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Interleukin-1 receptor-associated kinase 4 (IRAK4) plays a critical role in innate inflammatory processes. Here, we describe the discovery of two clinical candidate IRAK4 inhibitors, BAY1834845(zabedosertib) and BAY1830839, starting from a high-throughput screening hit derived from Bayer’s compound library. By exploiting binding site features distinct to IRAK4 using an in-house docking model, liabilities of the original hit could surprisingly be overcome to confer both candidates with a unique combination of good potency and selectivity. Favorable DMPK profiles and activity in animal inflammation models led to the selection of these two compounds for clinical development in patients.

The influence of the microstructure on the ionic conductivity and cell performance is a topic of broad scientific interest in solid-state batteries. The current understanding is that interfacial decomposition reactions during cycling induce local strain at the interfaces between solid electrolytes and the anode/cathode, as well as within the electrode composites. Characterizing the effects of internal strain on ion transport is particularly important, given the significant local chemomechanical effects caused by volumetric changes of the active materials during cycling. Here, we show the effects of internal strain on the bulk ionic transport of the argyrodite Li6PS5Br. Internal strain is reproducibly induced by applying pressures with values up to 10 GPa. An internal permanent strain is observed in the material, indicating long-range strain fields typical for dislocations. With increasing dislocation densities, an increase in the lithium ionic conductivity can be observed that extends into improved ionic transport in solid-state battery electrode composites. This work shows the potential of strain engineering as an additional approach for tuning ion conductors without changing the composition of the material itself.

A group of unsteady flow phenomena in turbomachinery is often referred to as “rotating instabilities.” They occur at flow conditions with very asymmetric velocity profiles, as found downstream of blade rows in axial compressors with large rotor tip clearance in stable operating points close to compressor stall or off-design operating points in steam turbines. In the present work, it is shown that such instabilities do not depend on the blading but also occur in blading-free flow channels. The theoretical proof is carried out with the tools and computational programs of spatial stability theory and Reynolds number dependent jumps in the transverse wavelengths at characteristic perturbation frequencies of the present asymmetric turbulent channel flow are discovered. Experimental investigations in a straight flow channel confirm the calculated frequency field and other characteristics of the perturbations. In agreement to theoretical results, a very asymmetric velocity profile across the channel height was found to trigger disturbances within a limited range of frequencies and not bound to the existence of blading. The notion of rotating instability is misleading in the characterization of this disturbance.

Civil society has played an important role in meeting the challenges of refugee migration in recent years. This commentary documents the importance of civic engagement for the integration of refugees by linking individual survey data on refugees to a regional measure of civic engagement in Germany. Using the density of newly established civic associations at the county level as a measure of civic engagement, we exploit regional differences in civic engagement in order to estimate its association with refugee integration outcomes. We find that in regions with particularly high levels of civic engagement, refugees have significantly more frequent contact to Germans, higher life satisfaction, and better German language skills. This correlation is robust to regional contextual factors such as the local population structure, economic strength, and the state of the labor market. In terms of language acquisition, women and refugees with a low level of education benefit the most from high civic engagement. Moreover, refugees with university degrees find significantly better-paying jobs in areas with higher civic engagement. However, no direct correlation could be established between civic engagement and the likelihood that refugees are employed. Nonetheless, the results suggest that support from civil society translates into improved access to government benefits. Our findings highlight that local civic engagement is an important complement to public assistance services and policy makers should give a high priority to partnering with the civil society to improve refugees’ integration outcomes.

Copanlisib is a pan–class I phosphoinositide 3-kinase (PI3K) inhibitor with preferred activity toward PI3Kα and PI3Kδ. Despite the clear overall clinical benefit, the number of patients achieving complete remissions with the single agent is relatively low, a problem shared by the vast majority of targeted agents. Here, we searched for novel copanlisib-based combinations. Copanlisib was tested as a single agent, in combination with an additional 17 drugs in 26 cell lines derived from mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), and T-cell lymphomas. In vivo experiments, transcriptome analyses, and immunoblotting experiments were also performed. Copanlisib as a single agent showed in vitro dose-dependent antitumor activity in the vast majority of the models. Combination screening identified several compounds that synergized with copanlisib. The strongest combination was with the B-cell lymphoma 2 (BCL2) inhibitor venetoclax. The benefit of the combination over single agents was also validated in an MZL xenograft model and in MCL primary cells, and was due to increased induction of apoptosis, an effect likely sustained by the reduction of the antiapoptotic proteins myeloid cell leukemia 1 (MCL1) and BCL-XL, observed in MCL and MZL cell lines, respectively. These data supported the rationale for the design of the Swiss Group for Clinical Cancer Research (SAKK) 66/18 phase 1 study currently exploring the combination of copanlisib and venetoclax in relapsed/refractory lymphomas.

