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Neutron capture on 241Am plays an important role in the nuclear energy production and also provides valuable information for the improvement of nuclear models and the statistical interpretation of the nuclear properties. A new experiment to measure the 241Am(n, γ) cross section in the thermal region and the first few resonances below 10 eV has been carried out at EAR2 of the n_TOF facility at CERN. Three neutron-insensitive C6D6 detectors have been used to measure the neutron-capture gamma cascade as a function of the neutron time of flight, and then deduce the neutron capture yield. Preliminary results will be presented and compared with previously obtained results at the same facility in EAR1. In EAR1 the gamma-ray background at thermal energies was about 90% of the signal while in EAR2 is up to a 25 factor much more favorable signal to noise ratio. We also extended the low energy limit down to subthermal energies. This measurement will allow a comparison with neutron capture measurements conducted at reactors and using a different experimental technique.
Blunt thoracic trauma (TxT) deteriorates clinical post-injury outcomes. Ongoing inflammatory changes promote the development of post-traumatic complications, frequently causing Acute Lung Injury (ALI). Club Cell Protein (CC)16, a pulmonary anti-inflammatory protein, correlates with lung damage following TxT. Whether CC16-neutralization influences the inflammatory course during ALI is elusive. Ninety-six male CL57BL/6N mice underwent a double hit model of TxT and cecal ligation puncture (CLP, 24 h post-TxT). Shams underwent surgical procedures. CC16 was neutralized by the intratracheal application of an anti-CC16-antibody, either after TxT (early) or following CLP (late). Euthanasia was performed at 6 or 24 h post-CLP. Systemic and pulmonary levels of IL-6, IL-1β, and CXCL5 were determined, the neutrophils were quantified in the bronchoalveolar lavage fluid, and histomorphological lung damage was assessed. ALI induced a significant systemic IL-6 increase among all groups, while the local inflammatory response was most prominent after 24 h in the double-hit groups as compared to the shams. Significantly increased neutrophilic infiltration upon double hit was paralleled with the enhanced lung damage in all groups as compared to the sham, after 6 and 24 h. Neutralization of CC16 did not change the systemic inflammation. However, early CC16-neutralization increased the neutrophilic infiltration and lung injury at 6 h post-CLP, while 24 h later, the lung injury was reduced. Late CC16-neutralization increased neutrophilic infiltration, 24 h post-CLP, and was concurrent with an enhanced lung injury. The data confirmed the anti-inflammatory potential of endogenous CC16 in the murine double-hit model of ALI.
Background: Polytraumatized patients undergo a strong immunological stress upon insult. Phagocytes (granulocytes and monocytes) play a substantial role in immunological defense against bacteria, fungi and yeast, and in the clearance of cellular debris after tissue injury. We have reported a reduced monocytes phagocytic activity early after porcine polytrauma before. However, it is unknown if both phagocyte types undergo those functional alterations, and if there is a pathogen-specific phagocytic behavior. We characterized the phagocytic activity and capacity of granulocytes and monocytes after polytrauma.
Methods: Eight pigs (Sus scrofa) underwent polytrauma consisting of lung contusion, liver laceration, tibial fracture and hemorrhagic shock with fluid resuscitation and fracture fixation with external fixator. Intensive care treatment including mechanical ventilation for 72 h followed. Phagocytic activity and capacity were investigated using an in vitro ex vivo whole blood stimulation phagocytosis assays before trauma, after surgery, 24, 48, and 72 h after trauma. Blood samples were stimulated with Phorbol-12-myristate-13-acetate and incubated with FITC-labeled E. coli, S. aureus or S. cerevisiae for phagocytosis assessment by flow cytometry.
Results: Early polytrauma-induced significant increase of granulocytes and monocytes declined to baseline values within 24 h. Percentage of E. coli-phagocytizing granulocytes significantly decreased after polytrauma and during further intensive care treatment, while their capacity significantly increased. Interestingly, both granulocytic phagocytic activity and capacity of S. aureus significantly decreased after trauma, although a recovery was observed after 24 h and yet was followed by another decrease. The percentage of S. cerevisiae-phagocytizing granulocytes significantly increased after 24 h, while their impaired capacity after surgery and 72 h later was detected. Monocytic E. coli-phagocytizing percentage did not change, while their capacity increased after 24–72 h. After a significant decrease in S. aureus-phagocytizing monocytes after surgery, a significant increase after 24 and 48 h was observed without capacity alterations. No significant changes in S. cerevisiae-phagocytizing monocytes occurred, but their capacity dropped 48 and 72 h.
Conclusion: Phagocytic activity and capacity of granulocytes and monocytes follow a different pattern and significantly change within 72 h after polytrauma. Both phagocytic activity and capacity show significantly different alterations depending on the pathogen strain, thus potentially indicating at certain and possibly more relevant infection causes after polytrauma.
Diversity-oriented synthesis (DOS) is a rich source for novel lead structures in Medicinal Chemistry. In this study, we present a DOS-compatible method for synthesis of compounds bearing a free thiol moiety. The procedure relies on Rh(II)-catalyzed coupling of dithiols to diazo building blocks. The synthetized library was probed against metallo-β-lactamases (MBLs) NDM-1 and VIM-1. Biochemical and biological evaluation led to identification of novel potent MBL inhibitors with antibiotic adjuvant activity.
Membrane proteins frequently assemble into higher order homo- or hetero-oligomers within their natural lipid environment. This complex formation can modulate their folding, activity as well as substrate selectivity. Non-disruptive methods avoiding critical steps, such as membrane disintegration, transfer into artificial environments or chemical modifications are therefore essential to analyze molecular mechanisms of native membrane protein assemblies. The combination of cell-free synthetic biology, nanodisc-technology and non-covalent mass spectrometry provides excellent synergies for the analysis of membrane protein oligomerization within defined membranes. We exemplify our strategy by oligomeric state characterization of various membrane proteins including ion channels, transporters and membrane-integrated enzymes assembling up to hexameric complexes. We further indicate a lipid-dependent dimer formation of MraY translocase correlating with the enzymatic activity. The detergent-free synthesis of membrane protein/nanodisc samples and the analysis by LILBID mass spectrometry provide a versatile platform for the analysis of membrane proteins in a native environment.
Mitochondria are involved in the aging processes that ultimately lead to neurodegeneration and the development of Alzheimer’s disease (AD). A healthy lifestyle, including a diet rich in antioxidants and polyphenols, represents one strategy to protect the brain and to prevent neurodegeneration. We recently reported that a stabilized hexanic rice bran extract (RBE) rich in vitamin E and polyphenols (but unsuitable for human consumption) has beneficial effects on mitochondrial function in vitro and in vivo (doi:10.1016/j.phrs.2013.06.008, 10.3233/JAD-132084). To enable the use of RBE as food additive, a stabilized ethanolic extract has been produced. Here, we compare the vitamin E profiles of both extracts and their effects on mitochondrial function (ATP concentrations, mitochondrial membrane potential, mitochondrial respiration and mitochondrial biogenesis) in PC12 cells. We found that vitamin E contents and the effects of both RBE on mitochondrial function were similar. Furthermore, we aimed to identify components responsible for the mitochondria-protective effects of RBE, but could not achieve a conclusive result. α-Tocotrienol and possibly also γ-tocotrienol, α-tocopherol and δ-tocopherol might be involved, but hitherto unknown components of RBE or a synergistic effect of various components might also play a role in mediating RBE’s beneficial effects on mitochondrial function.
A randomised, double-blind, placebo-controlled trial of trichuris suis ova in active crohn's disease
(2017)
BACKGROUND AND AIMS To investigate the efficacy and safety of three different dosages of embryonated, viable eggs of Trichuris suis [TSO] versus placebo for induction of remission in mildly-to-moderately active ileocolonic, uncomplicated Crohn's disease [CD].
METHODS Adults with active CD [n = 252] randomly received six fortnightly doses of 250, 2500, or 7500 TSO/15 ml suspension/day [TSO 250, TSO 2500, TSO 7500], or 15 ml placebo solution/day, in a double-blind fashion, with 4 weeks' follow-up. Primary endpoint was the rate of clinical remission [Crohn's Disease Activity Index [CDAI] < 150] at end of treatment, ie at Week 12 or withdrawal. Secondary endpoints included the course of clinical remission, rate of clinical response, change in CDAI, change in markers of inflammation, mucosal healing, and Physician's Global Assessment.
RESULTS Clinical remission at Week 12 occurred in 38.5%, 35.2%, and 47.2% of TSO 250, TSO 2500, and TSO 7500 patients, respectively, and in 42.9% of placebo recipients. TSO induced a dose-dependent immunological response. There was no response regarding laboratory markers of inflammation. Other secondary efficacy variables also showed no advantage of TSO over placebo for treatment of active CD. Administration of TSO did not result in any serious adverse drug reaction. Review of non-serious suspected adverse drug reactions following TSO did not reveal any safety concerns.
CONCLUSIONS Administration of 250-7500 TSO fortnightly over 12 weeks was safe and showed a dose-dependent immunological response, but no TSO dose showed a clinically relevant effect over placebo for induction of clinical remission or response in mildly-to-moderately active, ileocolonic CD.
Background & Aims: Acute‐on‐chronic liver failure (ACLF) is characterized by high short‐term mortality and systemic inflammation (SI). Recently, different cardiodynamic states were shown to independently predict outcomes in cirrhosis. The relationship between cardiodynamic states, SI, and portal hypertension and their impact on ACLF development remains unclear. The aim of this study was therefore to evaluate the interplay of cardiodynamic state and SI on fatal ACLF development in cirrhosis.
