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The thrombopoietin receptor agonist eltrombopag was successfully used against human cytomegalovirus (HCMV)-associated thrombocytopenia refractory to immunomodulatory and antiviral drugs. These effects were ascribed to the effects of eltrombopag on megakaryocytes. Here, we tested whether eltrombopag may also exert direct antiviral effects. Therapeutic eltrombopag concentrations inhibited HCMV replication in human fibroblasts and adult mesenchymal stem cells infected with six different virus strains and drug-resistant clinical isolates. Eltrombopag also synergistically increased the anti-HCMV activity of the mainstay drug ganciclovir. Time-of-addition experiments suggested that eltrombopag interfered with HCMV replication after virus entry. Eltrombopag was effective in thrombopoietin receptor-negative cells, and the addition of Fe3+ prevented the anti-HCMV effects, indicating that it inhibits HCMV replication via iron chelation. This may be of particular interest for the treatment of cytopenias after hematopoietic stem cell transplantation, as HCMV reactivation is a major reason for transplantation failure. Since therapeutic eltrombopag concentrations are effective against drug-resistant viruses, and synergistically increase the effects of ganciclovir, eltrombopag is also a drug-repurposing candidate for the treatment of therapy-refractory HCMV diseas.
The thrombopoietin receptor agonist eltrombopag was successfully used against human cytomegalovirus (HCMV)-associated thrombocytopenia refractory to immunomodulatory and antiviral drugs. These effects were ascribed to effects of eltrombopag on megakaryocytes. Here, we tested whether eltrombopag may also exert direct antiviral effects. Therapeutic eltrombopag concentrations inhibited HCMV replication in human fibroblasts and adult mesenchymal stem cells infected with six different virus strains and drug-resistant clinical isolates. Eltrombopag also synergistically increased the anti-HCMV activity of the mainstay drug ganciclovir. Time-of-addition experiments suggested that eltrombopag interferes with HCMV replication after virus entry. Eltrombopag was effective in thrombopoietin receptor-negative cells, and addition of Fe3+ prevented the anti-HCMV effects, indicating that it inhibits HCMV replication via iron chelation. This may be of particular interest for the treatment of cytopenias after haematopoietic stem cell transplantation, as HCMV reactivation is a major reason for transplantation failure. Since therapeutic eltrombopag concentrations are effective against drug-resistant viruses and synergistically increase the effects of ganciclovir, eltrombopag is also a drug repurposing candidate for the treatment of therapy-refractory HCMV disease.
The three-dimensional quantification of small-scale processes in the upper troposphere and lower stratosphere is one of the challenges of current atmospheric research and requires the development of new measurement strategies. This work presents the first results from the newly developed Gimballed Limb Observer for Radiance Imaging of the Atmosphere (GLORIA) obtained during the ESSenCe (ESa Sounder Campaign) and TACTS/ESMVal (TACTS: Transport and composition in the upper troposphere/lowermost stratosphere, ESMVal: Earth System Model Validation) aircraft campaigns. The focus of this work is on the so-called dynamics-mode data characterized by a medium-spectral and a very-high-spatial resolution. The retrieval strategy for the derivation of two- and three-dimensional constituent fields in the upper troposphere and lower stratosphere is presented. Uncertainties of the main retrieval targets (temperature, O3, HNO3, and CFC-12) and their spatial resolution are discussed. During ESSenCe, high-resolution two-dimensional cross-sections have been obtained. Comparisons to collocated remote-sensing and in situ data indicate a good agreement between the data sets. During TACTS/ESMVal, a tomographic flight pattern to sense an intrusion of stratospheric air deep into the troposphere was performed. It was possible to reconstruct this filament at an unprecedented spatial resolution of better than 500 m vertically and 20 × 20 km horizontally.