This study analyses the selection of a sample of 203 young male asylum seekers from Middle Eastern and African countries that recently arrived in Germany. The findings suggest that, on average, asylum seekers in our sample have 22% more years of schooling—the indicator used for human capital—when compared to same-aged males from their country of origin. In addition, the analysis suggests that asylum seekers in the sample often accumulated rather low or relatively high levels of schooling compared to same-aged males in their countries of origin. This phenomenon is even more pronounced for parental education. It is demonstrated that individual human capital influences short-run integration outcomes in Germany. The paper discusses potential economic explanations for the findings on immigrant selection and integration outcomes.

Rotating instability (RI) can be regarded as a pre-stall signal because such phenomena are usually detected when a compressor operates at a near-stall point. Since RI is closely relevant to aerodynamic, acoustic, and structural issues, its mechanism has attracted industrial concerns and in-depth analysis. In this paper, a low-speed axial single compressor rotor row is selected as the baseline research object. A circumferential casing groove is mounted over the shroud. The solid casing and the casing treated configurations were simulated using the zonal large eddy simulation model, and the simulations present remarkable predictions in capturing the averaged and dynamic characteristics of the investigated compressor. By implementing a data-driven method called dynamic mode decomposition, the mode with the highest amplitude is proved to be correlated to the dominant RI frequency. The spatial and temporal property of the RI is visualized. The results show that the casing groove has limited influence on the averaged flow field but manipulates the dynamic features. The groove allows the RIs to shift from around 0.5 blade passing frequency to higher frequencies in the upstream region and effectively suppresses the unsteadiness in the zones under and downstream of the groove. The RIs are triggered by the flow interaction of the tip leakage flow at the front part of the blade. It can be depicted as pressure waves staggering with the rotor blade and propagating over the blade tip region at around half of the blade speed. With the existence of the casing groove, the dominant wavelength changes, and the fluctuation is damped under the groove, which finally modifies the properties of RIs.

The 1st Snow Data Assimilation Workshop, organized under the COST Action ESSEM 1404 HarmoSnow, took place in Offenbach, Germany, on 8-9 March 2017. Of particular relevance for the workshop were thematic sessions on i) data assimilation methods and the use of snow observations, ii) snow observations and evaluation, iii) snow observations and physical snow models, and iv) snow observations and hydrological models. This report summarizes the scientific contributions presented at the workshop. The discussions mainly focused on methods for combining satellite observations with conventional in-situ snow measurements and modeling results, as well as on errors in the spatial and temporal representation of snow measurements for data assimilation in NWP and hydrological models. It has been shown that the assimilation of in-situ and satellite-based snow observations improves the quality of the snow analysis and forecast. However, in order to achieve this positive impact, a thorough quality control of the observational data is necessary, in particular because of the automation of the ground-based networks. [ABSTRACT FROM AUTHOR]

Colon cancer is a heterogeneous tumor driven by a subpopulation of cancer stem cells (CSCs). To study CSCs in colon cancer, we used limiting dilution spheroid and serial xenotransplantation assays to functionally define the frequency of CSCs in a panel of patient-derived cancer organoids. These studies demonstrated cancer organoids to be enriched for CSCs, which varied in frequency between tumors. Whole-transcriptome analysis identified WNT and Hedgehog signaling components to be enhanced in CSC-enriched tumors and in aldehyde dehydrogenase (ALDH)-positive CSCs. Canonical GLI-dependent Hedgehog signaling is a negative regulator of WNT signaling in normal intestine and intestinal tumors. Here, we show that Hedgehog signaling in colon CSCs is autocrine SHH-dependent, non-canonical PTCH1 dependent, and GLI independent. In addition, using small-molecule inhibitors and RNAi against SHH-palmitoylating Hedgehog acyltransferase (HHAT), we demonstrate that non-canonical Hedgehog signaling is a positive regulator of WNT signaling and required for colon CSC survival.