Results: At inclusion, hemodynamic measures including cardiac index (CI) and hepatic venous pressure gradient of 208 patients were measured. Patients were followed prospectively for fatal ACLF development (primary endpoint). SI was assessed by proinflammatory markers such as interleukins (ILs) 6 and 8 and soluble IL‐33 receptor (sIL‐33R). Patients were divided according to CI (<3.2; 3.2‐4.2; >4.2 L/min/m2) in hypo‐ (n = 84), normo‐ (n = 69) and hyperdynamic group (n = 55). After a median follow‐up of 3 years, the highest risk of fatal ACLF was seen in hyperdynamic (35%) and hypodynamic patients (25%) compared with normodynamic (14%) (P = .011). Hyperdynamic patients showed the highest rate of SI. The detectable level of IL‐6 was an independent predictor of fatal ACLF development.
Conclusions: Cirrhotic patients with hyperdynamic and hypodynamic circulation have a higher risk of fatal ACLF. Therefore, the cardiodynamic state is strongly associated with SI, which is an independent predictor of development of fatal ACLF.
Curcumin, the active constituent of Curcuma longa L. (family Zingiberaceae), has gained increasing interest because of its anti-cancer, anti-inflammatory, anti-diabetic, and anti-rheumatic properties associated with good tolerability and safety up to very high doses of 12 g. Nanoscaled micellar formulations on the base of Tween 80 represent a promising strategy to overcome its low oral bioavailability. We therefore aimed to investigate the uptake and transepithelial transport of native curcumin (CUR) vs. a nanoscaled micellar formulation (Sol-CUR) in a Caco-2 cell model. Sol-CUR afforded a higher flux than CUR (39.23 vs. 4.98 μg min−1 cm−2, respectively). This resulted in a higher Papp value of 2.11 × 10−6 cm/s for Sol-CUR compared to a Papp value of 0.56 × 10−6 cm/s for CUR. Accordingly a nearly 9.5 fold higher amount of curcumin was detected on the basolateral side at the end of the transport experiments after 180 min with Sol-CUR compared to CUR. The determined 3.8-fold improvement in the permeability of curcumin is in agreement with an up to 185-fold increase in the AUC of curcumin observed in humans following the oral administration of the nanoscaled micellar formulation compared to native curcumin. The present study demonstrates that the enhanced oral bioavailability of micellar curcumin formulations is likely a result of enhanced absorption into and increased transport through small intestinal epithelial cells.
Phlotoxin-1 (PhlTx1) is a peptide previously identified in tarantula venom (Phlogius species) that belongs to the inhibitory cysteine-knot (ICK) toxin family. Like many ICK-based spider toxins, the synthesis of PhlTx1 appears particularly challenging, mostly for obtaining appropriate folding and concomitant suitable disulfide bridge formation. Herein, we describe a procedure for the chemical synthesis and the directed sequential disulfide bridge formation of PhlTx1 that allows for a straightforward production of this challenging peptide. We also performed extensive functional testing of PhlTx1 on 31 ion channel types and identified the voltage-gated sodium (Nav) channel Nav1.7 as the main target of this toxin. Moreover, we compared PhlTx1 activity to 10 other spider toxin activities on an automated patch-clamp system with Chinese Hamster Ovary (CHO) cells expressing human Nav1.7. Performing these analyses in reproducible conditions allowed for classification according to the potency of the best natural Nav1.7 peptide blockers. Finally, subsequent in vivo testing revealed that intrathecal injection of PhlTx1 reduces the response of mice to formalin in both the acute pain and inflammation phase without signs of neurotoxicity. PhlTx1 is thus an interesting toxin to investigate Nav1.7 involvement in cellular excitability and pain
Although the 12C(n,p)12B and 12C(n,d)11B reactions are of interest in several fields of basic and applied Nuclear Physics the present knowledge of these two cross-sections is far from being accurate and reliable, with both evaluations and data showing sizable discrepancies. As part of the challenging n_TOF program on (n,cp) nuclear reactions study, the energy differential cross-sections of the 12C(n,p)12B and 12C(n,d)11 B reactions have been measured at CERN from the reaction thresholds up to 30 MeV neutron energy. Both measurements have been recently performed at the long flight-path (185 m) experimental area of the n_TOF facility at CERN using a pure (99.95%) rigid graphite target and two silicon telescopes. In this paper an overview of the experiment is presented together with a few preliminary results.
Reliable identification of chondrules, calcium-aluminum-rich inclusions (CAIs), carbonate grains, and Ca-phosphate grains at depth within untouched, unprepared chondritic samples by a nondestructive analytical method, such as synchrotron X-ray fluorescence (SXRF) computed tomography (CT), is an essential first step before intrusive analytical and sample preparation methods are performed. The detection of a local Ca-enrichment could indicate the presence of such a component, all of which contain Ca as major element and/or Ca-bearing minerals, allowing it to be precisely located at depth within a sample. However, the depth limitation from which Ca-K fluorescence can travel through a chondrite sample (e.g., ∼115 µm through material of 1.5 g cm−3) to XRF detectors leaves many Ca-bearing components undetected at deeper depths. In comparison, Sr-K lines travel much greater distances (∼1700 µm) through the same sample density and are, thus, detected from much greater depths. Here, we demonstrate a clear, positive, and preferential correlation between Ca and Sr and conclude that Sr-detection can be used as proxy for the presence of Ca (and, thus, Ca-bearing components) throughout mm-sized samples of carbonaceous chondritic material. This has valuable implications, especially for sample return missions from carbonaceous C-type asteroids, such as Ryugu or Bennu. Reliable localization, identification, and targeted analysis by SXRF of Ca-bearing chondrules, CAIs, and carbonates at depth within untouched, unprepared samples in the initial stages of a multianalysis investigation insures the valuable information they hold of pre- and post-accretion processes in the early solar system is neither corrupted nor destroyed in subsequent processing and analyses.
Biodiversity continues to decline in the face of increasing anthropogenic pressures such as habitat destruction, exploitation, pollution and introduction of alien species. Existing global databases of species’ threat status or population time series are dominated by charismatic species. The collation of datasets with broad taxonomic and biogeographic extents, and that support computation of a range of biodiversity indicators, is necessary to enable better understanding of historical declines and to project – and avert – future declines. We describe and assess a new database of more than 1.6 million samples from 78 countries representing over 28,000 species, collated from existing spatial comparisons of local-scale biodiversity exposed to different intensities and types of anthropogenic pressures, from terrestrial sites around the world. The database contains measurements taken in 208 (of 814) ecoregions, 13 (of 14) biomes, 25 (of 35) biodiversity hotspots and 16 (of 17) megadiverse countries. The database contains more than 1% of the total number of all species described, and more than 1% of the described species within many taxonomic groups – including flowering plants, gymnosperms, birds, mammals, reptiles, amphibians, beetles, lepidopterans and hymenopterans. The dataset, which is still being added to, is therefore already considerably larger and more representative than those used by previous quantitative models of biodiversity trends and responses. The database is being assembled as part of the PREDICTS project (Projecting Responses of Ecological Diversity In Changing Terrestrial Systems – www.predicts.org.uk). We make site-level summary data available alongside this article. The full database will be publicly available in 2015.
The ongoing pandemic caused by the Betacoronavirus SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus-2) demonstrates the urgent need of coordinated and rapid research towards inhibitors of the COVID-19 lung disease. The covid19-nmr consortium seeks to support drug development by providing publicly accessible NMR data on the viral RNA elements and proteins. The SARS-CoV-2 genome encodes for approximately 30 proteins, among them are the 16 so-called non-structural proteins (Nsps) of the replication/transcription complex. The 217-kDa large Nsp3 spans one polypeptide chain, but comprises multiple independent, yet functionally related domains including the viral papain-like protease. The Nsp3e sub-moiety contains a putative nucleic acid-binding domain (NAB) with so far unknown function and consensus target sequences, which are conceived to be both viral and host RNAs and DNAs, as well as protein-protein interactions. Its NMR-suitable size renders it an attractive object to study, both for understanding the SARS-CoV-2 architecture and drugability besides the classical virus’ proteases. We here report the near-complete NMR backbone chemical shifts of the putative Nsp3e NAB that reveal the secondary structure and compactness of the domain, and provide a basis for NMR-based investigations towards understanding and interfering with RNA- and small-molecule-binding by Nsp3e.
The SARS-CoV-2 genome encodes for approximately 30 proteins. Within the international project COVID19-NMR, we distribute the spectroscopic analysis of the viral proteins and RNA. Here, we report NMR chemical shift assignments for the protein Nsp3b, a domain of Nsp3. The 217-kDa large Nsp3 protein contains multiple structurally independent, yet functionally related domains including the viral papain-like protease and Nsp3b, a macrodomain (MD). In general, the MDs of SARS-CoV and MERS-CoV were suggested to play a key role in viral replication by modulating the immune response of the host. The MDs are structurally conserved. They most likely remove ADP-ribose, a common posttranslational modification, from protein side chains. This de-ADP ribosylating function has potentially evolved to protect the virus from the anti-viral ADP-ribosylation catalyzed by poly-ADP-ribose polymerases (PARPs), which in turn are triggered by pathogen-associated sensing of the host immune system. This renders the SARS-CoV-2 Nsp3b a highly relevant drug target in the viral replication process. We here report the near-complete NMR backbone resonance assignment (1H, 13C, 15N) of the putative Nsp3b MD in its apo form and in complex with ADP-ribose. Furthermore, we derive the secondary structure of Nsp3b in solution. In addition, 15N-relaxation data suggest an ordered, rigid core of the MD structure. These data will provide a basis for NMR investigations targeted at obtaining small-molecule inhibitors interfering with the catalytic activity of Nsp3b.
