variables. Both rules work online, in the presence of a continuous stream of input signals. The first rule, termed flow control, is based on a local comparison between the mean squared recurrent membrane potential and the mean squared activity of the neuron itself. It is derived from a global scaling condition on the dynamic flow of neural activities and requires the separability of external and recurrent input currents. We gained further insight into the adaptation dynamics of flow control by using a mean field approximation on the variances of neural activities that allowed us to describe the interplay between network activity and adaptation as a two-dimensional dynamical system. The second rule that we considered, variance control, directly regulates the variance of neural activities by locally scaling the recurrent synaptic weights. The target set point of this homeostatic mechanism is dynamically determined as a function of the variance of the locally measured external input. This functional relation was derived from the same mean-field approach that was used to describe the approximate dynamics of flow control.
The effectiveness of the presented mechanisms was tested numerically using different external input protocols. The network performance after adaptation was evaluated by training the network to perform a time delayed XOR operation on binary sequences. As our main result, we found that flow control can reliably regulate the spectral radius under different input statistics, but precise tuning is negatively affected by interneural correlations. Furthermore, flow control showed a consistent task performance over a wide range of input strengths/variances. Variance control, on the other side, did not yield the desired spectral radii with the same precision. Moreover, task performance was less consistent across different input strengths.
Given the better performance and simpler mathematical form of flow control, we concluded that a local control of the spectral radius via an implicit adaptation scheme is a realistic alternative to approaches using classical “set point” homeostatic feedback controls of neural firing.
Author summary How can a neural network control its recurrent synaptic strengths such that network dynamics are optimal for sequential information processing? An important quantity in this respect, the spectral radius of the recurrent synaptic weight matrix, is a non-local quantity. Therefore, a direct calculation of the spectral radius is not feasible for biological networks. However, we show that there exist a local and biologically plausible adaptation mechanism, flow control, which allows to control the recurrent weight spectral radius while the network is operating under the influence of external inputs. Flow control is based on a theorem of random matrix theory, which is applicable if inter-synaptic correlations are weak. We apply the new adaption rule to echo-state networks having the task to perform a time-delayed XOR operation on random binary input sequences. We find that flow-controlled networks can adapt to a wide range of input strengths while retaining essentially constant task performance.
Recurrent cortical network dynamics plays a crucial role for sequential information processing in the brain. While the theoretical framework of reservoir computing provides a conceptual basis for the understanding of recurrent neural computation, it often requires manual adjustments of global network parameters, in particular of the spectral radius of the recurrent synaptic weight matrix. Being a mathematical and relatively complex quantity, the spectral radius is not readily accessible to biological neural networks, which generally adhere to the principle that information about the network state should either be encoded in local intrinsic dynamical quantities (e.g. membrane potentials), or transmitted via synaptic connectivity. We present two synaptic scaling rules for echo state networks that solely rely on locally accessible variables. Both rules work online, in the presence of a continuous stream of input signals. The first rule, termed flow control, is based on a local comparison between the mean squared recurrent membrane potential and the mean squared activity of the neuron itself. It is derived from a global scaling condition on the dynamic flow of neural activities and requires the separability of external and recurrent input currents. We gained further insight into the adaptation dynamics of flow control by using a mean field approximation on the variances of neural activities that allowed us to describe the interplay between network activity and adaptation as a two-dimensional dynamical system. The second rule that we considered, variance control, directly regulates the variance of neural activities by locally scaling the recurrent synaptic weights. The target set point of this homeostatic mechanism is dynamically determined as a function of the variance of the locally measured external input. This functional relation was derived from the same mean-field approach that was used to describe the approximate dynamics of flow control.
The effectiveness of the presented mechanisms was tested numerically using different external input protocols. The network performance after adaptation was evaluated by training the network to perform a time delayed XOR operation on binary sequences. As our main result, we found that flow control can reliably regulate the spectral radius under different input statistics, but precise tuning is negatively affected by interneural correlations. Furthermore, flow control showed a consistent task performance over a wide range of input strengths/variances. Variance control, on the other side, did not yield the desired spectral radii with the same precision. Moreover, task performance was less consistent across different input strengths.
Given the better performance and simpler mathematical form of flow control, we concluded that a local control of the spectral radius via an implicit adaptation scheme is a realistic alternative to approaches using classical “set point” homeostatic feedback controls of neural firing.
Author summary How can a neural network control its recurrent synaptic strengths such that network dynamics are optimal for sequential information processing? An important quantity in this respect, the spectral radius of the recurrent synaptic weight matrix, is a non-local quantity. Therefore, a direct calculation of the spectral radius is not feasible for biological networks. However, we show that there exist a local and biologically plausible adaptation mechanism, flow control, which allows to control the recurrent weight spectral radius while the network is operating under the influence of external inputs. Flow control is based on a theorem of random matrix theory, which is applicable if inter-synaptic correlations are weak. We apply the new adaption rule to echo-state networks having the task to perform a time-delayed XOR operation on random binary input sequences. We find that flow-controlled networks can adapt to a wide range of input strengths while retaining essentially constant task performance.
We explore the phase structure of the 1+1 dimensional Gross-Neveu model at finite number of fermion flavors using lattice field theory. Besides a chirally symmetric phase and a homogeneously broken phase we find evidence for the existence of an inhomogeneous phase, where the condensate is a spatially oscillating function. Our numerical results include a crude μ-T phase diagram.
Standard monitoring of heart rate, blood pressure and arterial oxygen saturation during endoscopy is recommended by current guidelines on procedural sedation. A number of studies indicated a reduction of hypoxic (art. oxygenation < 90% for > 15 s) and severe hypoxic events (art. oxygenation < 85%) by additional use of capnography. Therefore, U.S. and the European guidelines comment that additional capnography monitoring can be considered in long or deep sedation. Integrated Pulmonary Index® (IPI) is an algorithm-based monitoring parameter that combines oxygenation measured by pulse oximetry (art. oxygenation, heart rate) and ventilation measured by capnography (respiratory rate, apnea > 10 s, partial pressure of end-tidal carbon dioxide [PetCO2]). The aim of this paper was to analyze the value of IPI as parameter to monitor the respiratory status in patients receiving propofol sedation during PEG-procedure. Patients reporting for PEG-placement under sedation were randomized 1:1 in either standard monitoring group (SM) or capnography monitoring group including IPI (IM). Heart rate, blood pressure and arterial oxygen saturation were monitored in SM. In IM additional monitoring was performed measuring PetCO2, respiratory rate and IPI. Capnography and IPI values were recorded for all patients but were only visible to the endoscopic team for the IM-group. IPI values range between 1 and 10 (10 = normal; 8–9 = within normal range; 7 = close to normal range, requires attention; 5–6 = requires attention and may require intervention; 3–4 = requires intervention; 1–2 requires immediate intervention). Results on capnography versus standard monitoring of the same study population was published previously. A total of 147 patients (74 in SM and 73 in IM) were included in the present study. Hypoxic events occurred in 62 patients (42%) and severe hypoxic events in 44 patients (29%), respectively. Baseline characteristics were equally distributed in both groups. IPI = 1, IPI < 7 as well as the parameters PetCO2 = 0 mmHg and apnea > 10 s had a high sensitivity for hypoxic and severe hypoxic events, respectively (IPI = 1: 81%/81% [hypoxic/severe hypoxic event], IPI < 7: 82%/88%, PetCO2: 69%/68%, apnea > 10 s: 84%/84%). All four parameters had a low specificity for both hypoxic and severe hypoxic events (IPI = 1: 13%/12%, IPI < 7: 7%/7%, PetCO2: 29%/27%, apnea > 10 s: 7%/7%). In multivariate analysis, only SM and PetCO2 = 0 mmHg were independent risk factors for hypoxia. IPI (IPI = 1 and IPI < 7) as well as the individual parameters PetCO2 = 0 mmHg and apnea > 10 s allow a fast and convenient conclusion on patients’ respiratory status in a morbid patient population. Sensitivity is good for most parameters, but specificity is poor. In conclusion, IPI can be a useful metric to assess respiratory status during propofol-sedation in PEG-placement. However, IPI was not superior to PetCO2 and apnea > 10 s.