This study analyses data collected among a group of young male refugees who participated in a randomised experiment. Refugees were randomly assigned to a soccer project aimed at facilitating social and labour market integration or to a control group. We evaluate the randomisation process, discuss the design and implementation of the survey and summarize the main findings of the survey by focusing on labour market activity, pre-migration characteristics, and the monetary costs of the escape. In addition, we provide a preliminary outlook on the effectiveness of the programme.

Angiogenic sprouting needs to be tightly controlled. It has been suggested that the Notch ligand dll4 expressed in leading tip cells restricts angiogenesis by activating Notch signalling in trailing stalk cells. Here, we show using live imaging in zebrafish that activation of Notch signalling is rather required in tip cells. Notch activation initially triggers expression of the chemokine receptor cxcr4a. This allows for proper tip cell migration and connection to the pre-existing arterial circulation, ultimately establishing functional arterial–venous blood flow patterns. Subsequently, Notch signalling reduces cxcr4a expression, thereby preventing excessive blood vessel growth. Finally, we find that Notch signalling is dispensable for limiting blood vessel growth during venous plexus formation that does not generate arteries. Together, these findings link the role of Notch signalling in limiting angiogenesis to its role during artery formation and provide a framework for our understanding of the mechanisms underlying blood vessel network expansion and maturation.

The application of patient-derived three-dimensional culture systems as disease-specific drug sensitivity models has enormous potential to connect compound screening and clinical trials. However, the implementation of complex cell-based assay systems in drug discovery requires reliable and robust screening platforms. Here we describe the establishment of an automated platform in 384-well format for three-dimensional organoid cultures derived from colon cancer patients. Single cells were embedded in an extracellular matrix by an automated workflow and subsequently self-organized into organoid structures within 4 days of culture before being exposed to compound treatment. We performed validation of assay robustness and reproducibility via plate uniformity and replicate-experiment studies. After assay optimization, the patient-derived organoid platform passed all relevant validation criteria. In addition, we introduced a streamlined plate uniformity study to evaluate patient-derived colon cancer samples from different donors. Our results demonstrate the feasibility of using patient-derived tumor samples for high-throughput assays and their integration as disease-specific models in drug discovery.

Background: The cattle sector is the most important economic production unit of the Irish farming and agri-food sector. Despite its relevance, there has been limited quantitative information about the structure of differing cattle production types and of the connections between them. This paper addresses this gap by providing, for the first time, an overview of the Irish cattle population structured by enterprise type. Methods & Results: We collected data from the cattle register for the period 2015 to 2019 and assigned registered herds to one of 18 different herd types using a recently published herd type classification approach. This allows, for the first time, to exploring changes in enterprise types and subtypes over time, and describing the movements between these subtypes and from these subtypes to slaughter. Conclusions: The overview and associated classification presented in this study will form the basis for a number of future comparative studies, including cross-sectoral assessments of profitability, estimation of the extent of animal health losses on Irish cattle farms or structural analysis of Greenhouse Gas (GHG) emissions across production systems.

In turbomachines, rotors and stators differ by the rotation of the former. Hence, half of each stage is directly influenced by rotation effects. The influence of rotation on the flow structure and its impact on the performance is studied through wall-resolving large Eddy simulations of a rotor with large relative tip gap size. The simulations are performed in a rotating frame with rotation accounted for through a Coriolis force term. In a first step, experimental results are used to provide validation. The main part of the study is the comparison of the results from two simulations, one representing the rotating configuration and one with the Coriolis force removed, without any other change. This setup allows a very clean assessment of the influence of rotation. The turbulence-resolving approach ensures that the turbulent flow features are well represented. The results show a significant impact of rotation on the secondary flow. In the tip region, the tip leakage vortex is enlarged and destabilized. Inside the tip gap, the flow is altered as well, with uniformization in the rotating case. At the blade midspan, no significant effects are observed on the suction side, while an earlier transition to turbulence is found on the pressure side. Near the hub, rotation effects are shown to reduce the corner separation significantly.