COMP and TSP-4 interact specifically with the novel GXKGHR motif only found in fibrillar collagens
(2018)
COMP (cartilage oligomeric matrix protein) is a member of the thrombospondin family and forms homopentamers as well as mixed heterooligomers with its closely related family member TSP-4. COMP is long known to bind to collagens and to influence collagen fibril formation. Recent work indicates that already intracellular interaction with collagen is important for collagen secretion. However, the exact binding site of COMP on the collagen triple helix has not been described up to now. In this study we have identified a GXKGHR motif on the collagen II helix to bind to COMP, using a recombinantly expressed collagen II peptide library. This binding sequence is conserved throughout evolution and we demonstrate that TSP-4 binds to the same sequence. The identified binding motif overlaps with the recognition sites of many other collagen-binding partners (e.g. PEDF, Heparin) and also spans the lysine residues, which form collagen cross-links. COMP might thereby protect collagen helices from premature modification and cross-linking. Interestingly, this motif is only found in classical fibrillar collagens, although COMP is known to also bind other types. This might indicate that COMP has a unique interface for fibrillar collagens, thus making it an interesting target for the development of antifibrotic drugs.
Objective: About 2% of all pregnancies are complicated by the implantation of the zygote outside the uterine cavity and termed ectopic pregnancy. Whereas a multitude of guidelines exists and related research is constantly growing, no thorough assessment of the global research architecture has been performed yet. Hence, we aim to assess the associated scientific activities in relation to geographical and chronological developments, existing research networks and socioeconomic parameters.
Design: Retrospective, descriptive study.
Setting: On the basis of the NewQIS platform, scientometric methods were combined with novel visualising techniques such as density-equalising mapping to assess the scientific output on ectopic pregnancy. Using the Web of Science, we identified all related entries from 1900 to 2012.
Results: 8040 publications were analysed. The USA and the UK were dominating the field in regard to overall research activity (2612 and 723 publications), overall citation numbers and country-specific H-Indices (US: 80, UK: 42). Comparison to economic power of the most productive countries demonstrated that Israel invested more resources in ectopic pregnancy-related research than other nations (853.41 ectopic pregnancy-specific publications per 1000 billlion US$ gross domestic product (GDP)), followed by the UK (269.97). Relation to the GDP per capita index revealed 49.3 ectopic pregnancy-specific publications per US$1000 GDP per capita for the USA in contrast to 17.31 for the UK. Semiqualitative indices such as country-specific citation rates ranked Switzerland first (24.7 citations per ectopic pregnancy-specific publication), followed by the Scandinavian countries Finland and Sweden. Low-income countries did not exhibit significant research activities.
Conclusions: This is the first in-depth analysis of global ectopic pregnancy research since 1900. It offers unique insights into the global scientific landscape. Besides the USA and the UK, Scandinavian countries and Switzerland can also be regarded as leading nations with regard to their relative socioeconomic input.
Background: Despite the numerous associations of vitamin D with health and disease, vitamin D deficiency is still common from a global perspective. While basic research, clinical and preventive activities grow constantly in vitamin D research, there is no in-depth analysis of the related global scientific productivity available so far.
Methods: Density equalizing mapping procedures (DEMP) were combined with socioeconomic benchmarks using the NewQIS platform.
Results: A total of 25,992 vitamin D-related research articles were identified between 1900 to 2014 with a significant increase (r2 = .6541) from 1900 to 2014. Authors located in Northern America – especially in the USA – distributed the majority of global vitamin D research, followed by their Western European counterparts. DEMP-analysis illustrates that Africa and South America exhibit only minor scientific productivity. Among high-income group countries, Scandinavian nations such as Denmark or Finland (2147.9 and 1607.7 vitamin D articles per GDP in 1000 billion USD) were highly active with regard to socioeconomic figures.
Conclusion: Networks dedicated to vitamin D research are present around the world. Overall, the Northern American and Western European nations occupy prominent positions. However, South American, African and Asian countries apart from Japan only play a minor role in the global research production related to vitamin D. Since vitamin D deficiency is currently increasing in the Americas, Europe and parts of the Middle East, research in these regions may need to be encouraged.
Background & Aims: In ACLF patients, an adequate risk stratification is essential, especially for liver transplant allocation, since ACLF is associated with high short-term mortality. The CLIF-C ACLF score is the best prognostic model to predict outcome in ACLF patients. While lung failure is generally regarded as signum malum in ICU care, this study aims to evaluate and quantify the role of pulmonary impairment on outcome in ACLF patients.
Methods: In this retrospective study, 498 patients with liver cirrhosis and admission to IMC/ICU were included. ACLF was defined according to EASL-CLIF criteria. Pulmonary impairment was classified into three groups: unimpaired ventilation, need for mechanical ventilation and defined pulmonary failure. These factors were analysed in different cohorts, including a propensity score-matched ACLF cohort.
Results: Mechanical ventilation and pulmonary failure were identified as independent risk factors for increased short-term mortality. In matched ACLF patients, the presence of pulmonary failure showed the highest 28-day mortality (83.7%), whereas mortality rates in ACLF with mechanical ventilation (67.3%) and ACLF without pulmonary impairment (38.8%) were considerably lower (p < .001). Especially in patients with pulmonary impairment, the CLIF-C ACLF score showed poor predictive accuracy. Adjusting the CLIF-C ACLF score for the grade of pulmonary impairment improved the prediction significantly.
Conclusions: This study highlights that not only pulmonary failure but also mechanical ventilation is associated with worse prognosis in ACLF patients. The grade of pulmonary impairment should be considered in the risk assessment in ACLF patients. The new score may be useful in the selection of patients for liver transplantation.
High precision measurement of the radiative capture cross section of 238U at the n_TOF CERN facility
(2017)
The importance of improving the accuracy on the capture cross-section of 238U has been addressed by the Nuclear Energy Agency, since its uncertainty significantly affects the uncertainties of key design parameters for both fast and thermal nuclear reactors. Within the 7th framework programme ANDES of the European Commission three different measurements have been carried out with the aim of providing the 238U(n,γ) cross-section with an accuracy which varies from 1 to 5%, depending on the energy range. Hereby the final results of the measurement performed at the n_TOF CERN facility in a wide energy range from 1 eV to 700 keV will be presented.
The 236U isotope plays an important role in nuclear systems, both for future and currently operating ones. The actual knowledge of the capture reaction of this isotope is satisfactory in the thermal region, but it is considered insufficient for Fast Reactor and ADS applications. For this reason the 236U(n, γ) reaction cross-section has been measured for the first time in the whole energy region from thermal energy up to 1 MeV at the n_TOF facility with two different detection systems: an array of C6D6 detectors, employing the total energy deposited method, and a FX1 total absorption calorimeter (TAC), made of 40 BaF2 crystals. The two n_TOF data sets agree with each other within the statistical uncertainty in the Resolved Resonance Region up to 800 eV, while sizable differences (up to ≃ 20%) are found relative to the current evaluated data libraries. Moreover two new resonances have been found in the n_TOF data. In the Unresolved Resonance Region up to 200 keV, the n_TOF results show a reasonable agreement with previous measurements and evaluated data.
Background: The photon strength functions (PSFs) and nuclear level density (NLD) are key ingredients for calculation of the photon interaction with nuclei, in particular the reaction cross sections. These cross sections are important especially in nuclear astrophysics and in the development of advanced nuclear technologies.
Purpose: The role of the scissors mode in the M1 PSF of (well-deformed) actinides was investigated by several experimental techniques. The analyses of different experiments result in significant differences, especially on the strength of the mode. The shape of the low-energy tail of the giant electric dipole resonance is uncertain as well. In particular, some works proposed a presence of the E1 pygmy resonance just above 7 MeV. Because of these inconsistencies additional information on PSFs in this region is of great interest.
Methods: The γ-ray spectra from neutron-capture reactions on the 234U, 236 U, and 238 U nuclei have been measured with the total absorption calorimeter of the n_TOF facility at CERN. The background-corrected sum-energy and multi-step-cascade spectra were extracted for several isolated s-wave resonances up to about 140 eV.
Results: The experimental spectra were compared to statistical model predictions coming from a large selection of models of photon strength functions and nuclear level density. No combination of PSF and NLD models from literature is able to globally describe our spectra. After extensive search we were able to find model combinations with modified generalized Lorentzian (MGLO) E1 PSF, which match the experimental spectra as well as the total radiative widths.
Conclusions: The constant temperature energy dependence is favored for a NLD. The tail of giant electric dipole resonance is well described by the MGLO model of the E1 PSF with no hint of pygmy resonance. The M1 PSF must contain a very strong, relatively wide, and likely double-resonance scissors mode. The mode is responsible for about a half of the total radiative width of neutron resonances and significantly affects the radiative cross section.
An important experimental program on Nuclear Astrophysics is being carried out at the n_TOF since several years, in order to address the still open issues in stellar and primordial nucleosynthesis. Several neutron capture reactions relevant to s-process nucleosynthesis have been measured so far, some of which on important branching point radioisotopes. Furthermore, the construction of a second experimental area has recently opened the way to challenging measurements of (n, charged particle) reactions on isotopes of short half-life. The Nuclear Astrophysics program of the n_TOF Collaboration is here described, with emphasis on recent results relevant for stellar nucleosynthesis, stellar neutron sources and primordial nucleosynthesis.