Aims: Stroke is a major complication after transcatheter aortic valve implantation (TAVI). Although multifactorial, it remains unknown whether the valve deployment system itself has an impact on the incidence of early stroke. We performed a meta- and network analysis to investigate the 30-day stroke incidence of self-expandable (SEV) and balloon-expandable (BEV) valves after transfemoral TAVI.
Methods and results: Overall, 2723 articles were searched directly comparing the performance of SEV and BEV after transfemoral TAVI, from which 9 were included (3086 patients). Random effects models were used for meta- and network meta-analysis based on a frequentist framework. Thirty-day incidence of stroke was 1.8% in SEV and 3.1% in BEV (risk ratio of 0.62, 95% confidence interval (CI) 0.49–0.80, p = 0.004). Treatment ranking based on network analysis (P-score) revealed CoreValve with the best performance for 30-day stroke incidence (75.2%), whereas SAPIEN had the worst (19.0%). However, network analysis showed no inferiority of SAPIEN compared with CoreValve (odds ratio 2.24, 95% CI 0.70–7.2).
Conclusion: Our analysis indicates higher 30-day stroke incidence after transfemoral TAVI with BEV compared to SEV. We could not find evidence for superiority of a specific valve system. More randomized controlled trials with head-to-head comparison of SEV and BEV are needed to address this open question.
Congenital diaphragmatic hernia (CDH) is a relatively common and life-threatening birth defect, characterized by incomplete formation of the diaphragm. Because CDH herniation occurs at the same time as preacinar airway branching, normal lung development becomes severely disrupted, resulting almost invariably in pulmonary hypoplasia. Despite various research efforts over the past decades, the pathogenesis of CDH and associated lung hypoplasia remains poorly understood. With the advent of molecular techniques, transgenic animal models of CDH have generated a large number of candidate genes, thus providing a novel basis for future research and treatment. This review article offers a comprehensive overview of genes and signaling pathways implicated in CDH etiology, whilst also discussing strengths and limitations of transgenic animal models in relation to the human condition.
The Rnf complex is a Na+ coupled respiratory enzyme in a fermenting bacterium, Thermotoga maritima
(2020)
rnf genes are widespread in bacteria and biochemical and genetic data are in line with the hypothesis that they encode a membrane-bound enzyme that oxidizes reduced ferredoxin and reduces NAD and vice versa, coupled to ion transport across the cytoplasmic membrane. The Rnf complex is of critical importance in many bacteria for energy conservation but also for reverse electron transport to drive ferredoxin reduction. However, the enzyme has never been purified and thus, ion transport could not be demonstrated yet. Here, we have purified the Rnf complex from the anaerobic, fermenting thermophilic bacterium Thermotoga maritima and show that is a primary Na+ pump. These studies provide the proof that the Rnf complex is indeed an ion (Na+) translocating, respiratory enzyme. Together with a Na+-F1FO ATP synthase it builds a simple, two-limb respiratory chain in T. maritima. The physiological role of electron transport phosphorylation in a fermenting bacterium is discussed.
For large isospin asymmetries, perturbation theory predicts the quantum chromodynamic (QCD) ground state to be a superfluid phase of u and d¯ Cooper pairs. This phase, which is denoted as the Bardeen-Cooper-Schrieffer (BCS) phase, is expected to be smoothly connected to the standard phase with Bose-Einstein condensation (BEC) of charged pions at μI≥mπ/2 by an analytic crossover. A first hint for the existence of the BCS phase, which is likely characterised by the presence of both deconfinement and charged pion condensation, comes from the lattice observation that the deconfinement crossover smoothly penetrates into the BEC phase. To further scrutinize the existence of the BCS phase, in this article we investigate the complex spectrum of the massive Dirac operator in 2+1-flavor QCD at nonzero temperature and isospin chemical potential. The spectral density near the origin is related to the BCS gap via a generalization of the Banks-Casher relation to the case of complex Dirac eigenvalues (derived for the zero-temperature, high-density limits of QCD at nonzero isospin chemical potential).
Accurate measurement of the standard 235U(n,f) cross section from thermal to 170 keV neutron energy
(2020)
An accurate measurement of the 235U(n,f) cross section from thermal to 170 keV of neutron energy has recently been performed at n_TOF facility at CERN using 6Li(n,t)4He and 10B(n,α)7Li as references. This measurement has been carried out in order to investigate a possible overestimation of the 235U fission cross section evaluation provided by most recent libraries between 10 and 30 keV. A custom experimental apparatus based on in-beam silicon detectors has been used, and a Monte Carlo simulation in GEANT4 has been employed to characterize the setup and calculate detectors efficiency. The results evidenced the presence of an overestimation in the interval between 9 and 18 keV and the new data may be used to decrease the uncertainty of 235U(n,f) cross section in the keV region.
Two-particle correlation functions were measured for pp, p, p, and pairs in Pb–Pb collisions at √sNN = 2.76 TeV and √sNN = 5.02 TeV recorded by the ALICE detector. From a simultaneous fit to all obtained correlation functions, real and imaginary components of the scattering lengths, as well as the effective ranges, were extracted for combined p and p pairs and, for the first time, for pairs. Effective averaged scattering parameters for heavier baryon–antibaryon pairs, not measured directly, are also provided. The results reveal similarly strong interaction between measured baryon–antibaryon pairs, suggesting that they all annihilate in the same manner at the same pair relative momentum k∗. Moreover, the reported significant non-zero imaginary part and negative real part of the scattering length provide motivation for future baryon–antibaryon bound state searches.
Measurements of K∗(892)0 and φ(1020) resonance production in Pb–Pb and pp collisions at √sNN = 5.02 TeV with the ALICE detector at the Large Hadron Collider are reported. The resonances are measured at midrapidity (|y| < 0.5) via their hadronic decay channels and the transverse momentum (pT) distributions are obtained for various collision centrality classes up to pT = 20 GeV/c. The pT-integrated yield ratio K∗(892)0/K in Pb–Pb collisions shows significant suppression relative to pp collisions and decreases towards more central collisions. In contrast, the φ(1020)/K ratio does not show any suppression. Furthermore, the measured K∗(892)0/K ratio in central Pb–Pb collisions is significantly suppressed with respect to the expectations based on a thermal model calculation, while the φ(1020)/K ratio agrees with the model prediction. These measurements are an experimental demonstration of rescattering of K∗(892)0 decay products in the hadronic phase of the collisions. The K∗(892)0/K yield ratios in Pb–Pb and pp collisions are used to estimate the time duration between chemical and kinetic freeze-out, which is found to be ∼ 4–7 fm/c for central collisions. The pT-differential ratios of K∗(892)0/K, φ(1020)/K, K∗(892)0/π , φ(1020)/π , p/K∗(892)0 and p/φ(1020) are also presented for Pb–Pb and pp collisions at √sNN = 5.02 TeV. These ratios show that the rescattering effect is predominantly a low-pT phenomenon.
Accurate neutron capture cross section data for minor actinides (MAs) are required to estimate the production and transmutation rates of MAs in light water reactors with a high burnup, critical fast reactors like Gen-IV systems and other innovative reactor systems such as accelerator driven systems (ADS). Capture reactions of 244Cm open the path for the formation of heavier Cm isotopes and of heavier elements such as Bk and Cf. In addition, 244Cm shares nearly 50% of the total actinide decay heat in irradiated reactor fuels with a high burnup, even after three years of cooling.