Objective To evaluate the safety profile of blood sugar limits in intensive care unit (ICU) patients.Methods Adult patients with ICU stay >36 h, more than two blood sugar measurements and antibiotic therapy concordant with locally adapted guidelines were included. For analyses, one study cohort was defined in two ways: as a narrow group, euglycaemic patients’ blood sugar levels 80–150 mg/dl; as a moderate group, euglycaemic patients’ blood sugar levels 80–180 mg/dl. Dysglycaemia was defined as blood sugar levels <80 mg/dl for >5% of measurements, and >150 mg/dl or >180 mg/dl (narrow or moderate groups, respectively) for >10% of measurements. The primary endpoint was ICU mortality (euglycaemia versus dysglycaemia).Results The study comprised 668 patients. When defined as a narrow group, ICU mortality was 3% (four of 135) euglycaemic versus 10% (54/533) dysglycaemic patients (odds ratio [OR] 3.692, 95% confidence interval [CI] 1.313, 10.382). When defined as a moderate group, ICU mortality was 6% (21/351) euglycaemic versus 12% (37/317) dysglycaemic patients (OR 2.077, 95% CI 1.188, 3.630). Frequency of severe hypoglycaemia (blood sugar <40 mg/dl) was not different between the narrow and moderate euglycaemic ranges.Conclusions Euglycaemia was associated with lower ICU mortality than dysglycaemia, and incidence of hypoglycaemia was low overall in this study. Based on current published evidence, therapeutic targets should be defined according to individual patient characteristics.

Coastal communities around the world face an increasing risk from flooding as a result of rising sea level, increasing storminess and land subsidence. Salt marshes can act as natural buffer zones, providing protection from waves during storms. However, the effectiveness of marshes in protecting the coastline during extreme events when water levels are at a maximum and waves are highest is poorly understood. Here we experimentally assess wave dissipation under storm surge conditions in a 300-metre-long wave flume tank that contains a transplanted section of natural salt marsh. We find that the presence of marsh vegetation causes considerable wave attenuation, even when water levels and waves are highest. From a comparison with experiments without vegetation, we estimate that up to 60% of observed wave reduction is attributed to vegetation. We also find that although waves progressively flatten and break vegetation stems and thereby reduce dissipation, the marsh substrate remained stable and resistant to surface erosion under all conditions. The effectiveness of storm wave dissipation and the resilience of tidal marshes even at extreme conditions suggest that salt marsh ecosystems can be a valuable component of coastal protection schemes.

Despite recent advances in medical procedures, cardiovascular disease remains a clinical challenge and the leading cause of mortality in the western world. The condition causes progressive smooth muscle cell (SMC) dedifferentiation, proliferation, and migration that contribute to vascular restenosis. The incidence of disease of the internal mammary artery (IMA), however, is much lower than in nearly all other arteries. The etiology of this IMA disease resistance is not well understood. Here, using paired primary IMA and coronary artery SMCs, serum stimulation, siRNA knockdowns, and verifications in porcine vessels in vivo, we investigate the molecular mechanisms that could account for this increased disease resistance of internal mammary SMCs. We show that the residue-specific phosphorylation profile of the retinoblastoma tumor suppressor protein (Rb) appears to differ significantly between IMA and coronary artery SMCs in cultured human cells. We also report that the differential profile of Rb phosphorylation may follow as a consequence of differences in the content of cyclin-dependent kinase 2 (CDK2) and the CDK4 phosphorylation inhibitor p15. Finally, we present evidence that siRNA-mediated CDK2 knockdown alters the profile of Rb phosphorylation in coronary artery SMCs, as well as the proliferative response of these cells to mitogenic stimulation. The intrinsic functional and protein composition specificity of the SMCs population in the coronary artery may contribute to the increased prevalence of restenosis and atherosclerosis in the coronary arteries as compared with the internal mammary arteries.