The 33S(n,α)30Si cross section measurement, using 10B(n,α) as reference, at the n_TOF Experimental Area 2 (EAR2) facility at CERN is presented. Data from 0.01 eV to 100 keV are provided and, for the first time, the cross section is measured in the range from 0.01 eV to 10 keV. These data may be used for a future evaluation of the cross section because present evaluations exhibit large discrepancies. The 33S(n,α)30Si reaction is of interest in medical physics because of its possible use as a cooperative target to boron in Neutron Capture Therapy (NCT).
The spent fuel of current nuclear reactors contains fissile plutonium isotopes that can be combined with 238U to make mixed oxide (MOX) fuel. In this way the Pu from spent fuel is used in a new reactor cycle, contributing to the long-term sustainability of nuclear energy. The use of MOX fuels in thermal and fast reactors requires accurate capture and fission cross sections. For the particular case of 242Pu, the previous neutron capture cross section measurements were made in the 70's, providing an uncertainty of about 35% in the keV region. In this context, the Nuclear Energy Agency recommends in its “High Priority Request List” and its report WPEC-26 that the capture cross section of 242Pu should be measured with an accuracy of at least 7–12% in the neutron energy range between 500 eV and 500 keV. This work presents a brief description of the measurement performed at n_TOF-EAR1, the data reduction process and the first ToF capture measurement on this isotope in the last 40 years, providing preliminary individual resonance parameters beyond the current energy limits in the evaluations, as well as a preliminary set of average resonance parameters.
The Cosmological Lithium Problem refers to the large discrepancy between the abundance of primordial 7Li predicted by the standard theory of Big Bang Nucleosynthesis and the value inferred from the so-called “Spite plateau” in halo stars. A possible explanation for this longstanding puzzle in Nuclear Astrophysics is related to the incorrect estimation of the destruction rate of 7Be, which is responsible for the production of 95% of primordial Lithium. While charged-particle induced reactions have mostly been ruled out, data on the 7Be(n,α) and 7Be(n,p) reactions are scarce or completely missing, so that a large uncertainty still affects the abundance of 7Li predicted by the standard theory of Big Bang Nucleosynthesis. Both reactions have been measured at the n_TOF facility at CERN, providing for the first time data in a wide neutron energy range.
The CERN n_TOF neutron beam facility is characterized by a very high instantaneous neutron flux, excellent TOF resolution at the 185 m long flight path (EAR-1), low intrinsic background and coverage of a wide range of neutron energies, from thermal to a few GeV. These characteristics provide a unique possibility to perform high-accuracy measurements of neutron-induced reaction cross-sections and angular distributions of interest for fundamental and applied Nuclear Physics. Since 2001, the n_TOF Collaboration has collected a wealth of high quality nuclear data relevant for nuclear astrophysics, nuclear reactor technology, nuclear medicine, etc. The overall efficiency of the experimental program and the range of possible measurements has been expanded with the construction of a second experimental area (EAR-2), located 20 m on the vertical of the n_TOF spallation target. This upgrade, which benefits from a neutron flux 30 times higher than in EAR-1, provides a substantial extension in measurement capabilities, opening the possibility to collect data on neutron cross-section of isotopes with short half-lives or available in very small amounts. This contribution will outline the main characteristics of the n_TOF facility, with special emphasis on the new experimental area. In particular, we will discuss the innovative features of the EAR-2 neutron beam that make possible to perform very challenging measurements on short-lived radioisotopes or sub-mg samples, out of reach up to now at other neutron facilities around the world. Finally, the future perspectives of the facility will be presented.
The neutron capture cross section of several key unstable isotopes acting as branching points in the s-process are crucial for stellar nucleosynthesis studies, but they are very challenging to measure due to the difficult production of sufficient sample material, the high activity of the resulting samples, and the actual (n,γ) measurement, for which high neutron fluxes and effective background rejection capabilities are required. As part of a new program to measure some of these important branching points, radioactive targets of 147Pm and 171Tm have been produced by irradiation of stable isotopes at the ILL high flux reactor. Neutron capture on 146Nd and 170Er at the reactor was followed by beta decay and the resulting matrix was purified via radiochemical separation at PSI. The radioactive targets have been used for time-of-flight measurements at the CERN n_TOF facility using the 19 and 185 m beam lines during 2014 and 2015. The capture cascades were detected using a set of four C6D6 scintillators, allowing to observe the associated neutron capture resonances. The results presented in this work are the first ever determination of the resonance capture cross section of 147Pm and 171Tm. Activation experiments on the same 147Pm and 171Tm targets with a high-intensity 30 keV quasi-Maxwellian flux of neutrons will be performed using the SARAF accelerator and the Liquid-Lithium Target (LiLiT) in order to extract the corresponding Maxwellian Average Cross Section (MACS). The status of these experiments and preliminary results will be presented and discussed as well.
73Ge(n, γ ) cross sections were measured at the neutron time-of-flight facility n_TOF at CERN up to neutron energies of 300 keV, providing for the first time experimental data above 8 keV. Results indicate that the stellar cross section at kT = 30 keV is 1.5 to 1.7 times higher than most theoretical predictions. The new cross sections result in a substantial decrease of 73Ge produced in stars, which would explain the low isotopic abundance of 73Ge in the solar system.
he study of the resonant structures in neutron-nucleus cross-sections, and therefore of the compound-nucleus reaction mechanism, requires spectroscopic measurements to determine with high accuracy the energy of the neutron interacting with the material under study.
To this purpose, the neutron time-of-flight facility n_TOF has been operating since 2001 at CERN. Its characteristics, such as the high intensity instantaneous neutron flux, the wide energy range from thermal to few GeV, and the very good energy resolution, are perfectly suited to perform high-quality measurements of neutron-induced reaction cross sections. The precise and accurate knowledge of these cross sections plays a fundamental role in nuclear technologies, nuclear astrophysics and nuclear physics.
Two different measuring stations are available at the n_TOF facility, called EAR1 and EAR2, with different characteristics of intensity of the neutron flux and energy resolution. These experimental areas, combined with advanced detection systems lead to a great flexibility in performing challenging measurement of high precision and accuracy, and allow the investigation isotopes with very low cross sections, or available only in small quantities, or with very high specific activity.
The characteristics and performances of the two experimental areas of the n_TOF facility will be presented, together with the most important measurements performed to date and their physics case. In addition, the significant upcoming measurements will be introduced.
Neutron-induced reaction cross sections are important for a wide variety of research fields ranging from the study of nuclear level densities, nucleosynthesis to applications of nuclear technology like design, and criticality and safety assessment of existing and future nuclear reactors, radiation dosimetry, medical applications, nuclear waste transmutation, accelerator-driven systems and fuel cycle investigations. Simulations and calculations of nuclear technology applications largely rely on evaluated nuclear data libraries. The evaluations in these libraries are based both on experimental data and theoretical models. CERN’s neutron time-of-flight facility n_TOF has produced a considerable amount of experimental data since it has become fully operational with the start of its scientific measurement programme in 2001. While for a long period a single measurement station (EAR1) located at 185 m from the neutron production target was available, the construction of a second beam line at 20 m (EAR2) in 2014 has substantially increased the measurement capabilities of the facility. An outline of the experimental nuclear data activities at n_TOF will be presented.
The accurate knowledge of the neutron-induced fission cross-sections of actinides and other isotopes involved in the nuclear fuel cycle is essential for the design of advanced nuclear systems, such as Generation-IV nuclear reactors. Such experimental data can also provide the necessary feedback for the adjustment of nuclear model parameters used in the evaluation process, resulting in the further development of nuclear fission models. In the present work, the 240Pu(n,f) cross-section was measured at CERN's n_TOF facility relative to the well-known 235U(n,f) cross section, over a wide range of neutron energies, from meV to almost MeV, using the time-of-flight technique and a set-up based on Micromegas detectors. This measurement was the first experiment to be performed at n_TOF's new experimental area (EAR-2), which offers a significantly higher neutron flux compared to the already existing experimental area (EAR-1). Preliminary results as well as the experimental procedure, including a description of the facility and the data handling and analysis, are presented.
The 14N(n,p)14C reaction is of interest in neutron capture therapy, where nitrogen-related dose is the main component due to low-energy neutrons, and in astrophysics, where 14N acts as a neutron poison in the s-process. Several discrepancies remain between the existing data obtained in partial energy ranges: thermal energy, keV region and resonance region. Purpose: Measuring the 14N(n,p)14C cross section from thermal to the resonance region in a single measurement for the first time, including characterization of the first resonances, and providing calculations of Maxwellian averaged cross sections (MACS). Method: Time-of-flight technique. Experimental Area 2 (EAR-2) of the neutron time-of-flight (n_TOF) facility at CERN. 10B(n,α)7Li and 235U(n,f) reactions as references. Two detection systems running simultaneously, one on-beam and another off-beam. Description of the resonances with the R-matrix code sammy. Results: The cross section has been measured from sub-thermal energy to 800 keV resolving the two first resonances (at 492.7 and 644 keV). A thermal cross-section (1.809±0.045 b) lower than the two most recent measurements by slightly more than one standard deviation, but in line with the ENDF/B-VIII.0 and JEFF-3.3 evaluations has been obtained. A 1/v energy dependence of the cross section has been confirmed up to tens of keV neutron energy. The low energy tail of the first resonance at 492.7 keV is lower than suggested by evaluated values, while the overall resonance strength agrees with evaluations. Conclusions: Our measurement has allowed to determine the 14N(n,p) cross-section over a wide energy range for the first time. We have obtained cross-sections with high accuracy (2.5 %) from sub-thermal energy to 800 keV and used these data to calculate the MACS for kT = 5 to kT = 100 keV.
Background: We analyzed whether co-occurring mutations influence the outcome of systemic therapy in ALK-rearranged non-small-cell lung cancer (NSCLC).