Experimental data for this isotope are very scarce due to the difficulties of providing isotopically enriched samples and because the high intrinsic activity of the samples requires the use of neutron facilities with high instantaneous flux. The only two previous experimental data sets for this neutron capture cross section have been obtained in 1969 using a nuclear explosion and, more recently, at J-PARC in 2010. The neutron capture cross sections have been measured at n_TOF with the same samples that the previous experiments in J-PARC. The samples were measured at n_TOF Experimental Area 2 (EAR-2) with three C6D6 detectors and also in Experimental Area 1 (EAR-1) with the Total Absorption Calorimeter (TAC). Preliminary results assessing the quality and limitations of these new experimental datasets are presented for the experiments in both areas. Preliminary yields of both measurements will be compared with evaluated libraries for the first time.
233U is the fissile nuclei in the Th-U fuel cycle with a particularily small neutron capture cross setion which is on average about one order of magnitude lower than its fission cross section. Hence, the measurement of the 233U(n, γ) cross section relies on a method to accurately distinguish between capture and fission γ-rays. A measurement of the 233U α-ratio has been performed at the n_TOF facility at CERN using a so-called fission tagging setup, coupling n_TOF 's Total Absorption Calorimeter with a novel fission chamber to tag the fission γ-rays. The experimental setup is described and essential parts of the analysis are discussed. Finally, a preliminary 233U α-ratio is presented.
We have measured the capture cross section of the 155Gd and 157Gd isotopes between 0.025 eV and 1 keV. The capture events were recorded by an array of 4 C6D6 detectors, and the capture yield was deduced exploiting the total energy detection system in combination with the Pulse Height Weighting Techniques. Because of the large cross section around thermal neutron energy, 4 metallic samples of different thickness were used to prevent problems related to self-shielding. The samples were isotopically enriched, with a cross contamination of the other isotope of less than 1.14%. The capture yield was analyzed with an R-Matrix code to describe the cross section in terms of resonance parameters. Near thermal energies, the results are significantly different from evaluations and from previous time-of-flight experiments. The data from the present measurement at n_TOF are publicly available in the experimental nuclear reaction database EXFOR.
Feasibility, design and sensitivity studies on innovative nuclear reactors that could address the issue of nuclear waste transmutation using fuels enriched in minor actinides, require high accuracy cross section data for a variety of neutron-induced reactions from thermal energies to several tens of MeV. The isotope 241Am (T1/2= 433 years) is present in high-level nuclear waste (HLW), representing about 1.8 % of the actinide mass in spent PWR UOx fuel. Its importance increases with cooling time due to additional production from the β-decay of 241Pu with a half-life of 14.3 years. The production rate of 241 Am in conventional reactors, including its further accumulation through the decay of 241Pu and its destruction through transmutation/incineration are very important parameters for the design of any recycling solution. In the present work, the 241 Am(n,f) reaction cross-section was measured using Micromegas detectors at the Experimental Area 2 of the n_TOF facility at CERN. For the measurement, the 235U(n,f) and 238U(n,f) reference reactions were used for the determination of the neutron flux. In the present work an overview of the experimental setup and the adopted data analysis techniques is given along with preliminary results.
The (n, γ) cross sections of the gadolinium isotopes play an important role in the study of the stellar nucleosynthesis. In particular, among the isotopes heavier than Fe, 154Gd together with 152Gd have the peculiarity to be mainly produced by the slow capture process, the so-called s-process, since they are shielded against the β-decay chains from the r-process region by their stable samarium isobars. Such a quasi pure s-process origin makes them crucial for testing the robustness of stellar models in galactic chemical evolution (GCE). According to recent models, the 154Gd and 152Gd abundances are expected to be 15-20% lower than the reference un-branched s-process 150Sm isotope. The close correlation between stellar abundances and neutron capture cross sections prompted for an accurate measurement of 154Gd cross section in order to reduce the uncertainty attributable to nuclear physics input and eventually rule out one of the possible causes of present discrepancies between observation and model predictions. To this end, the neutron capture cross section of 154Gd was measured in a wide neutron energy range (from thermal up to some keV) with high resolution in the first experimental area of the neutron time-of-flight facility n_TOF (EAR1) at CERN. In this contribution, after a brief description of the motivation and of the experimental setup used in the measurement, the preliminary results of the 154Gd neutron capture reaction as well as their astrophysical implications are presented.
Monte Carlo simulations and n-p differential scattering data measured with Proton Recoil Telescopes
(2020)
The neutron-induced fission cross section of 235U, a standard at thermal energy and between 0.15 MeV and 200 MeV, plays a crucial role in nuclear technology applications. The long-standing need of improving cross section data above 20 MeV and the lack of experimental data above 200 MeV motivated a new experimental campaign at the n_TOF facility at CERN. The measurement has been performed in 2018 at the experimental area 1 (EAR1), located at 185 m from the neutron-producing target (the experiment is presented by A. Manna et al. in a contribution to this conference). The 235U(n,f) cross section from 20 MeV up to about 1 GeV has been measured relative to the 1H(n,n)1H reaction, which is considered the primary reference in this energy region. The neutron flux impinging on the 235U sample (a key quantity for determining the fission events) has been obtained by detecting recoil protons originating from n-p scattering in a C2H4 sample. Two Proton Recoil Telescopes (PRT), consisting of several layers of solid-state detectors and fast plastic scintillators, have been located at proton scattering angles of 25.07° and 20.32°, out of the neutron beam. The PRTs exploit the ΔE-E technique for particle identification, a basic requirement for the rejection of charged particles from neutron-induced reactions in carbon. Extensive Monte Carlo simulations were performed to characterize proton transport through the different slabs of silicon and scintillation detectors, to optimize the experimental set-up and to deduce the efficiency of the whole PRT detector. In this work we compare measured data collected with the PRTs with a full Monte Carlo simulation based on the Geant-4 toolkit.
Since the start of its operation in 2001, based on an idea of Prof. Carlo Rubbia [1], the neutron time of-flight facility of CERN, n_TOF, has become one of the most forefront neutron facilities in the world for wide-energy spectrum neutron cross section measurements. Thanks to the combination of excellent neutron energy resolution and high instantaneous neutron flux available in the two experimental areas, the second of which has been constructed in 2014, n_TOF is providing a wealth of new data on neutron-induced reactions of interest for nuclear astrophysics, advanced nuclear technologies and medical applications. The unique features of the facility will continue to be exploited in the future, to perform challenging new measurements addressing the still open issues and long-standing quests in the field of neutron physics. In this document the main characteristics of the n_TOF facility and their relevance for neutron studies in the different areas of research will be outlined, addressing the possible future contribution of n_TOF in the fields of nuclear astrophysics, nuclear technologies and medical applications. In addition, the future perspectives of the facility will be described including the upgrade of the spallation target, the setup of an imaging installation and the construction of a new irradiation area.
Neutron-induced fission cross sections of isotopes involved in the nuclear fuel cycle are vital for the design and safe operation of advanced nuclear systems. Such experimental data can also provide additional constraints for the adjustment of nuclear model parameters used in the evaluation process, resulting in the further development of fission models. In the present work, the 237Np(n,f) cross section was studied at the EAR2 vertical beam-line at CERN's n_TOF facility, over a wide range of neutron energies, from meV to MeV, using the time-of-flight technique and a set-up based on Micromegas detectors, in an attempt to provide accurate experimental data. Preliminary results in the 200 keV – 14 MeV neutron energy range as well as the experimental procedure, including a description of the facility and the data handling and analysis, will be presented.
We have measured the γ-rays following neutron capture on 240Pu and 244 Cm at the n_TOF facility at CERN with the Total Absorption Calorimeter (TAC) and with C6D6 organic scintillators. The TAC is made of 40 BaF2 crystals operating in coincidence and covering almost the entire solid angle. This allows to obtain information concerning the energy spectra and the multiplicity of the measured capture γ-ray cascades. Additional information is also obtained from the C6D6 detectors. We have analyzed the measured data in order to draw conclusions about the Photon Strength Functions (PSFs) of 241Pu and 245Cm below their neutron separation energies. The analysis has been performed by fitting the PSFs to the experimental results, using the differential evolution method, in order to find neutron capture cascades capable of reproducing at the same time a great variety of deposited energy spectra.