The three-dimensional quantification of small scale processes in the upper troposphere and lower stratosphere is one of the challenges of current atmospheric research and requires the development of new measurement strategies. This work presents first results from the newly developed Gimballed Limb Observer for Radiance Imaging of the Atmosphere (GLORIA) obtained during the ESSenCe and TACTS/ESMVal aircraft campaigns. The focus of this work is on the so-called dynamics mode data characterized by a medium spectral and a very high spatial resolution. The retrieval strategy for the derivation of two- and three-dimensional constituent fields in the upper troposphere and lower stratosphere is presented. Uncertainties of the main retrieval targets (temperature, O3, HNO3 and CFC-12) and their spatial resolution are discussed. During ESSenCe, high resolution two-dimensional cross-sections have been obtained. Comparisons to collocated remote-sensing and in-situ data indicate a good agreement between the data sets. During TACTS/ESMVal a tomographic flight pattern to sense an intrusion of stratospheric air deep into the troposphere has been performed. This filament could be reconstructed with an unprecedented spatial resolution of better than 500 m vertically and 20 km × 20 km horizontally.
Background and Aims: Prothrombin induced by vitamin K absence-II (PIVKA-II) is a serum biomarker linked to hepatocellular carcinoma (HCC), showing superiority to alpha-fetoprotein (AFP) for early disease detection. We aimed to assess the clinical and analytical performance of the Elecsys® PIVKA-II immunoassay in diagnosing HCC and evaluate PIVKA-II's technical performance.
Methods: Serum samples from adult cases (i.e. patients with a first-time HCC diagnosis; n = 168) and disease controls (i.e. patients without HCC with an at-risk condition; n = 208) were assessed. An AFP cut-off of 20 ng/mL was used to differentiate between HCC cases and disease controls. Clinical performance of the Elecsys PIVKA-II assay was compared with that of comparator assays (Lumipulse G PIVKA-II, μTASWako DCP, ARCHITECT PIVKA-II) using receiver operating characteristic curve analysis to determine the area under the curve (AUC) values.
Results: The Elecsys PIVKA-II assay compared favorably with comparator assays. Using a 28.4 ng/mL cut-off, the Elecsys PIVKA-II assay detected HCC with 86.9% sensitivity and 83.7% specificity. Clinical performance of the Elecsys PIVKA-II assay (AUC: 90.8%) was equivalent to that of comparator assays (AUC: 88.3–89.6%). Relatively high PIVKA-II concentrations were observed for cholangiocarcinoma and pancreatic cancer with the Elecsys assay in specificity panel analyses, indicating that high PIVKA-II concentrations should not be used alone in the absence of other clinical data.
Conclusions: The Elecsys PIVKA-II assay showed good analytical performance under routine laboratory conditions, comparing favorably with comparator assays. These findings support the suitability of the Elecsys PIVKA-II assay as an aid in HCC diagnosis.
Non-standard errors
(2021)
In statistics, samples are drawn from a population in a data-generating process (DGP). Standard errors measure the uncertainty in sample estimates of population parameters. In science, evidence is generated to test hypotheses in an evidence-generating process (EGP). We claim that EGP variation across researchers adds uncertainty: non-standard errors. To study them, we let 164 teams test six hypotheses on the same sample. We find that non-standard errors are sizeable, on par with standard errors. Their size (i) co-varies only weakly with team merits, reproducibility, or peer rating, (ii) declines significantly after peer-feedback, and (iii) is underestimated by participants.
Chlorine monoxide (ClO) plays a key role in stratospheric ozone loss processes at midlatitudes. We present two balloonborne in situ measurements of ClO conducted in northern hemisphere midlatitudes during the period of the maximum of total inorganic chlorine loading in the atmosphere. Both ClO measurements were conducted on board the TRIPLE balloon payload, launched in November 1996 in Le´on, Spain, and in May 1999 in Aire sur l’Adour, France. For both flights a ClO daylight and night time vertical profile could be derived over an altitude range of approximately 15–31 km. ClO mixing ratios are compared to model simulations performed with the photochemical box model version of the Chemical Lagrangian Model of the Stratosphere (CLaMS). Simulations along 24-h backward trajectories were performed to study the diurnal variation of ClO in the midlatitude lower stratosphere. Model simulations for the flight launched in Aire sur l’Adour 1999 show a good agreement with the ClO measurements. For the flight launched in Le´on 1996, a similar good agreement is found, except at around ~ 650 K potential temperature (~26km altitude). However, a tendency is found that for solar zenith angles greater than 86°–87° the simulated ClO mixing ratios substantially overestimate measured ClO by approximately a factor of 2.5 or more for both flights. Therefore we conclude that no indication can be deduced from the presented ClO measurements that substantial uncertainties exist in midlatitude chlorine chemistry of the stratosphere. An exception is the situation at solar zenith angles greater than 86°–87° where model simulations substantial overestimate ClO observations.