Patients and methods: ALK-rearranged stage IIIB/IV NSCLC patients were analyzed with next-generation sequencing and fluorescence in situ hybridization analyses on a centralized diagnostic platform. Median progression-free survival (PFS) and overall survival (OS) were determined in the total cohort and in treatment-related sub-cohorts. Cox regression analyses were carried out to exclude confounders.
Results: Among 216 patients with ALK-rearranged NSCLC, the frequency of pathogenic TP53 mutations was 23.8%, while other co-occurring mutations were rare events. In ALK/TP53 co-mutated patients, median PFS and OS were significantly lower compared with TP53 wildtype patients [PFS 3.9 months (95% CI: 2.4–5.6) versus 10.3 months (95% CI: 8.6–12.0), P < 0.001; OS 15.0 months (95% CI: 5.0–24.9) versus 50.0 months (95% CI: 22.9–77.1), P = 0.002]. This difference was confirmed in all treatment-related subgroups including chemotherapy only [PFS first-line chemotherapy 2.6 months (95% CI: 1.3–4.1) versus 6.2 months (95% CI: 1.8–10.5), P = 0.021; OS 2.0 months (95% CI: 0.0–4.6) versus 9.0 months (95% CI: 6.1–11.9), P = 0.035], crizotinib plus chemotherapy [PFS crizotinib 5.0 months (95% CI: 2.9–7.2) versus 14.0 months (95% CI: 8.0–20.1), P < 0.001; OS 17.0 months (95% CI: 6.7–27.3) versus not reached, P = 0.049] and crizotinib followed by next-generation ALK-inhibitor [PFS next-generation inhibitor 5.4 months (95% CI: 0.1–10.7) versus 9.9 months (95% CI: 6.4–13.5), P = 0.039; OS 7.0 months versus 50.0 months (95% CI: not reached), P = 0.001).
Conclusions: In ALK-rearranged NSCLC co-occurring TP53 mutations predict an unfavorable outcome of systemic therapy. Our observations encourage future research to understand the underlying molecular mechanisms and to improve treatment outcome of the ALK/TP53 co-mutated subgroup.
Background: Polytrauma and respiratory tract damage after thoracic trauma cause about 25% of mortality among severely injured patients. Thoracic trauma can lead to the development of severe lung complications such as acute respiratory distress syndrome, and is, therefore, of great interest for monitoring in intensive care units (ICU). In recent years, club cell protein (CC)16 with its antioxidant properties has proven to be a potential outcome-related marker. In this study, we evaluated whether CC16 constitutes as a marker of lung damage in a porcine polytrauma model.
Methods: In a 72 h ICU polytrauma pig model (thoracic trauma, tibial fracture, hemorrhagic shock, liver laceration), blood plasma samples (0, 3, 9, 24, 48, 72 h), BAL samples (72 h) and lung tissue (72 h) were collected. The trauma group (PT) was compared to a sham group. CC16 as a possible biomarker for lung injury in this model, and IL-8 concentrations as known indicator for ongoing inflammation during trauma were determined by ELISA. Histological analysis of ZO-1 and determination of total protein content were used to show barrier disruption and edema formation in lung tissue from the trauma group.
Results: Systemic CC16 levels were significantly increased early after polytrauma compared vs. sham. After 72 h, CC16 concentration was significantly increased in lung tissue as well as in BAL in PT vs. sham. Similarly, IL-8 and total protein content in BAL were significantly increased in PT vs. sham. Evaluation of ZO-1 staining showed significantly lower signal intensity for polytrauma.
Conclusion: The data confirm for the first time in a larger animal polytrauma model that lung damage was indicated by systemic and/or local CC16 response. Thus, early plasma and late BAL CC16 levels might be suitable to be used as markers of lung injury in this polytrauma model.
Background: Polytrauma and respiratory tract damage after thoracic trauma cause about 25% of mortality among severely injured patients. Thoracic trauma can lead to the development of severe lung complications such as acute respiratory distress syndrome, and is, therefore, of great interest for monitoring in intensive care units (ICU). In recent years, club cell protein (CC)16 with its antioxidant properties has proven to be a potential outcome-related marker. In this study, we evaluated whether CC16 constitutes as a marker of lung damage in a porcine polytrauma model.
Methods: In a 72 h ICU polytrauma pig model (thoracic trauma, tibial fracture, hemorrhagic shock, liver laceration), blood plasma samples (0, 3, 9, 24, 48, 72 h), BAL samples (72 h) and lung tissue (72 h) were collected. The trauma group (PT) was compared to a sham group. CC16 as a possible biomarker for lung injury in this model, and IL-8 concentrations as known indicator for ongoing inflammation during trauma were determined by ELISA. Histological analysis of ZO-1 and determination of total protein content were used to show barrier disruption and edema formation in lung tissue from the trauma group.
Results: Systemic CC16 levels were significantly increased early after polytrauma compared vs. sham. After 72 h, CC16 concentration was significantly increased in lung tissue as well as in BAL in PT vs. sham. Similarly, IL-8 and total protein content in BAL were significantly increased in PT vs. sham. Evaluation of ZO-1 staining showed significantly lower signal intensity for polytrauma.
Conclusion: The data confirm for the first time in a larger animal polytrauma model that lung damage was indicated by systemic and/or local CC16 response. Thus, early plasma and late BAL CC16 levels might be suitable to be used as markers of lung injury in this polytrauma model.
The neutron capture cross section of 154Gd was measured from 1 eV to 300 keV in the experimental area located 185 m from the CERN n_TOF neutron spallation source, using a metallic sample of gadolinium, enriched to 67% in 154Gd. The capture measurement, performed with four C6D6 scintillation detectors, has been complemented by a transmission measurement performed at the GELINA time-of-flight facility (JRC-Geel), thus minimising the uncertainty related to sample composition. An accurate Maxwellian averaged capture cross section (MACS) was deduced over the temperature range of interest for s process nucleosynthesis modelling. We report a value of 880(50) mb for the MACS at kT = 30 keV, significantly lower compared to values available in literature. The new adopted 154Gd(n,γ) cross section reduces the discrepancy between observed and calculated solar s-only isotopic abundances predicted by s-process nucleosynthesis models.
CXCL12-CXCR4 signaling controls multiple physiological processes and its dysregulation is associated with cancers and inflammatory diseases. To discover as-yet-unknown endogenous ligands of CXCR4, we screened a blood-derived peptide library for inhibitors of CXCR4-tropic HIV-1 strains. This approach identified a 16 amino acid fragment of serum albumin as an effective and highly specific CXCR4 antagonist. The endogenous peptide, termed EPI-X4, is evolutionarily conserved and generated from the highly abundant albumin precursor by pH-regulated proteases. EPI-X4 forms an unusual lasso-like structure and antagonizes CXCL12-induced tumor cell migration, mobilizes stem cells, and suppresses inflammatory responses in mice. Furthermore, the peptide is abundant in the urine of patients with inflammatory kidney diseases and may serve as a biomarker. Our results identify EPI-X4 as a key regulator of CXCR4 signaling and introduce proteolysis of an abundant precursor protein as an alternative concept for chemokine receptor regulation.
i-TED is an innovative detection system which exploits Compton imaging techniques to achieve a superior signal-to-background ratio in (n,γ) cross-section measurements using time-of-flight technique. This work presents the first experimental validation of the i-TED apparatus for high-resolution time-of-flight experiments and demonstrates for the first time the concept proposed for background rejection. To this aim both 197Au(n,γ) and 56Fe(n,γ) reactions were measured at CERN n\_TOF using an i-TED demonstrator based on only three position-sensitive detectors. Two \cds detectors were also used to benchmark the performance of i-TED. The i-TED prototype built for this study shows a factor of ∼3 higher detection sensitivity than state-of-the-art \cds detectors in the ∼10~keV neutron energy range of astrophysical interest. This paper explores also the perspectives of further enhancement in performance attainable with the final i-TED array consisting of twenty position-sensitive detectors and new analysis methodologies based on Machine-Learning techniques.
The idea of slow-neutron capture nucleosynthesis formulated in 1957 triggered a tremendous experimental effort in different laboratories worldwide to measure the relevant nuclear physics input quantities, namely (n,γ) cross sections over the stellar temperature range (from few eV up to several hundred keV) for most of the isotopes involved from Fe up to Bi. A brief historical review focused on total energy detectors will be presented to illustrate how, advances in instrumentation have led, over the years, to the assessment and discovery of many new aspects of s-process nucleosynthesis and to the progressive refinement of theoretical models of stellar evolution. A summary will be presented on current efforts to develop new detection concepts, such as the Total-Energy Detector with γ-ray imaging capability (i-TED). The latter is based on the simultaneous combination of Compton imaging with neutron time-of-flight (TOF) techniques, in order to achieve a superior level of sensitivity and selectivity in the measurement of stellar neutron capture rates.
Fission program at n_TOF
(2019)
Since its start in 2001 the n_TOF collaboration developed a measurement program on fission, in view of advanced fuels in new generation reactors. A special effort was made on measurement of cross sections of actinides, exploiting the peculiarity of the n_TOF neutron beam which spans a huge energy domain, from the thermal region up to GeV. Moreover fission fragment angular distributions have also been measured. An overview of the cross section results achieved with different detectors is presented, including a discussion of the 237Np case where discrepancies showed up between different detector systems. The results on the anisotropy of the fission fragments and its implication on the mechanism of neutron absorption, and in applications, are also shown.