The modal -calculus extends basic modal logic with second-order quantification in terms of arbitrarily nested fixpoint operators. Its satisfiability problem is EXPTIME-complete. Decision procedures for the modal -calculus are not easy to obtain though since the arbitrary nesting of fixpoint constructs requires some combinatorial arguments for showing the well-foundedness of least fixpoint unfoldings. The tableau-based decision procedures so far also make assumptions on the unfoldings of fixpoint formulas, e.g., explicitly require formulas to be in guarded normal form. In this paper we present a tableau calculus for deciding satisfiability of arbitrary, i.e., not necessarily guarded -calculus formulas. It is based on a new unfolding rule for greatest fixpoint formulas which allows unguarded formulas to be handled without an explicit transformation into guarded form, thus avoiding a (seemingly) exponential blow-up in formula size. We prove soundness and completeness of the calculus, and compare it empirically to using guarded transformation instead. The new unfolding rule can also be used to handle nested star operators in PDL formulas correctly.

Atherosclerosis is a chronic disease of the arteries and accounts for about 50 percent of all deaths in industrialized countries. For its treatment, patients primarily need to undergo lifestyle changes, concerning their diet or sportive behavior, while additional pharmaceutical approaches help to reduce major risk factors such as hypertension and hyperlipidemia. However, these two areas of treatment are only briefly mentioned here. Instead, this article focuses on literature and patents from the last decade focusing on invasive surgical procedures necessary for treatment of diseased blood vessels in severe cases of atherosclerosis. Described herein are synthetic grafts and so-called autografts, which are harvested from the patient for bypass surgery. In addition, implantable stents are discussed, which deal with different atherosclerotic aspects, such as restenosis, re-endothelialization, neointimal hyperplasia and thrombosis. And finally, publications and inventions are presented from the relatively new field of artificial tissue engineering incorporating stem cells or biomaterials to construct new vessels as substitutes for diseased veins and arteries.

This paper analyses the complexity of model checking fixpoint logic with Chop – an extension of the modal μ-calculus with a sequential composition operator. It uses two known game-based characterisations to derive the following results: the combined model checking complexity as well as the data complexity of FLC are EXPTIME-complete. This is already the case for its alternation-free fragment. The expression complexity of FLC is trivially P-hard and limited from above by the complexity of solving a parity game, i.e.in UP ∩ co-UP. For any fragment of fixed alternation depth, in particular alternation- free formulas it is P-complete.

AbstractIn 1984. Danecki proved that satisfiability in IPDL, i.e., Propositional Dynamic Logic (PDL) extended with an intersection operator on programs, is decidabie in deterministic double exponential time. Since then, the exact complexity of IPDL has remained an open problem: the best known lower bound was the ExpTime one stemming from plain PDL until, in 2004. the first author established ExpSpace-hardness. In this paper, we finally close the gap and prove that IPDL is hard for 2-ExpTime. thus 2-ExpTime-complete. We then sharpen our lower bound, showing that it even applies to IPDL without the test operator interpreted on tree structures.

Molecular probes can be used to identify and characterize phytoplankton species by DNA dot blot or in situ hybridization with subsequent detection by fluorescence microscopy or flow cytometry. More or less conserved regions on the rRNA genes make it possible to develop probes that are specific for different taxonomic levels from higher groups, like eukaryotes, down to species and even strain levels. These hierarchical probes can be used to estimate biodiversity at a variety of taxonomic levels and are a valuable tool for analysing microalgae and answering ecological questions.

Objectives:To evaluate the value of the thyrotropin-releasing hormone (TRH) stimulation test in the diagnostic work-up of the thyroid function in patients with pituitary pathology. Methods:To compare the thyrotropin (TSH) response and the absolute and fold changes after TRH administration in 35 patients with pituitary pathology and 26 normal subjects. Results:Nine of the patients and 2 of the normal subjects had a pathological response. No difference in the thyrotropic response to TRH was found either for the actual values, or for the absolute or fold changes of TSH between the groups. Conclusion:The role of the TRH test in the evaluation of thyroid function in patients with pituitary pathology is modest. The best variables for evaluation of the presence of central hypothyroidism are still a free thyroxine estimate combined with an inappropriately low TSH.