The study of neutron-induced reactions on actinides is of considerable importance for the design of advanced nuclear systems and alternative fuel cycles. Specifically, 230Th is produced from the α-decay of 234U as a byproduct of the 232Th/233U fuel cycle, thus the accurate knowledge of its fission cross section is strongly required. However, few experimental datasets exist in literature with large deviations among them, covering the energy range between 0.2 to 25 MeV. In addition, the study of the 230Th(n,f) cross-section is of great interest in the research on the fission process related to the structure of the fission barriers. Previous measurements have revealed a large resonance at En=715 keV and additional fine structures, but with high discrepancies among the cross-section values of these measurements. This contribution presents preliminary results of the 230Th(n,f) cross-section measurements at the CERN n_TOF facility. The high purity targets of the natural, but very rare isotope 230Th, were produced at JRC-Geel in Belgium. The measurements were performed at both experimental areas (EAR-1 and EAR-2) of the n_TOF facility, covering a very broad energy range from thermal up to at least 100 MeV. The experimental setup was based on Micromegas detectors with the 235U(n,f) and 238U(n,f) reaction cross-sections used as reference.
New measurements of the 7Be(n,α)4He and 7Be(n,p)7Li reaction cross sections from thermal to keV neutron energies have been recently performed at CERN/n_TOF. Based on the new experimental results, astrophysical reaction rates have been derived for both reactions, including a proper evaluation of their uncertainties in the thermal energy range of interest for big bang nucleosynthesis studies. The new estimate of the 7Be destruction rate, based on these new results, yields a decrease of the predicted cosmological 7Li abundance insufficient to provide a viable solution to the cosmological lithium problem.
The design and operation of innovative nuclear systems requires a better knowledge of the capture and fission cross sections of the Pu isotopes. For the case of capture on 242Pu, a reduction of the uncertainty in the fast region down to 8-12% is required. Moreover, aiming at improving the evaluation of the fast energy range in terms of average parameters, the OECD NEA High Priority Request List (HPRL) requests high-resolution capture measurements with improved accuracy below 2 keV. The current uncertainties also affect the thermal point, where previous experiments deviate from each other by 20%. A fruitful collaboration betwen JGU Mainz and HZ Dresden-Rossendorf within the EC CHANDA project resulted in a 242Pu sample consisting of a stack of seven fission-like targets making a total of 95(4) mg of 242Pu electrodeposited on thin (11.5 μm) aluminum backings. This contribution presents the results of a set of measurements of the 242Pu(n, γ) cross section from thermal to 500 keV combining different neutron beams and techniques. The thermal point was determined at the Budapest Research Reactor by means of Neutron Activation Analysis and Prompt Gamma Analysis, and the resolved (1 eV - 4 keV) and unresolved (1 - 500 keV) resonance regions were measured using a set of four Total Energy detectors at the CERN n_TOF-EAR1.
Setup for the measurement of the 235U(n,f) cross section relative to n-p scattering up to 1 GeV
(2020)
The neutron induced fission of 235U is extensively used as a reference for neutron fluence measurements in various applications, ranging from the investigation of the biological effectiveness of high energy neutrons, to the measurement of high energy neutron cross sections of relevance for accelerator driven nuclear systems. Despite its widespread use, no data exist on neutron induced fission of 235U above 200 MeV. The neutron facility n_TOF offers the possibility to improve the situation. The measurement of 235U(n,f) relative to the differential n-p scattering cross-section, was carried out in September 2018 with the aim of providing accurate and precise cross section data in the energy range from 10 MeV up to 1 GeV. In such measurements, Recoil Proton Telescopes (RPTs) are used to measure the neutron flux while the fission events are detected and counted with dedicated detectors. In this paper the measurement campaign and the experimental set-up are illustrated.
We determine the magnetic susceptibility of thermal QCD matter by means of first principles lattice simulations using staggered quarks with physical masses. A novel method is employed that only requires simulations at zero background field, thereby circumventing problems related to magnetic flux quantization. After a careful continuum limit extrapolation, diamagnetic behavior (negative susceptibility) is found at low temperatures and strong paramagnetism (positive susceptibility) at high temperatures. We revisit the decomposition of the magnetic susceptibility into spin- and orbital angular momentum- related contributions. The spin term — related to the normalization of the photon lightcone distribution amplitude at zero temperature — is calculated non-perturbatively and extrapolated to the continuum limit. Having access to both the full magnetic susceptibility and the spin term, we calculate the orbital angular momentum contribution for the first time. The results reveal the opposite of what might be expected based on a free fermion picture. We provide a simple parametrization of the temperature- and magnetic field-dependence of the QCD equation of state that can be used in phenomenological studies.
Central nervous hyperarousal is as a key component of current pathophysiological concepts of chronic insomnia disorder. However, there are still open questions regarding its exact nature and the mechanisms linking hyperarousal to sleep disturbance. Here, we aimed at studying waking state hyperarousal in insomnia by the perspective of resting-state vigilance dynamics. The VIGALL (Vigilance Algorithm Leipzig) algorithm has been developed to investigate resting-state vigilance dynamics, and it revealed, for example, enhanced vigilance stability in depressive patients. We hypothesized that patients with insomnia also show a more stable vigilance regulation. Thirty-four unmedicated patients with chronic insomnia and 25 healthy controls participated in a twenty-minute resting-state electroencephalography (EEG) measurement following a night of polysomnography. Insomnia patients showed enhanced EEG vigilance stability as compared to controls. The pattern of vigilance hyperstability differed from that reported previously in depressive patients. Vigilance hyperstability was also present in insomnia patients showing only mildly reduced sleep efficiency. In this subgroup, vigilance hyperstability correlated with measures of disturbed sleep continuity and arousal. Our data indicate that insomnia disorder is characterized by hyperarousal at night as well as during daytime.
The transcription factor ∆Np63 is a master regulator of epithelial cell identity and essential for the survival of squamous cell carcinoma (SCC) of lung, head and neck, oesophagus, cervix and skin. Here, we report that the deubiquitylase USP28 stabilizes ∆Np63 and maintains elevated ∆NP63 levels in SCC by counteracting its proteasome‐mediated degradation. Impaired USP28 activity, either genetically or pharmacologically, abrogates the transcriptional identity and suppresses growth and survival of human SCC cells. CRISPR/Cas9‐engineered in vivo mouse models establish that endogenous USP28 is strictly required for both induction and maintenance of lung SCC. Our data strongly suggest that targeting ∆Np63 abundance via inhibition of USP28 is a promising strategy for the treatment of SCC tumours.
Introduction: Cancer patients tend to prefer oral instead of parenteral chemotherapy. To date, there is little evidence on the medication adherence in cancer patients. We investigated medication adherence to tyrosine kinase inhibitors in patients suffering from non-small cell lung cancer. Methods: Tyrosine kinase inhibitor adherence was measured electronically by MEMS® (medication event monitoring system) over at least six months. Adherence rates were calculated in terms of Dosing Compliance, Timing Compliance, Taking Compliance, and Drug Holidays. Patients were dichotomized as adherent when Dosing Compliance and Timing Compliance were ≥80%, Taking Compliance ranged between 90 and 110%, and <1 Drug Holiday was registered. Quality of life was assessed by two questionnaires (EORTC QLQ-C30 version 3.0, EORTC QLQ-LC13) at three time points. Adverse drug events were reported via patient diaries. Results: Out of 32 patients enrolled, data from 23 patients were evaluable. Median Dosing Compliance, Taking Compliance, and Timing Compliance adherence rates of tyrosine kinase inhibitor intake amounted to 100%, 98%, and 99%, respectively; Drug Holidays were observed in three patients. Four patients were dichotomized as non-adherent. Three of them had a twice-daily tyrosine kinase inhibitor regimen. Median quality of life scores amounted to 67 (max. 100) and remained unchanged over the study period. Fatigue and rash were the most frequently reported adverse drug events. Conclusion: Medication adherence of non-small cell lung cancer patients treated with tyrosine kinase inhibitors was extraordinarily high and is likely to support the effectiveness of tyrosine kinase inhibitor treatment and a good quality of life over a long period of time. Adherence facilitating information and education is especially relevant for patients taking tyrosine kinase inhibitors in a twice-daily regimen.