CD4+CD25+ regulatory T cells (Tregs) represent a specialized subpopulation of T cells, which are essential for maintaining peripheral tolerance and preventing autoimmunity. The immunomodulatory effects of Tregs depend on their activation status. Here we show that, in contrast to conventional anti-CD4 monoclonal antibodies (mAbs), the humanized CD4-specific monoclonal antibody tregalizumab (BT-061) is able to selectively activate the suppressive properties of Tregs in vitro. BT-061 activates Tregs by binding to CD4 and activation of signaling downstream pathways. The specific functionality of BT-061 may be explained by the recognition of a unique, conformational epitope on domain 2 of the CD4 molecule that is not recognized by other anti-CD4 mAbs. We found that, due to this special epitope binding, BT-061 induces a unique phosphorylation of T-cell receptor complex-associated signaling molecules. This is sufficient to activate the function of Tregs without activating effector T cells. Furthermore, BT-061 does not induce the release of pro-inflammatory cytokines. These results demonstrate that BT-061 stimulation via the CD4 receptor is able to induce T-cell receptor-independent activation of Tregs. Selective activation of Tregs via CD4 is a promising approach for the treatment of autoimmune diseases where insufficient Treg activity has been described. Clinical investigation of this new approach is currently ongoing.
The neutron capture cross section of some unstable nuclei is especially relevant for s-process nucleosynthesis studies. This magnitude is crucial to determine the local abundance pattern, which can yield valuable information of the s-process stellar environment. In this work we describe the neutron capture (n,γ) measurement on two of these nuclei of interest, 204Tl and 171Tm, from target production to the final measurement, performed successfully at the n_TOF facility at CERN in 2014 and 2015. Preliminary results on the ongoing experimental data analysis will also be shown. These results include the first ever experimental observation of capture resonances for these two nuclei.
The slow neutron capture process (s-process) is responsible for producing about half of the elemental abundances heavier than iron in the universe. Neutron capture cross sections on stable isotopes are a key nuclear physics input for s-process studies. The 72Ge(n, γ) cross section has an important influence on production of isotopes between Ge and Zr during s-process in massive stars and therefore experimental data are urgently required. 72Ge(n, γ) was measured at the neutron time-of-flight facility n_TOF (CERN) for the first time at stellar energies. The measurement was performed using an enriched 72GeO2 sample at a flight path of 185m with a set of liquid scintillation detectors (C6D6). The motivation, experiment and current status of the data analysis are reported.
Treatment‐related complications contribute substantially to morbidity and mortality in acute myeloid leukemia (AML) patients undergoing induction chemotherapy. Although AML patients are susceptible to fluid overload (FO) (e.g., in the context of chemotherapy protocols, during sepsis treatment or to prevent tumor lysis syndrome), little attention has been paid to its role in AML patients undergoing induction chemotherapy. AML patients receiving induction chemotherapy between 2014 and 2019 were included in this study. FO was defined as ≥5% weight gain on day 7 of induction chemotherapy compared to baseline weight determined on the day of admission. We found FO in 23 (12%) of 187 AML patients undergoing induction chemotherapy. Application of >100 ml crystalloid fluids/kg body weight until day 7 of induction chemotherapy was identified as an independent risk factor for FO. AML patients with FO suffered from a significantly increased 90-day mortality rate and FO was demonstrated as an independent risk factor for 90-day mortality. Our data suggests an individualized, weight-adjusted calculation of crystalloid fluids in order to prevent FO-related morbidity and mortality in AML patients during induction chemotherapy. Prospective trials are required to determine the adequate fluid management in this patient population.
Previous studies in developing Xenopus and zebrafish reported that the phosphate transporter slc20a1a is expressed in pronephric kidneys. The recent identification of SLC20A1 as a monoallelic candidate gene for cloacal exstrophy further suggests its involvement in the urinary tract and urorectal development. However, little is known of the functional role of SLC20A1 in urinary tract development. Here, we investigated this using morpholino oligonucleotide knockdown of the zebrafish ortholog slc20a1a. This caused kidney cysts and malformations of the cloaca. Moreover, in morphants we demonstrated dysfunctional voiding and hindgut opening defects mimicking imperforate anus in human cloacal exstrophy. Furthermore, we performed immunohistochemistry of an unaffected 6-week-old human embryo and detected SLC20A1 in the urinary tract and the abdominal midline, structures implicated in the pathogenesis of cloacal exstrophy. Additionally, we resequenced SLC20A1 in 690 individuals with bladder exstrophy-epispadias complex (BEEC) including 84 individuals with cloacal exstrophy. We identified two additional monoallelic de novo variants. One was identified in a case-parent trio with classic bladder exstrophy, and one additional novel de novo variant was detected in an affected mother who transmitted this variant to her affected son. To study the potential cellular impact of SLC20A1 variants, we expressed them in HEK293 cells. Here, phosphate transport was not compromised, suggesting that it is not a disease mechanism. However, there was a tendency for lower levels of cleaved caspase-3, perhaps implicating apoptosis pathways in the disease. Our results suggest SLC20A1 is involved in urinary tract and urorectal development and implicate SLC20A1 as a disease-gene for BEEC.
Qualitätsstandards (QS) sind messbare Konstrukte, die helfen sollen, Versorgungslücken quantitativ zu erfassen, um langfristig die Versorgungsqualität zu verbessern. Die Assessment of SpondyloArthritis International Society (ASAS) hat kürzlich erstmals internationale QS für das Management von Patient*innen mit axialer Spondyloarthritis (axSpA) konsentiert und veröffentlicht. Die Deutsche Gesellschaft für Rheumatologie (DGRh) hat daraufhin beschlossen, diese Standards durch eine Gruppe von Expert*innen aus unterschiedlichen Versorgungsbereichen zu übersetzen, zu prüfen und ggf. zu übernehmen. Vor diesem Hintergrund wurden erstmals nationale QS für das Management von Patient*innen mit axSpA für Deutschland entwickelt. Hierbei wurde v. a. auf Machbarkeit und Praxisrelevanz geachtet. Letztlich wurden 9 QS definiert, mit denen die Qualität der Versorgung in Deutschland gemessen und verbessert werden kann bzw. soll.
Background: Bipolar disorder is associated with circadian disruption and a high risk of suicidal behavior. In a previous exploratory study of patients with bipolar I disorder, we found that a history of suicide attempts was associated with differences between winter and summer levels of solar insolation. The purpose of this study was to confirm this finding using international data from 42% more collection sites and 25% more countries. Methods: Data analyzed were from 71 prior and new collection sites in 40 countries at a wide range of latitudes. The analysis included 4876 patients with bipolar I disorder, 45% more data than previously analyzed. Of the patients, 1496 (30.7%) had a history of suicide attempt. Solar insolation data, the amount of the sun’s electromagnetic energy striking the surface of the earth, was obtained for each onset location (479 locations in 64 countries). Results: This analysis confirmed the results of the exploratory study with the same best model and slightly better statistical significance. There was a significant inverse association between a history of suicide attempts and the ratio of mean winter insolation to mean summer insolation (mean winter insolation/mean summer insolation). This ratio is largest near the equator which has little change in solar insolation over the year, and smallest near the poles where the winter insolation is very small compared to the summer insolation. Other variables in the model associated with an increased risk of suicide attempts were a history of alcohol or substance abuse, female gender, and younger birth cohort. The winter/summer insolation ratio was also replaced with the ratio of minimum mean monthly insolation to the maximum mean monthly insolation to accommodate insolation patterns in the tropics, and nearly identical results were found. All estimated coefficients were significant at p < 0.01. Conclusion: A large change in solar insolation, both between winter and summer and between the minimum and maximum monthly values, may increase the risk of suicide attempts in bipolar I disorder. With frequent circadian rhythm dysfunction and suicidal behavior in bipolar disorder, greater understanding of the optimal roles of daylight and electric lighting in circadian entrainment is needed.
Different treatment options for acetabular fractures in the elderly and nonagenarians exist; a consistent guideline has not been established, yet. The purpose of this study is to give an overview of how those fractures can be handled and compares two different surgical treatment methods.
A total of 89 patients ≥ 18 years between 2016 and 2021 with acetabular fractures in our department received a surgical intervention with plate fixation via the Stoppa approach or a total hip arthroplasty with a Burch–Schneider ring and integrated cup. 60 patients ≥ 65 were compared in two groups, 29 patients between 65 and 79 and 31 patients ≥ 80. For comparison, data on operation times, hospitalization, complications during operation and hospital stay, blood loss and postoperative mobilization were collected.
Characteristics could be found for indications for operative osteosynthesis or endoprosthetics based on the X-ray analysis. There was a tendency to treat simple fractures with osteosynthesis. Patients between 65 and 79 with an osteosynthesis had benefits in almost every comparison. Patients ≥ 80 with a plate fixation had advantages in the categories of postoperative complications, blood loss and transfusion of erythrocyte concentrates. Statistical significant differences were noticed in both groups regarding the operation time. Patients between 65 and 79 with osteosynthesis had significant benefits for postoperative complications, hospitalization, number of blood transfusions and postoperative mobilization.
Finding the best supportive treatment option is difficult, and decision-making must respect fracture patterns and individual risk factors. This study shows that plate fixation via the Stoppa approach has some benefits.