A model study is performed to simulate the effect of the observed atmospheric CO2 increase and O3 decrease on the northern hemisphere (NH) summer middle atmosphere meridional circulation. It is found that, due to a reduction of gravity wave filtering through the stratospheric / mesospheric easterly jet, the mesopause region meridional wind at midlatitudes decreases by up to 2ms-1, i.e. about 25%, if the middle atmospheric CO2 content is increased by 10% and O3 is reduced up to 10% at high latitudes reflecting the changes of atmospheric composition over the last 30 years. The model results are in good agreement with midlatitude long-term radar wind measurements at that altitude. Mit Hilfe eines einfachen Zirkulationsmodells wurde der Einfluss des beobachteten CO2-Anstiegs und des OzonrÜckgangs auf die mesosphÄrische Meridionalzirkulation der sommerlichen NordhemisphÄre untersucht. Es ergibt sich, dass durch eine Verringerung der Filterwirkung der Ostwinde in der StratosphÄre und MesosphÄre in Bezug auf Schwerewellen der Meridionalwind um 25% reduziert wird, wenn der Gehalt an CO2 in der mittleren AtmosphÄre um etwa 10% steigt und derjenige von O3 um 10% sinkt. Diese Modellergebnisse sind in Übereinstimmung mit Ergebnissen von Radarwindmessungen.

OBJECTIVE: The insulin-tolerance test (ITT) is currently considered to be the gold standard for evaluating adults suspected of GH deficiency (GHD). The aim of this study was to determine factors that may influence nadir blood glucose (BG) when using a mean insulin dose of 0.1 IU/kg body weight. Furthermore, we wanted to evaluate the safety and GH-related aspects of the ITT. DESIGN: ITT was performed in 277 patients, of whom 255 (129 females) were eligible for evaluation. RESULTS: Multiple regression analysis, including the whole population, showed that the major determining factors for nadir BG were basal BG and body mass index (BMI) (P<0.02). No serious adverse event was recorded. Sixty-three percent of all patients tested had severe GHD with peak GH response to hypoglycaemia below 7.8 mIU/l. The positive predictive value for IGF-I was 0.82 and the negative predictive value was 0.47, using a cut-off value corresponding to -2 s.d. GH peak response to hypoglycaemia decreased with increasing numbers of other pituitary hormone deficiencies. CONCLUSIONS: When determining the dose of insulin based on weight, factors like pre-test BG and BMI should also be considered. We propose an algorithm stating that the dose of insulin should be 0.1 IU insulin/kg body weight minus 2 IU if pre-test BG is <4.0 mmol/l and minus 2 IU if BMI is <20 kg/m(2) in order to take these factors into account. Our findings furthermore support the concept that the low-dose ITT is a safe test in adults, when performed in experienced hands. It was confirmed that IGF-I is not sufficient when diagnosing GHD in adults, and reliable stimulation tests like ITT are required in the diagnosis.

Sequence variation among 22 isolates representing a global distribution of the prymnesiophyte genus Phaeocystishas been compared using nuclear-encoded 18S rRNA genes and two non-coding regions: the ribosomal DNA internal transcribed spacer 1 (ITS1) separating the 18S rRNA and 5.8S rRNA genes and the plastid ribulose-1,5-bisphosphate carboxylase/oxygenase (RUBISCO) spacer flanked by short stretches of the adjacent large and small subunits (rbcL and rbcS). 18S rRNA can only resolve major species complexes. The analysis suggests that an undescribed unicellular Phaeocystissp. (isolate PLY 559) is a sister taxon to the Mediterranean unicellular Phaeocystis jahnii; this clade branched prior to the divergence of all other Phaeocystisspecies, including the colonial ones. Little divergence was seen among the multiple isolates sequenced from each colonial species complex. RUBISCO spacer regions are even more highly conserved among closely related colonial Phaeocystisspecies and are identical in Phaeocystis antarctica, Phaeocystis pouchetiiand two warm-temperate strains of Phaeocystis globosa, with a single base substitution in two cold-temperate strains of P. globosa. The RUBISCO spacer sequences from two predominantly unicellular Phaeocystisisolates from the Mediterranean Sea and PLY 559 were clearly different from other Phaeocystisstrains. In contrast, ITS1 exhibited substantial inter- and intraspecific sequence divergence and showed more resolution among the taxa. Distinctly different copies of the ITS1 region were found in P. globosa, even among cloned DNA from a single strain, suggesting that it is a species complex and making this region unsuitable for phylogenetic analysis in this species. However, among nine P. antarcticastrains, four ITS1 haplotypes could be separated. Using the branching order in the ITS1 tree we have attempted to trace the biogeographic history of the dispersal of strains in Antarctic coastal waters.