This essay explores the problem of legitimation crises in deliberative systems. For some time now, theorists of deliberative democracy have started to embrace a “systemic approach.” But if deliberative democracy is to be understood in the context of a system of multiple moving parts, then we must confront the possibility that that system’s dynamics may admit of breakdowns, contradictions, and tendencies toward crisis. Yet such crisis potentials remain largely unexplored in deliberative theory. The present article works toward rectifying this lacuna, using the 2016 Brexit and Trump votes as examples of a particular kind of “legitimation crisis” that results in a sequence of failures in the deliberative system. Drawing on recent work of Rainer Forst, I identify this particular kind of legitimation crisis as a “justification crisis.”
Stored and cooled, highly-charged ions offer unprecedented capabilities for precision studies in the realm of atomic, nuclear structure and astrophysics[1]. After the successful investigation of the 96Ru(p,7)97Rh reaction cross section in 2009[2], the first measurement of the 124Xe(p,7)125Cs reaction cross section has been performed with decelerated, fully-ionized 124Xe ions in 2016 at the Experimental Storage Ring (ESR) of GSI[3]. Using a Double Sided Silicon Strip Detector, introduced directly into the ultra-high vacuum environment of a storage ring, the 125Cs proton-capture products have been successfully detected. The cross section has been measured at 5 different energies between 5.5AMeV and 8AMeV, on the high energy tail of the Gamow-window for hot, explosive scenarios such as supernovae and X-ray binaries. The elastic scattering on the H2 gas jet target is the major source of background to count the (p,7) events. Monte Carlo simulations show that an additional slit system in the ESR in combination with the energy information of the Si detector will enable background free measurements of the proton-capture products. The corresponding hardware is being prepared and will increase the sensitivity of the method tremendously.
Psychotherapists in mental health institutions as a professional group are part of the medical system, and from this perspective, as representing an occupation that serves the public health interests, as well as those of the individual seeking help. Despite the different existing therapeutic approaches and diverse forms of therapy deriving from these approaches critical theories, however, consider psychotherapy as a profession with a specific jurisdictional claim and own highly specific interests. In contrast to most of the recent discussion around therapy culture, in this article, I argue that sociology and social theory could benefit from an understanding of psychotherapy as a profession with a separate logic and claim for jurisdiction for mental health. Moreover, I present some general trends showing that, regarding psychotherapy, we face a concurrence of a professionalisation, and simultaneously, an already ongoing deprofessionalisation. To develop my argument, I first discuss the perspectives of sociology of the psychotherapy professions. Second, I present the potential lack of professionalism in four dimensions. Third, I discuss possible tendencies of deprofessionalisation. Finally, I conclude by pointing out the importance of theorising the psychotherapy professions for medical sociology.
Aims: The study aimed to evaluate the prevalence of mental distress in patients with newly diagnosed bladder cancer, the cancer-information search behavior, and the influence of information seeking on distress. Methods: One hundred and one bladder cancer patients answered 2 established questionnaires (“Hospital Anxiety and Depression Scale” [HADS] and the “Fragebogen zur Belastung von Krebskranken” [FBK-R23]) for evaluation of mental distress and a self-developed questionnaire with questions concerning information seeking and socioeconomic facts. Results: Regarding risk group stratification, 57.4% were classified as high-risk and 42.6% as low-risk tumor-bearing patients. Analysis of mental distress showed that 23.2% had a score above the HADS-A cutoff, 25.3% above the HADS-D cutoff, and 21.4% showed a pathologic FBK-R23 score. Overall, 75% felt well informed about their illness. Risk group stratification did not correlate with HADS-A, HADS-D, or FBK-R23 score. Furthermore, active search for information or the use of the Internet did not correlate with the HADS-A, HADS-D, or FBK-R23 score. However, the quality of the urologist’s information and the feeling of being informed correlated with the grade of mental distress. Conclusion: Besides the treatment of bladder cancer, informing the patient about the disease in a psychologically wholesome manner and working together with psycho-oncologically trained psychologists are essential tasks for the treating urologist.
Background: Data on the arrhythmic burden of women at risk for sudden cardiac death are limited, especially in patients using the wearable cardioverter-defibrillator (WCD).
Objective: We aimed to characterize WCD compliance, atrial and ventricular arrhythmic burden, and WCD outcomes by sex in patients enrolled in the Prospective Registry of Patients Using the Wearable Cardioverter Defibrillator (WEARIT-II U.S. Registry).
Methods: In the WEARIT-II Registry, we stratified 2000 patients by sex into women (n = 598) and men (n = 1402). WCD wear time, ventricular and atrial arrhythmic events during WCD use, and implantable cardioverter-defibrillator (ICD) implantation rates at the end of WCD use were evaluated.
Results: The mean WCD wear time was similar in women and men (94 days vs 90 days; P = .145), with longer daily use in women (21.4 h/d vs 20.7 h/d; P = .001). Burden of ventricular tachycardia or ventricular fibrillation was higher in women, with 30 events per 100 patient-years compared with 18 events per 100 patient-years in men (P = .017), with similar findings for treated and non-treated ventricular tachycardia/ventricular fibrillation. Recurrent atrial arrhythmias/sustained ventricular tachycardia was also more frequent in women than in men (167 events per 100 patient-years vs 73 events per 100 patient-years; P = .042). However, ICD implantation rate at the end of WCD use was similar in both women and men (41% vs 39%; P = .448).
Conclusion: In the WEARIT-II Registry, we have shown a higher burden of ventricular and atrial arrhythmic events in women than in men. ICD implantation rates at the end of WCD use were similar. Our findings warrant monitoring women at risk for sudden cardiac death who have a high burden of atrial and ventricular arrhythmias while using the WCD.
Determination of a minimal postmortem interval via age estimation of necrophagous diptera has been restricted to the juvenile stages and the time until emergence of the adult fly, i.e. up until 2–6 weeks depending on species and temperature. Age estimation of adult flies could extend this period by adding the age of the fly to the time needed for complete development. In this context pteridines are promising metabolites, as they accumulate in the eyes of flies with increasing age. We studied adults of the blow fly Lucilia sericata at constant temperatures of 16 °C and 25 °C up to an age of 25 days and estimated their pteridine levels by fluorescence spectroscopy. Age was given in accumulated degree days (ADD) across temperatures. Additionally, a mock case was set up to test the applicability of the method. Pteridine increases logarithmically with increasing ADD, but after 70–80 ADD the increase slows down and the curve approaches a maximum. Sex had a significant impact (p < 4.09 × 10−6) on pteridine fluorescence level, while body-size and head-width did not. The mock case demonstrated that a slight overestimation of the real age (in ADD) only occurred in two out of 30 samples. Age determination of L. sericata on the basis of pteridine levels seems to be limited to an age of about 70 ADD, but depending on the ambient temperature this could cover an extra amount of time of about 5–7 days after completion of the metamorphosis.
Aim: The primary aim of this study was to analyze frequency and characteristics of combined facial and peripheral trauma with consecutive hospitalization and treatment.
Materials and methods: The study included all patients with concomitant orthopedic-traumatolgical (OT) and craniomaxillofacial (CMF) injuries admitted to our level I trauma center in 2018. The data were collected by analysis of the institution’s database and radiological reviews and included age, sex, injury type, weekday and time of presentation. All patients were examined and treated by a team of surgeons specialized in OT and CMF directly after presentation.