We study a set of German open-end mutual funds for a time period during which this industry emerged from its infancy. In those years, the distribution channel for mutual funds was dominated by the brick-and-mortar retail networks of the large universal banks. Using monthly observations from 12/1986 through 12/1998, we investigate if cross-sectional return differences across mutual funds affect their market shares. Although such a causal relation has been established in highly competitive markets, such as the United States, the rigid distribution system in place in Germany at the time may have caused retail performance and investment performance to uncouple. In fact, although we observe stark differences in investment performance across mutual funds (and over time), we find no evidence that cross-sectional performance differences affect the market shares of these funds. Klassifikation: G 23
Starting from (MeO)3SiCH2Cl (10) and Ph2(H)SiCH2OH (16), respectively, the (hydroxymethyl)diphenyl(piperidinoalkyl)silanes (HOCH2)Ph2Si(CH2)2NC5H10 (6) and (HOCH2)Ph2Si(CH2)3NC5H10 (8) have been synthesized [10→Ph2(MeO)SiCH2Cl (11)→Ph2(CH2=CH)SiCH2Cl (12)→Ph2(CH2=CH)SiCH2OAc (13)→Ph2(CH2=CH)SiCH2OH (14)→Ph2(CH2=CH)SiCH2OSiMe3 (15)→6; 16→Ph2(H)SiCH2OSiMe3 (17)→8; NC5H10 = piperidino]. N-Quaternization of 6 and 8 with MeI gave the corresponding methiodides 7 and 9, respectively. As shown by IR-spectroscopic studies, compounds 6 and 8 form intramolecular O-H···N hydrogen bonds in solution (CCl4). In the crystal, 6 (space group Pna21; two crystallographically independent molecules) also forms intramolecular O-H···N hydrogen bonds whereas 8 (space group P1̅) forms intermolecular O-H···N hydrogen bonds leading to the formation of centrosymmetric dimers (single-crystal X-ray diffraction studies). The (hydroxymethyl) silanes 6-9 and the related silanols (HO)Ph2Si(CH2)2NC5H 10 (sila-pridinol; 1), sila-pridinol methiodide (2), (HO)Ph2Si(CH2)3NC5H10 (sila-difenidol; 3) and sila-difenidol methiodide (4) were investigated for their antimuscarinic properties. In functional pharmacological experiments as well as in radioligand competition studies, all compounds behaved as simple competitive antagonists at muscarinic M1-, M2-, M3- and M4-receptors. In general, the silanols 1-4 displayed higher receptor affinities (up to 100-fold) than the corresponding (hydroxymethyl) silanes 6-9 . In the (hydroxymethyl)silane series, compound 7 was found to be the most potent muscarinic antagonist [pA2/pKi= 8,71/8,6 (M1), 8,23/7,8 (M2), 8,19/7,8 (M3); pKi = 8,2 (M4)]. In the silanol series, the related compound 2 showed the most interesting antimuscarinic properties [pA2/pKi = 10,37/9,6 (M1), 8,97/8,8 (M2), 9,08/8,8 (M3); pKi = 9,4 (M4)].
Background: Although being considered as a rarely observed HIV-1 protease mutation in clinical isolates, the L76V-prevalence increased 1998-2008 in some European countries most likely due to the approval of Lopinavir, Amprenavir and Darunavir which can select L76V. Beside an enhancement of resistance, L76V is also discussed to confer hypersusceptibility to the drugs Atazanavir and Saquinavir which might enable new treatment strategies by trying to take advantage of particular mutations. Results: Based on a cohort of 47 L76V-positive patients, we examined if there might exist a clinical advantage for L76V-positive patients concerning long-term success of PI-containing regimens in patients with limited therapy options. Genotypic- and phenotypic HIV-resistance tests from 47 mostly multi-resistant, L76V-positive patients throughout Germany were accomplished retrospectively 1999-2009. Five genotype-based drug-susceptibility predictions received from online interpretation-tools for Atazanavir, Saquinavir, Amprenavir and Lopinavir, were compared to phenotype-based predictions that were determined by using a recombinant virus assay along with a Virtual Phenotype™(Virco). The clinical outcome of the L76V-adapted follow-up therapy was determined by monitoring viral load for 96 weeks. Conclusions: In this analysis, the mostly used interpretation systems overestimated the L76V-mutation concerning Atazanavir- and SQV resistance. In fact, a clear benefit in drug susceptibility for these drugs was observed in phenotype analysis after establishment of L76V. More importantly, long-term therapy success was significantly higher in patients receiving Atazanavir and/or Saquinavir plus one L76V-selecting drug compared to patients without L76V-selecting agents (p = 0.002). In case of L76V-occurrence ATV and/or SQV may represent encouraging options for patients in deep salvage situations.
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.
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.
Measurement of the 244Cm and 246Cm neutron-induced capture cross sections at the n_TOF facility
(2019)
The neutron capture reactions of the 244Cm and 246Cm isotopes open the path for the formation of heavier Cm isotopes and heavier elements such as Bk and Cf in a nuclear reactor. In addition, both isotopes belong to the minor actinides with a large contribution to the decay heat and to the neutron emission in irradiated fuels. There are only two previous 244Cm and 246Cm capture cross section measurements: one in 1969 using a nuclear explosion [1] and the most recent data measured at J-PARC in 2010 [2]. The data for both isotopes are very scarce due to the difficulties in performing the measurements: high intrinsic activity of the samples and limited facilities capable of providing isotopically enriched samples.
We have measured both neutron capture cross sections at the n_TOF Experimental Area 2 (EAR-2) with three C6 D6 detectors and also at Area 1 (EAR-1) with the TAC. Preliminary results assessing the quality and limitations (back-ground subtraction, measurement technique and counting statistics) of this new experimental datasets are presented and discussed.
Study of the photon strength functions and level density in the gamma decay of the n + 234U reaction
(2019)
The accurate calculations of neutron-induced reaction cross sections are relevant for many nuclear applications. The photon strength functions and nuclear level densities are essential inputs for such calculations. These quantities for 235U are studied using the measurement of the gamma de-excitation cascades in radiative capture on 234U with the Total Absorption Calorimeter at n_TOF at CERN. This segmented 4π gamma calorimeter is designed to detect gamma rays emitted from the nucleus with high efficiency. This experiment provides information on gamma multiplicity and gamma spectra that can be compared with numerical simulations. The code DICEBOXC is used to simulate the gamma cascades while GEANT4 is used for the simulation of the interaction of these gammas with the TAC materials. Available models and their parameters are being tested using the present data. Some preliminary results of this ongoing study are presented and discussed.
233U is of key importance among the fissile nuclei in the Th-U fuel cycle. A particularity of 233U is its small neutron capture cross-section, which is on average about one order of magnitude lower than the fission cross-section. The accuracy in the measurement of the 233U capture cross-section depends crucially on an efficient capture-fission discrimination, thus a combined set-up of fission and γ-detectors is needed. A measurement of the 233U capture cross-section and capture-to-fission ratio was performed at the CERN n_TOF facility. The Total Absorption Calorimeter (TAC) of n_TOF was employed as γ-detector coupled with a novel compact ionization chamber as fission detector. A brief description of the experimental set-up will be given, and essential parts of the analysis procedure as well as the preliminary response of the set-up to capture are presented and discussed.
New neutron cross section measurements of minor actinides have been performed recently in order to reduce the uncertainties in the evaluated data, which is important for the design of advanced nuclear reactors and, in particular, for determining their performance in the transmutation of nuclear waste. We have measured the 241Am(n,γ) cross section at the n_TOF facility between 0.2 eV and 10 keV with a BaF2 Total Absorption Calorimeter, and the analysis of the measurement has been recently concluded. Our results are in reasonable agreement below 20 eV with the ones published by C. Lampoudis et al. in 2013, who reported a 22% larger capture cross section up to 110 eV compared to experimental and evaluated data published before. Our results also indicate that the 241Am(n,γ) cross section is underestimated in the present evaluated libraries between 20 eV and 2 keV by 25%, on average, and up to 35% for certain evaluations and energy ranges.
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.
The accuracy on neutron capture cross section of fissile isotopes must be improved for the design of future nuclear systems such as Gen-IV reactors and Accelerator Driven Systems. The High Priority Request List of the Nuclear Energy Agency, which lists the most important nuclear data requirements, includes also the neutron capture cross sections of fissile isotopes such as 233,235U and 239,241Pu. A specific experimental setup has been used at the CERN n_TOF facility for the measurement of the neutron capture cross section of 235U by a set of micromegas fission detectors placed inside a segmented BaF2 Total Absorption Calorimeter.
The experimental area 2 (EAR-2) at CERNs neutron time-of-flight facility (n_TOF), which is operational since 2014, is designed and built as a short-distance complement to the experimental area 1 (EAR-1). The Parallel Plate Avalanche Counter (PPAC) monitor experiment was performed to characterize the beam pro↓le and the shape of the neutron 'ux at EAR-2. The prompt γ-flash which is used for calibrating the time-of-flight at EAR-1 is not seen by PPAC at EAR-2, shedding light on the physical origin of this γ-flash.
Monte Carlo (MC) simulations are an essential tool to determine fundamental features of a neutron beam, such as the neutron flux or the γ-ray background, that sometimes can not be measured or at least not in every position or energy range. Until recently, the most widely used MC codes in this field had been MCNPX and FLUKA. However, the Geant4 toolkit has also become a competitive code for the transport of neutrons after the development of the native Geant4 format for neutron data libraries, G4NDL. In this context, we present the Geant4 simulations of the neutron spallation target of the n_TOF facility at CERN, done with version 10.1.1 of the toolkit. The first goal was the validation of the intra-nuclear cascade models implemented in the code using, as benchmark, the characteristics of the neutron beam measured at the first experimental area (EAR1), especially the neutron flux and energy distribution, and the time distribution of neutrons of equal kinetic energy, the so-called Resolution Function. The second goal was the development of a Monte Carlo tool aimed to provide useful calculations for both the analysis and planning of the upcoming measurements at the new experimental area (EAR2) of the facility.