Sequence variation among 22 isolates representing a global distribution of the prymnesiophyte genus Phaeocystis has been compared using nuclear-encoded 18S rRNA genes and two non-coding regions: the ribosomal DNA internal transcribed spacer 1 (ITS1) separating the 18S rRNA and 5·8S rRNA genes and the plastid ribulose-1,5-bisphosphate carboxylase/oxygenase (RUBISCO) spacer flanked by short stretches of the adjacent large and small subunits (rbcL and rbcS). 18S rRNA can only resolve major species complexes. The analysis suggests that an undescribed unicellular Phaeocystis sp. (isolate PLY 559) is a sister taxon to the Mediterranean unicellular Phaeocystis jahnii; this clade branched prior to the divergence of all other Phaeocystis species, including the colonial ones. Little divergence was seen among the multiple isolates sequenced from each colonial species complex. RUBISCO spacer regions are even more highly conserved among closely related colonial Phaeocystis species and are identical in Phaeocystis antarctica, Phaeocystis pouchetii and two warm-temperate strains of Phaeocystis globosa, with a single base substitution in two cold-temperate strains of P. globosa. The RUBISCO spacer sequences from two predominantly unicellular Phaeocystis isolates from the Mediterranean Sea and PLY 559 were clearly different from other Phaeocystis strains. In contrast, ITS1 exhibited substantial inter- and intraspecific sequence divergence and showed more resolution among the taxa. Distinctly different copies of the ITS1 region were found in P. globosa, even among cloned DNA from a single strain, suggesting that it is a species complex and making this region unsuitable for phylogenetic analysis in this species. However, among nine P. antarctica strains, four ITS1 haplotypes could be separated. Using the branching order in the ITS1 tree we have attempted to trace the biogeographic history of the dispersal of strains in Antarctic coastal waters.

The systematic position of the genus Cryothecomonashas been determined from an analysis of the nuclear-encoded small subunit ribosomal RNA gene of Cryothecomonas longipesand two strains of Cryothecomonas aestivalis. Our phylogenetic trees inferred from maximum likelihood, distance and maximum parsimony methods robustly show that the genus Cryothecomonasclusters within the phylum Cercozoa, and is related to the sarcomonad flagellate Heteromita globosa.Morphological data supporting the taxonomic placement of Cryothecomonasnear the sarcomonad flagellates has been compiled from the literature. The high number of nucleotide substitutions found between two morphologically indistinguishable strains of Cryothecomonas aestivalissuggests the possibility of cryptic species within Cryothecomonas aestivalis.

For an axial compressor stator with tip gap, the boundary layer (BL) in the hub endwall region has a significant influence on the development and progression of the tip leakage vortex. Herein, the so-called BL skew, which develops through relative motion of the hub, is of particular interest. Therefore, experimental and numerical investigations of a single axial compressor stator row with varying tip gap height (tip gap height/chord length =2.0%|5.4%|6.7%) have been conducted. Comparing cases with rotating or stationary hub endwall segments upstream of the examined vanes allowed to determine the effect of the skewed and un-skewed inflow BL. The steady-state flow fields up- and downstream of the stator row were measured using five-hole pressure probes. For validation and to improve the understanding of the existing flow phenomena, 3D-Reynolds-averaged Navier–Stokes (RANS) CFD simulations using a commercial flow solver were carried out. Furthermore, analog cases with no tip gap were examined and considered in the comparisons to extend the knowledge on this BL characteristic. The results show that the BL skew has a major influence on the trajectory and size of the tip leakage vortex for the cases with tip clearance. The effect of reduction of the produced losses decreases with increasing tip gap height.

Novel treatment options for metastatic colorectal cancer (CRC) are urgently needed to improve patient outcome. Here, we screen a library of non-characterized small molecules against a heterogeneous collection of patient-derived CRC spheroids. By prioritizing compounds with inhibitory activity in a subset of—but not all—spheroid cultures, NCT02 is identified as a candidate with minimal risk of non-specific toxicity. Mechanistically, we show that NCT02 acts as molecular glue that induces ubiquitination of cyclin K (CCNK) and proteasomal degradation of CCNK and its complex partner CDK12. Knockout of CCNK or CDK12 decreases proliferation of CRC cells in vitroand tumor growth in vivo. Interestingly, sensitivity to pharmacological CCNK/CDK12 degradation is associated with TP53 deficiency and consensus molecular subtype 4 in vitroand in patient-derived xenografts. We thus demonstrate the efficacy of targeted CCNK/CDK12 degradation for a CRC subset, highlighting the potential of drug-induced proteolysis for difficult-to-treat types of cancer.