Results: A total number of 1040 combined OT and CMF patients were identified. Mean age was 33.0 ± 26.2 years. 67.3% (n = 700) were male patients. Primary presentation happened most frequently on Sundays (n = 199) and between 7 and 8 pm (n = 74). 193 OT fractures were documented, where cervical spine injuries were most frequent (n = 30). 365 facial and skull fractures were recorded. 10.8% of the 204 patients with fractures of the viscerocranium presented with at least one fracture of the extremity, 7.8% (16/204) with cervical spine fractures, 33.3% (68/204) with signs of closed brain trauma and 9.8% (20/204) with intracranial hemorrhage.
Discussion: The study shows a high frequency of combined facial with OT-injuries and brain damage in a predominantly young and male cohort. Attendance by interdisciplinary teams of both CMF and OT surgeons specialized in cervical spine trauma surgery is highly advisable for adequate treatment.
Conclusion: Diagnostics and treatment should be performed by a highly specialized OT and CMF team, with a consulting neurosurgeon in a level-1 trauma center to avoid missed diagnoses and keep mortality low.
Corporate governance is the set of rules, be they legal or self-regulatory, practices and processes pursuant to which an insurance undertaking is administrated. Good corporate governance is not only key to establishing oneself and succeeding in a competitive environment but also to safeguarding the interests of all stakeholders in an insurance undertaking. It is insofar not surprising that mandatory requirements on the administration of insurance undertakings have become rather prolific in recent years, in an attempt by regulators to protect especially policyholders against perceived risks hailing from improperly governed insurance undertakings. In Germany this has been regarded by many undertakings as an overly paternalistic approach of the legislator, especially considering that the German insurance sector has experienced for decades if not centuries a remarkably low number of insolvencies and that German insurers were neither the trigger nor the (especially) endangered actors in the financial crisis commencing in 2007. Notwithstanding the true core of this criticism, that the insurance industry was taken to a certain degree hostage by the shortcomings within the banking sector, the reform of German Insurance Supervisory Law via implementation of the Solvency II-System has brought many advances in the sense of better governance of insurance undertakings and has also brought to light many deficiencies that the administration of some insurance undertakings may have suffered from in the past, which are now more properly addressed.
High-intensity functional training (HIFT) has become a popular method in the sports and fitness sector. In contrast to unimodal approaches such as strength or endurance training, it has been hypothesized to induce concurrent adaptations in multiple markers of motor function. However, to date, the effectiveness of HIFT in this regard has not been studied. The present systematic review quantified the chronic effects of HIFT on motor function in healthy individuals. A multilevel meta-analysis with a robust random effects meta-regession model was used to pool the standardized mean differences (SMD) between (a) HIFT and (b) no-exercise (NEX) as well as conventional endurance, resistance and balance training for outcomes of muscle strength, endurance capacity and balance. The influence of possible effect modifiers such as program duration, session duration, age or sex was examined in a moderator analysis. Seventeen papers with moderate to high methodological quality (PEDro scale) were identified. Compared to NEX, HIFT had small to moderate positive effects on endurance capacity (SMD: 0.42, 95% CI 0.07–0.78, p = 0.03) and strength (0.60, 95% CI 0.02–1.18, p = 0.04) but no effect on balance (SMD: − 0.10, 95% CI − 1.13 to 0.92, p = 0.42). Regarding endurance, HIFT showed similar effectiveness as moderate-intensity endurance training (SMD: − 0.11, 95% CI − 1.17 to 0.95, p = 0.75) and high-intensity interval endurance training (SMD: − 0.15, 95% CI − 1.4 to 1.1, p = 0.66). No comparisons of HIFT vs. classical resistance or balance training were found. Moderator analyses revealed no influence of most effect modifiers. However, regarding endurance, females seemed to respond more strongly to HIFT in the comparison to NEX (p < .05). HIFT appears to represent an appropriate method to induce chronic improvements in motor function. While being superior to NEX and non-inferior to endurance training, current evidence does not allow a comparison against resistance and balance training. The impact of possible effect moderators should be further elucidated in future research.
Hintergrund: Mit dem Masterplan 2020 und den an mehreren Universitäten eingeführten Modellstudiengängen befindet sich das Medizinstudium aktuell im Umbruch. Sowohl im Regel- als auch im Modellstudiengang werden medizinrechtliche Aspekte überwiegend im Rahmen rechtsmedizinischer Ausbildungsabschnitte unterrichtet. Allerdings werden Studierende bereits während Famulaturen oder im praktischen Jahr mit juristischen Fragen konfrontiert.
Ziel der Studie war es herauszufinden, ob und in welchem Umfang Studierende der Humanmedizin insbesondere zur ärztlichen Aufklärung und zu den ärztlichen Informationspflichten bis zum Beginn des 4. bzw. 5. klinischen Semesters auf medizinrechtliche Aspekte vorbereitet wurden, und ob Verbesserungen bei der medizinrechtlichen Lehre gewünscht werden.
Material und Methoden: Zwischen den Sommersemestern 2017 und 2019 wurde zu Beginn des Kurses für Rechtsmedizin eine quantitative, standardisierte Umfrage mit insgesamt 373 Studierenden durchgeführt.
Ergebnisse: Wenngleich 98,8 % der Studierenden angaben, Aufklärungsgespräche bereits (mehrfach) praktisch ausgeübt zu haben, bestanden deutliche Defizite in Bezug auf die juristischen Anforderungen an das ärztliche Aufklärungsgespräch und dessen Delegation. So gaben lediglich 5,1 % der Studierenden an, die rechtlichen Grundlagen der ärztlichen Aufklärung sowie die entsprechende Norm aus dem Zivilrecht zu kennen. Über 80 % der Befragten fühlten sich unzureichend auf die rechtlichen Aspekte des praktischen Jahres vorbereitet. Über 90 % der Studierenden wünschten sich eine bessere medizinrechtliche Ausbildung.
Diskussion: Eine fächerübergreifende Etablierung sowie eine über das gesamte Studium verteilte Lehre von Medizinrecht könnte die Vorbereitung auf das praktische Jahr verbessern und das Verständnis für die rechtlichen Anforderungen an die ärztliche Berufstätigkeit fördern. Nach dem derzeitigen Stand der Umsetzung des Masterplans 2020 soll das Medizinrecht in der Learning Opportunities, Objectives and Outcomes Platform (LOOOP) als verbindlicher Ausbildungs- und Lehrinhalt etabliert werden.
Background: The feedback given to students plays an important role in their efficiency related to learning practical skills. In the present study, diverse feedback modalities have been investigated. Our hypothesis is that individualized and unsupervised video feedback can produce a similar learning experience as performing practical skills in an oral and maxillofacial surgery setting with conventional direct expert feedback (control group).
Methods: This prospective, randomized, controlled, and blinded study compared direct expert feedback (DEF), individualized video feedback (IVF) and unsupervised video feedback (UVF). The participants were fourth-year dental students from University Goethe in Frankfurt. The students were assigned to one of the three feedback methods (n = 20 per group) using simple randomization. All participants watched an instruction video for an interdental (‘Ernst’) ligature and periphery venous catheterization. Next, the students were video recorded performing the tasks by themselves (pre-test). Following this, every student received feedback using one of the above-mentioned feedback modalities. The participants then performed the same task again while being video recorded (post-test) to measure the acquired competence. Six weeks later, the students participated in an objective structured clinical examination (OSCE) to evaluate their long-term knowledge retention. All examiners were blinded regarding the students’ instructional approach and their affiliation in terms of the learning group.
Results: For the interdental ligature, we found significant improvements in performance in each feedback modality group between the pre-test and post-test (p < 0.001). UVF had the strongest effect on performance time. The comparison between each group in the post-test showed no significant differences between the three groups.
Conclusion: This study showed that IVF and UVF can be considered an alternative or adjunct to conventional methods (i.e. DEF) when learning procedural skills in oral and maxillofacial surgery. However, DEF showed to be the most effective method of feedback and therefore preferable in teaching.