Destruction of the cosmic γ-ray emitter 26Al in massive stars: study of the key 26Al(n,p) reaction
(2021)
The 26Al(n,p)26Mg reaction is the key reaction impacting on the abundances of the cosmic γ-ray emitter 26Al produced in massive stars and impacts on the potential pollution of the early solar system with 26Al by asymptotic giant branch stars. We performed a measurement of the 26Al(n,p)26Mg cross section at the high-flux beam line EAR-2 at the n_TOF facility (CERN). We report resonance strengths for eleven resonances, nine being measured for the first time, while there is only one previous measurement for the other two. Our resonance strengths are significantly lower than the only previous values available. Our cross-section data range to 150 keV neutron energy, which is sufficient for a reliable determination of astrophysical reactivities up to 0.5 GK stellar temperature.
The bile acid activated transcription factor farnesoid X receptor (FXR) regulates numerous metabolic processes and is a rising target for the treatment of hepatic and metabolic disorders. FXR agonists have revealed efficacy in treating non-alcoholic steatohepatitis (NASH), diabetes and dyslipidemia. Here we characterize imatinib as first-in-class allosteric FXR modulator and report the development of an optimized descendant that markedly promotes agonist induced FXR activation in a reporter gene assay and FXR target gene expression in HepG2 cells. Differential effects of imatinib on agonist-induced bile salt export protein and small heterodimer partner expression suggest that allosteric FXR modulation could open a new avenue to gene-selective FXR modulators.
Sepsis is a serious clinical condition which can cause life-threatening organ dysfunction, and has limited therapeutic options. The paradigm of limiting excessive inflammation and promoting anti-inflammatory responses is a simplified concept. Yet, the absence of intrinsic anti-inflammatory signaling at the early stage of an infection can lead to an exaggerated activation of immune cells, including monocytes and macrophages. There is emerging evidence that endogenous molecules control those mechanisms. Here we aimed to identify and describe the dynamic changes in monocyte and macrophage subsets and lung damage in CL57BL/6N mice undergoing blunt chest trauma with subsequent cecal ligation and puncture. We showed that early an increase in systemic and activated Ly6C+CD11b+CD45+Ly6G− monocytes was paralleled by their increased emigration into lungs. The ratio of pro-inflammatory Ly6ChighCD11b+CD45+Ly6G− to patrolling Ly6ClowCD11b+CD45+Ly6G− monocytes significantly increased in blood, lungs and bronchoalveolar lavage fluid (BALF) suggesting an early transition to inflammatory phenotypes during early sepsis development. Similar to monocytes, the level of pro-inflammatory Ly6ChighCD45+F4/80+ macrophages increased in lungs and BALF, while tissue repairing Ly6ClowCD45+F4/80+ macrophages declined in BALF. Levels of inflammatory mediators TNF-α and MCP-1 in blood and RAGE in lungs and BALF were elevated, and besides their boosting of inflammation via the recruitment of cells, they may promote monocyte and macrophage polarization, respectively, toward the pro-inflammatory phenotype. Neutralization of uteroglobin increased pro-inflammatory cytokine levels, activation of inflammatory phenotypes and their recruitment to lungs; concurrent with increased pulmonary damage in septic mice. In in vitro experiments, the influence of uteroglobin on monocyte functions including migratory behavior, TGF-β1 expression, cytotoxicity and viability were proven. These results highlight an important role of endogenous uteroglobin as intrinsic anti-inflammatory signal upon sepsis-induced early lung injury, which modules the early monocyte/macrophages driven inflammation.
We present the first measurements of charge-dependent correlations on angular difference variables η1 − η2 (pseudorapidity) and φ1 − φ2 (azimuth) for primary charged hadrons with transverse momentum 0.15 <= pt <= 2 GeV/c and |η| <= 1.3 from Au–Au collisions at √sNN = 130 GeV. We observe correlation structures not predicted by theory but consistent with evolution of hadron emission geometry with increasing centrality from one-dimensional fragmentation of color strings along the beam direction to an at least two-dimensional hadronization geometry along the beam and azimuth directions of a hadron-opaque bulk medium.
The SARS-CoV-2 virus is the cause of the respiratory disease COVID-19. As of today, therapeutic interventions in severe COVID-19 cases are still not available as no effective therapeutics have been developed so far. Despite the ongoing development of a number of effective vaccines, therapeutics to fight the disease once it has been contracted will still be required. Promising targets for the development of antiviral agents against SARS-CoV-2 can be found in the viral RNA genome. The 5′- and 3′-genomic ends of the 30 kb SCoV-2 genome are highly conserved among Betacoronaviruses and contain structured RNA elements involved in the translation and replication of the viral genome. The 40 nucleotides (nt) long highly conserved stem-loop 4 (5_SL4) is located within the 5′-untranslated region (5′-UTR) important for viral replication. 5_SL4 features an extended stem structure disrupted by several pyrimidine mismatches and is capped by a pentaloop. Here, we report extensive 1H, 13C, 15N and 31P resonance assignments of 5_SL4 as the basis for in-depth structural and ligand screening studies by solution NMR spectroscopy.
The stem-loop (SL1) is the 5'-terminal structural element within the single-stranded SARS-CoV-2 RNA genome. It is formed by nucleotides 7–33 and consists of two short helical segments interrupted by an asymmetric internal loop. This architecture is conserved among Betacoronaviruses. SL1 is present in genomic SARS-CoV-2 RNA as well as in all subgenomic mRNA species produced by the virus during replication, thus representing a ubiquitous cis-regulatory RNA with potential functions at all stages of the viral life cycle. We present here the 1H, 13C and 15N chemical shift assignment of the 29 nucleotides-RNA construct 5_SL1, which denotes the native 27mer SL1 stabilized by an additional terminal G-C base-pair.
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.
Background and Objectives: Proteins of the coagulation system contribute to autoimmune inflammation in patients with multiple sclerosis (MS). On blood-brain barrier (BBB) disruption, fibrinogen enters the CNS and is rapidly converted to fibrin, unfolding pleiotropic autoimmune mechanisms. Fibrin accumulation leads to subsequent proteolytic degradation that results in D-dimer generation. The primary objective of this study was to determine intrathecal levels of D-dimer in CSF as a measure of intrathecal coagulation cascade activation and to evaluate its diagnostic utility in patients with MS in contrast to healthy subjects. Key secondary objectives included analysis of CSF D-dimer in differential diagnoses of MS and its relation to routine clinical markers of disease activity.
Methods: Patients admitted for the assessment of suspected MS were prospectively recruited from October 2017 to December 2020. Blood plasma and citrated CSF samples were analyzed using a highly sensitive luminescent oxygen channeling immunoassay. Intrathecal generation of D-dimer was analyzed by adjusting for CSF/serum albumin (Qalb) and CSF/plasma D-dimer quotients (QD-dimer), and corresponding CSF fibrinogen levels were determined. Final diagnoses after full evaluation and clinical data were recorded.
Results: Of 187 patients, 113 patients received a diagnosis of MS or clinically/radiologically isolated syndrome. We found increased intrathecal CSF D-dimer generation levels (QD-dimer/Qalb-index) for patients with relapsing-remitting MS (RRMS; n = 71, median 4.7, interquartile range [IQR] 2.5–8.0) when compared with those for disease controls (n = 22, median 2.6, IQR 2.1–4.8, p = 0.031). Absolute CSF D-dimer values correlated with CSF fibrinogen levels (r = 0.463; p < 0 .001) and CSF leukocytes (r = 0.273; p = 0.003) and were elevated in MS patients with contrast enhancement (CE) compared with MS patients without CE on MRI (n = 48, median 6 ng/mL, and IQR 3–15.25 vs n = 41, median 4 ng/mL, and IQR 2–7; p = 0.026). Exploratory subgroup analyses indicated a correlation of intrathecal inflammatory activity and CSF D-dimer levels.
Discussion: D-dimer in CSF can be reliably determined and correlates with markers of CNS inflammation and CSF fibrinogen levels. Adjusted for BBB dysfunction, CSF D-dimer may allow the identification of intrathecal coagulation cascade activation in patients with MS.
Classification of Evidence: This study provides Class I evidence that CSF D-dimer levels are elevated in patients with RRMS.
No association between Parkinson disease and autoantibodies against NMDA-type glutamate receptors
(2019)
Background: IgG-class autoantibodies to N-Methyl-D-Aspartate (NMDA)-type glutamate receptors define a novel entity of autoimmune encephalitis. Studies examining the prevalence of NMDA IgA/IgM antibodies in patients with Parkinson disease with/without dementia produced conflicting results. We measured NMDA antibodies in a large, well phenotyped sample of Parkinson patients without and with cognitive impairment (n = 296) and controls (n = 295) free of neuropsychiatric disease. Detailed phenotyping and large numbers allowed statistically meaningful correlation of antibody status with diagnostic subgroups as well as quantitative indicators of disease severity and cognitive impairment.
Methods: NMDA antibodies were analysed in the serum of patients and controls using well established validated assays. We used anti-NMDA antibody positivity as the main independent variable and correlated it with disease status and phenotypic characteristics.
Results: The frequency of NMDA IgA/IgM antibodies was lower in Parkinson patients (13%) than in controls (22%) and higher than in previous studies in both groups. NMDA IgA/IgM antibodies were neither significantly associated with diagnostic subclasses of Parkinson disease according to cognitive impairment, nor with quantitative indicators of disease severity and cognitive impairment. A positive NMDA antibody status was positively correlated with age in controls but not in Parkinson patients.
Conclusion: It is unlikely albeit not impossible that NMDA antibodies play a significant role in the pathogenesis or progression of Parkinson disease e.g. to Parkinson disease with dementia, while NMDA IgG antibodies define a separate disease of its own.