Chlorine monoxide (ClO) plays a key role in stratospheric ozone loss processes at midlatitudes. We present two balloon-borne in situ measurements of ClO conducted in northern hemisphere midlatitudes during the period of the maximum of total inorganic chlorine loading in the atmosphere. Both ClO measurements were conducted on board the TRIPLE balloon payload, launched in November 1996 in León, Spain, and in May 1999 in Aire sur l'Adour, France. For both flights a ClO daylight and night-time vertical profile was derived over an altitude range of approximately 15-35 km. ClO mixing ratios are compared to model simulations performed with the photochemical box model version of the Chemical Lagrangian Model of the Stratosphere (CLaMS). Simulations along 24-hour backward trajectories were performed to study the diurnal variation of ClO in the midlatitude lower stratosphere. Model simulations for the flight launched in Aire sur l'Adour 1999 show an excellent agreement with the ClO measurements. For the flight launched in León 1996, an overall good agreement is found, whereas the flight is characterized by a more complex dynamical situation due to a possible mixture of vortex and non-vortex air. We note that for both flights at solar zenith angles greater than 86°-87° simulated ClO mixing ratios are higher than observed ClO mixing ratios. However, the present findings indicate that no substantial uncertainties exist in midlatitude chlorine chemistry of the stratosphere.
Large-scale genetic census of an elusive carnivore, the European wildcat (Felis s. silvestris)
(2016)
The European wildcat, Felis silvestris silvestris, serves as a prominent target species for the reconnection of central European forest habitats. Monitoring of this species, however, appears difficult due to its elusive behaviour and the ease of confusion with domestic cats. Recently, evidence for multiple wildcat occurrences outside its known distribution has accumulated in several areas across Central Europe, questioning the validity of available distribution data for this species. Our aim was to assess the fine-scale distribution and genetic status of the wildcat in its central European distribution range. We compiled and analysed genetic samples from roadkills and hundreds of recent hair-trapping surveys and applied phylogenetic and genetic clustering methods to discriminate wild and domestic cats and identify population subdivision. 2220 individuals were confirmed as either wildcat (n = 1792) or domestic cat (n = 342), and the remaining 86 (3.9 %) were identified as hybrids between the two. Remarkably, genetic distinction of domestic cats, wildcats and their hybrids was only possible when taking into account the presence of two highly distinct genetic lineages of wildcats, with a suture zone in central Germany. 44 % of the individual wildcats where sampled outside the previously published distribution. Our analyses confirm a relatively continuous spatial presence of wildcats across large parts of the study area in contrast to previous analyses indicating a highly fragmented distribution. Our results suggest that wildcat conservation and management should take advantage of the higher than previously assumed dispersal potential of wildcats, which may use wildlife corridors very efficiently.
The tetracycline-binding RNA aptamer (TC-aptamer) is a synthetic riboswitch that binds the antibiotic tetracycline (TC) with exceptionally high affinity. Although a crystal structure exists of the TC-bound state, little is known about the conformational dynamics and changes upon ligand binding. In this study, pulsed electron paramagnetic resonance techniques for measuring distances (PELDOR) in combination with rigid nitroxide spin labels (Çm spin label) were used to investigate the conformational flexibility of the TC-aptamer in the presence and absence of TC at different Mg2+ concentrations. TC was found to be the essential factor for stabilizing the tertiary structure at intermediate Mg2+ concentrations. At higher Mg2+ concentrations, Mg2+ alone is sufficient to stabilize the tertiary structure. In addition, the orientation of the two spin-labeled RNA helices with respect to each other was analyzed with orientation-selective PELDOR and compared to the crystal structure. These results demonstrate for the first time the unique value of the Çm spin label in combination with PELDOR to provide information about conformational flexibilities and orientations of secondary structure elements of biologically relevant RNAs.