Background: Patients with rare diseases (RDs) are often diagnosed too late or not at all. Clinical decision support systems (CDSSs) could support the diagnosis in RDs. The MIRACUM (Medical Informatics in Research and Medicine) consortium, which is one of four funded consortia in the German Medical Informatics Initiative, will develop a CDSS for RDs based on distributed clinical data from ten university hospitals. This qualitative study aims to investigate (1) the relevant organizational conditions for the operation of a CDSS for RDs when diagnose patients (e.g. the diagnosis workflow), (2) which data is necessary for decision support, and (3) the appropriate user group for such a CDSS.
Methods: Interviews were carried out with RDs experts. Participants were recruited from staff physicians at the Rare Disease Centers (RDCs) at the MIRACUM locations, which offer diagnosis and treatment of RDs.
An interview guide was developed with a category-guided deductive approach. The interviews were recorded on an audio device and then transcribed into written form. We continued data collection until all interviews were completed. Afterwards, data analysis was performed using Mayring’s qualitative content analysis approach.
Results: A total of seven experts were included in the study. The results show that medical center guides and physicians from RDC B-centers (with a focus on different RDs) are involved in the diagnostic process. Furthermore, interdisciplinary case discussions between physicians are conducted.
The experts explained that RDs exist which cannot be fully differentiated, but rather described only by their overall symptoms or findings: diagnosis is dependent on the disease or disease group. At the end of the diagnostic process, most centers prepare a summary of the patient case. Furthermore, the experts considered both physicians and experts from the B-centers to be potential users of a CDSS. The experts also have different experiences with CDSS for RDs.
Conclusions: This qualitative study is a first step towards establishing the requirements for the development of a CDSS for RDs. Further research is necessary to create solutions by also including the experts on RDs.
We discuss the potential of light-nuclei measurements in heavy-ion collisions at intermediate energies for the search of the hypothetical QCD critical end-point. A previous proposal based on neutron density fluctuations has brought appealing experimental evidences of a maximum in the ratio of the number of tritons times protons, divided over deuterons square, O tpd. However these results are difficult to reconcile with the state-of-the-art statistical thermal model predictions. Based on the idea that the QCD critical point can lead to a substantial attraction among nucleons, we propose new light-nuclei multiplicity ratios involving He in which the maximum would be more noticeable. We argue that the experimental extraction is feasible by presenting these ratios formed from actual measurements of total and differential yields at low and high collision energies from FOPI and ALICE experiments, respectively. We also illustrate the possible behavior of these ratios at intermediate energies applying a semiclassical method based on flucton paths using the preliminary NA49 and STAR data for O tpd as input.
“Protection of the environment“ and “sustainability“ are more significant than ever. The legal system contributes an important share to the protection of the environment. However, an overview of the German private environmental liability law shows that conventional tort law is not a suitable basis for civil liability for the environmental consequences of officially approved emissions of greenhouse gases. In general, one of the main problems of private environmental liability law lies in proving the individual causality of the conduct of an emitter, as the lawsuit of a Peruvian homeowner against a German energy company pending before the Higher Regional Court of Hamm illustratively demonstrates. The outcome of this lawsuit, which may have an outstanding significance for the status and development of private environmental liability law in Germany, is awaited with great anticipation. The article also briefly examines recent developments in private environmental liability law outside Germany and the question to what extent insurance can be an instrument to protect the environment.
Background: Rare Diseases (RDs), which are defined as diseases affecting no more than 5 out of 10,000 people, are often severe, chronic and life-threatening. A main problem is the delay in diagnosing RDs. Clinical decision support systems (CDSSs) for RDs are software systems to support clinicians in the diagnosis of patients with RDs. Due to their clinical importance, we conducted a scoping review to determine which CDSSs are available to support the diagnosis of RDs patients, whether the CDSSs are available to be used by clinicians and which functionalities and data are used to provide decision support.
Methods: We searched PubMed for CDSSs in RDs published between December 16, 2008 and December 16, 2018. Only English articles, original peer reviewed journals and conference papers describing a clinical prototype or a routine use of CDSSs were included. For data charting, we used the data items “Objective and background of the publication/project”, “System or project name”, “Functionality”, “Type of clinical data”, “Rare Diseases covered”, “Development status”, “System availability”, “Data entry and integration”, “Last software update” and “Clinical usage”.
Results: The search identified 636 articles. After title and abstracting screening, as well as assessing the eligibility criteria for full-text screening, 22 articles describing 19 different CDSSs were identified. Three types of CDSSs were classified: “Analysis or comparison of genetic and phenotypic data,” “machine learning” and “information retrieval”. Twelve of nineteen CDSSs use phenotypic and genetic data, followed by clinical data, literature databases and patient questionnaires. Fourteen of nineteen CDSSs are fully developed systems and therefore publicly available. Data can be entered or uploaded manually in six CDSSs, whereas for four CDSSs no information for data integration was available. Only seven CDSSs allow further ways of data integration. thirteen CDSS do not provide information about clinical usage.
Conclusions: Different CDSS for various purposes are available, yet clinicians have to determine which is best for their patient. To allow a more precise usage, future research has to focus on CDSSs RDs data integration, clinical usage and updating clinical knowledge. It remains interesting which of the CDSSs will be used and maintained in the future.
Background: Combined inhibition of phosphatidylinositol 3-kinase (PI3K) and the mammalian target of rapamycin (mTOR) complexes may be an efficient treatment for acute leukemia. The primary objective of this phase I single center open label study was to determine the maximum tolerated dose (MTD) and recommended phase II dose (RP2D) of the dual pan-class I PI3K and mTOR inhibitor BEZ235 in patients with advanced leukemia.
Methods: Herein patients > 18 years of age who had relapsed or showed refractory leukemia were treated with BEZ235 (orally at 300–400 mg BID (cohort − 1/1)) to assess safety, tolerability, preliminary efficacy and pharmacokinetic (PK). Adverse events data and serious adverse events were analyzed and haematological and clinical biochemistry toxicities were assessed from laboratory test parameters. Response was assessed for the first time at the end of cycle 1 (day 29) and after every subsequent cycle. Pharmacokinetic and pharmacodynamic analyses of BEZ235 were also included (BEZ235 plasma levels, phosphorylation of AKT, S6 and 4EBP1). On statistics this trial is a multiple ascending dose study in which a following variant of the 3 + 3 rule (“Rolling Six”), a minimum of 6 and a maximum of 12 patients was recruited for the dose escalation and another 5 were planned for the expansion phase.
Results: Twenty-four patients with ALL (n = 11) or AML (n = 12) or CML-BP (n = 1) were enrolled. All patients had failed one (n = 5) or more lines of therapy (n = 5) and 14 patients were in refractory / refractory relapse. No formal MTD was defined, stomatitis and gastrointestinal toxicity at 400 mg BID dose was considered incompatible with prolonged treatment. The RP2D of BEZ235 was defined as 300 mg BID. Four of 24 patients showed clinical benefit. Twenty-two of 24 patients discontinued because of progression, (median time to progression 27 days (4d-112d). There was no association between PK parameters and efficacy or tolerability.
Conclusions: Combined inhibition of PI3K and mTOR inhibits a clinically meaningful driver pathway in a small subset of patients with ALL, with no benefit in patients with AML.
Trial registration: ClinicalTrials.gov, identifier NCT01756118. retrospectively registered 19th December 2012, https://clinicaltrials.gov/ct2/show/NCT01756118.
Unter Endometriose versteht man das Auftreten von endometrialen Zellen und Zellverbänden außerhalb des Cavum uteri, welche dem hormonellen Zyklus unterliegen und zu rezidivierenden Beschwerden führen können. Die Inzidenz wird je nach Quelle mit 2–15 % der Frauen im reproduktionsfähigen Alter angegeben. Schmerzen und Fertilitätseinschränkung sind die führenden Symptome. Unter Kinderwunschpatientinnen liegt die Inzidenz bei 20–48 %.