Twenty-one cultures of the Alexandrium tamarense/catenella/fundyensespecies-complex, isolated from a bloom at the Orkney Islands, north of Scotland, were examined morphologically and tested for toxicity using HPLC analyses. All cultures belong to the morpho-species of A. tamarense(Labour) Balech rather than A. fundyenseBalech and are as toxic as the most toxic A. fundyenseisolates from North America. A subset was genetically analysed using sequence data from the D1/D2 region of the LSU rRNA gene (656 nt). Genetic analyses indicated that these A. tamarensepopulations were related to North American isolates. At least three classes of the D1/D2 region were found in the cloned material. Sufficient base substitutions in the D1/D2 region preclude introduction into the Orkneys by human mechanisms (i.e., in ballast water or in shellfish stocks). The sequence analysis supports a dispersal hypothesis in recent evolutionary time of North American stocks of A. tamarenseinto Northern European waters via currents, possibly as part of the hypothesised original dispersal in the North Atlantic from the Pacific. In contrast, other Western European isolates of A. tamarense, whose D1/D2 region has been sequenced, are non-toxic and belong to a different gene pool.

Linear cascades are commonly used as surrogate geometries when performing fundamental studies of turbomachinery blading. Several effects are not accounted for in linear cascades, such as the relative motion between blade and endwall. In this study, three different relative endwall velocities are analyzed. The effect of the relative motion between endwall and blade in a linear compressor cascade is studied through direct numerical simulations. Results show a significant change in the secondary flow structure within the passage. Most notably, the tip leakage vortex is displaced away from the blade. Still, the blade spanwise range affected by the secondary flow field is similar to the case without relative endwall motion. At the outlet plane, a stratification of the total pressure losses and the exit flow angle is found, which overshadows any blade wake effects near the endwall.

Film cooling and internal passage cooling play a fundamental role in turbine blade cooling. As the cooling holes are fed by the internal crossflow, interaction of these both cooling strategies is implicated. The influence of film hole extraction on the internal flow field and heat transfer of a ribbed cooling channel is investigated in this study. Therefore, a rectangular cooling channel (AR = 2:1) is equipped with parallel ribs of four different geometries (90 deg ribs, 60 deg ribs, 60 deg V-shaped ribs, and 60 deg Λ-shaped ribs) and also with bleed holes at varying positions between the ribs. The different geometrical configurations are examined using 2D-particle image velocimetry (PIV) for flow measurements and transient thermochromic liquid crystal (TLC) technique for heat transfer measurements. Depending on the rib-induced heat transfer pattern, cooling hole positions in the rib segments are found, which can enhance passage internal heat transfer. 90 deg and 60 deg ribs show the best results for upstream hole positions regardless of the lateral positioning. V and Λ ribs reveal a benefit for lateral positioned cooling holes near the upstream rib.

We consider hybridisations of the full branching time logic CTL⁎and its prominent fragments CTL, CTL+and FCTL+through the addition of nominals, binders and jumps. We formally define three types of hybridisations by restricting the interplay between hybrid operators and path formulas contrary to previous proposals in the literature which ignored potential problems with a formal semantics. We then investigate the model checking problem for these logics obtaining expression complexities from PSpace-completeness to non-elementary decidability and data complexities ranging from NLogSpaceto PSpace. Lastly, we identify a family of fragments of these hybrid logics, called the bounded fragments, that (in some cases) have the same model checking complexity as their non-hybrid counterparts.

Jourdan: Bayer Pharma AG: Employment. Berthold:Bayer Pharma AG: Employment. Rossi:Gilead: Honoraria, Research Funding; Abbvie: Honoraria; Janseen: Honoraria. Lange:Bayer Pharma AG: Employment. Politz:Bayer Pharma AG: Employment.