Background: With refinements in diagnosis and therapy of gliomas, the importance of survival time as the sole outcome parameter has decreased, and patient-centered outcome parameters have gained interest. Pursuing a profession is an indispensable component of human happiness. The aim of this study was to analyze the professional outcomes besides their neuro-oncological and functional evaluation after surgery for gliomas in eloquent areas.
Methods: We assessed neuro-oncological and functional outcomes of patients with gliomas WHO grades II and III undergoing surgery between 2012 and 2018. All patients underwent routine follow-up and adjuvant treatment. Treatment and survival parameters were collected prospectively. Repercussions of the disease on the patients’ professional status, socio-economic situation, and neurocognitive function were evaluated retrospectively with questionnaires.
Results: We analyzed data of 58 patients with gliomas (WHO II: 9; III: 49). Median patient age was 35.8 years (range 21–63 years). Awake surgery techniques were applied in 32 patients (55.2%). Gross total and subtotal tumor resections were achieved in 33 (56.9%) and 17 (29.3%) patients, respectively, whereas in 8 patients (13.8%) resection had to remain partial. Most patients (n = 46; 79.3%) received adjuvant treatment. Median follow up was 43.8 months (range 11–82 months). After treatment 41 patients (70.7%) were able to resume a working life. Median time until returning to work was 8.0 months (range 0.2–22.0 months). To be younger than 40 at the time of the surgery was associated with a higher probability to return to work (p < .001). Multivariable regression analysis showed that patient age < 40 years as well as occupational group and self-reported fatigue were factors independently associated with the ability to return to work.
Conclusion: The ability to resume professional activities following brain tumor surgery is an important patient-oriented outcome parameter. We found that the majority of patients with gliomas were able to return to work following surgical and adjuvant treatment. Preservation of neurological function is of utmost relevance for individual patients´ quality of life.
One current goal in native mass spectrometry is the assignment of binding affinities to noncovalent complexes. Here we introduce a novel implementation of the existing laser-induced liquid bead ion desorption (LILBID) mass spectrometry method: this new method, LILBID laser dissociation curves, assesses binding strengths quantitatively. In all LILBID applications, aqueous sample droplets are irradiated by 3 µm laser pulses. Variation of the laser energy transferred to the droplet during desorption affects the degree of complex dissociation. In LILBID laser dissociation curves, laser energy transfer is purposely varied, and a binding affinity is calculated from the resulting complex dissociation. A series of dsDNAs with different binding affinities was assessed using LILBID laser dissociation curves. The binding affinity results from the LILBID laser dissociation curves strongly correlated with the melting temperatures from UV melting curves and with dissociation constants from isothermal titration calorimetry, standard solution phase methods. LILBID laser dissociation curve data also showed good reproducibility and successfully predicted the melting temperatures and dissociation constants of three DNA sequences. LILBID laser dissociation curves are a promising native mass spectrometry binding affinity method, with reduced time and sample consumption compared to melting curves or titrations.
Background: Healthy volunteer registry donors have become the backbone of stem cell transplantation programs. While most registrants will never become actual donors, a small minority are called upon twice, most commonly for the same patient because of poor graft function. Anecdotal evidence provides no hard reasons to disallow second-time mobilized apheresis, but few centers have treated enough two-time donors for definitive conclusions. Moreover, for reasons unknown, the efficiency of G-CSF varies greatly between donations.
Methods: Comparison of outcomes of first vs. second donations can formally confirm G-CSF responsiveness as intrinsically, likely genetically, determined. In our database, we identified 60 donors (1.3%) who received two cycles of G-CSF 24 days to 4 years apart and systematically compared mobilization outcomes.
Results: First and second mobilization and collection proceeded without severe or unusual adverse effects. First-time mobilization efficiency was highly predictive of second-time mobilization. Neither mobilization efficiency nor time lag between donations affected the similarity of first- and second-time mobilization outcomes.
Conclusions: With the caveat that only donors with an unremarkable first donation were cleared for a second, our data indicate that a second donation is feasible, equally tolerable as a first donation, and efficient. Moreover, the data strongly support the notion of donor-intrinsic variables dictating mobilization response and argue against relevant damage to the stem cell compartment during mobilization with rhG-CSF.
The Izu–Bonin–Mariana volcanic arc is situated at a convergent plate margin where subduction initiation triggered the formation of MORB-like forearc basalts as a result of decompression melting and near-trench spreading. International Ocean Discovery Program (IODP) Expedition 352 recovered samples within the forearc basalt stratigraphy that contained unusual macroscopic globular textures hosted in andesitic glass (Unit 6, Hole 1440B). It is unclear how these andesites, which are unique in a stratigraphic sequence dominated by forearc basalts, and the globular textures therein may have formed. Here, we present detailed textural evidence, major and trace element analysis, as well as B and Sr isotope compositions, to investigate the genesis of these globular andesites. Samples consist of K2O-rich basaltic globules set in a glassy groundmass of andesitic composition. Between these two textural domains a likely hydrated interface of devitrified glass occurs, which, based on textural evidence, seems to be genetically linked to the formation of the globules. The andesitic groundmass is Cl rich (ca. 3000 µg/g ), whereas globules and the interface are Cl poor (ca. 300 µg/g ). Concentrations of fluid-mobile trace elements also appear to be fractionated in that globules and show enrichments in B, K, Rb, Cs, and Tl, but not in Ba and W relative to the andesitic groundmass, whereas the interface shows depletions in the latter, but is enriched in the former. Interestingly, globules and andesitic groundmass have identical Sr isotopic composition within analytical uncertainty ( 87Sr∕86Sr of 0.70580 ± 10 ), indicating that they likely formed from the same source. However, globules show high δ11 B (ca. + 7 ‰ ), whereas their host andesites are isotopically lighter (ca. – 1 ‰ ), potentially indicating that whatever process led to their formation either introduced heavier B isotopes to the globules, or induced stable isotope fractionation of B between globules and their groundmass. Based on the bulk of the textural information and geochemical data obtained from these samples, we conclude that these andesites likely formed as a result of the assimilation of shallowly altered oceanic crust (AOC) during forearc basaltic magmatism. Assimilation likely introduced radiogenic Sr, as well as heavier B isotopes to comparatively unradiogenic and low δ11B forearc basalt parental magmas (average 87Sr∕86Sr of 0.703284). Moreover, the globular textures are consistent with their formation being the result of fluid-melt immiscibility that was potentially induced by the rapid release of water from assimilated AOC whose escape likely formed the interface. If the globular textures present in these samples are indeed the result of fluid-melt immiscibility, then this process led to significant trace element and stable isotope fractionation. The textures and chemical compositions of the globules highlight the need for future experimental studies aimed at investigating the exsolution process with respect to potential trace element and isotopic fractionation in arc magmas that have perhaps not been previously considered.
1H, 13C, and 15N backbone chemical shift assignments of coronavirus-2 non-structural protein Nsp10
(2020)
The international Covid19-NMR consortium aims at the comprehensive spectroscopic characterization of SARS-CoV-2 RNA elements and proteins and will provide NMR chemical shift assignments of the molecular components of this virus. The SARS-CoV-2 genome encodes approximately 30 different proteins. Four of these proteins are involved in forming the viral envelope or in the packaging of the RNA genome and are therefore called structural proteins. The other proteins fulfill a variety of functions during the viral life cycle and comprise the so-called non-structural proteins (nsps). Here, we report the near-complete NMR resonance assignment for the backbone chemical shifts of the non-structural protein 10 (nsp10). Nsp10 is part of the viral replication-transcription complex (RTC). It aids in synthesizing and modifying the genomic and subgenomic RNAs. Via its interaction with nsp14, it ensures transcriptional fidelity of the RNA-dependent RNA polymerase, and through its stimulation of the methyltransferase activity of nsp16, it aids in synthesizing the RNA cap structures which protect the viral RNAs from being recognized by the innate immune system. Both of these functions can be potentially targeted by drugs. Our data will aid in performing additional NMR-based characterizations, and provide a basis for the identification of possible small molecule ligands interfering with nsp10 exerting its essential role in viral replication.