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The calcium isotopes are an ideal system to investigate the evolution of shell structure and magic numbers. Although the properties of surface nucleons in calcium have been well studied, probing the structure of deeply bound nucleons remains a challenge. Here, we report on the first measurement of unbound states in 53Ca and 55Ca, populated from 54,56Ca(p,pn) reactions at a beam energy of around 216 MeV/nucleon at the RIKEN Radioactive Isotopes Beam Factory. The resonance properties, partial cross sections, and momentum distributions of these unbound states were analyzed. Orbital angular momentum l assignments were extracted from momentum distributions based on calculations using the distorted wave impulse approximation (DWIA) reaction model. The resonances at excitation energies of 5516(41)keV in 53Ca and 6000(250)keV in 55Ca indicate a significant l =3 component, providing the first experimental evidence for the ν0f7/2 single-particle strength of unbound hole states in the neutron-rich Ca isotopes. The observed excitation energies and cross-sections point towards extremely localized and well separated strength distributions, with some fragmentation for the ν0f7/2 orbital in 55Ca. These results are in good agreement with predictions from shell-model calculations using the effective GXPF1Bs interaction and ab initio calculations and diverge markedly from the experimental distributions in the nickel isotones at Z=28.

Gamma decays were observed in 56Ca and 58Ca following quasi-free one-proton knockout reactions from 57,59Sc beams at ≈200 MeV/nucleon. For 56Ca, a γ ray transition was measured to be 1456(12) keV, while for 58Ca an indication for a transition was observed at 1115(34) keV. Both transitions were tentatively assigned as the 21+→0gs+ decays, and were compared to results from ab initio and conventional shell-model approaches. A shell-model calculation in a wide model space with a marginally modified effective nucleon-nucleon interaction depicts excellent agreement with experiment for 21+ level energies, two-neutron separation energies, and reaction cross sections, corroborating the formation of a new nuclear shell above the N = 34 shell. Its constituents, the 0f5/2 and 0g9/2 orbitals, are almost degenerate. This degeneracy precludes the possibility for a doubly magic 60Ca and potentially drives the dripline of Ca isotopes to 70Ca or even beyond.

Groundwater levels are monitored by environmental agencies to support the sustainable use of groundwater resources. For this purpose continuous and spatially comprehensive monitoring in high spatial and temporal resolution is desired. This leads to large datasets that have to be checked for quality and analysed to distinguish local anthropogenic influences from natural variability of the groundwater level dynamics at each well. Both technical problems with the measurements as well as local anthropogenic influences can lead to local anomalies in the hydrographs. We suggest a fast and efficient screening method for the identification of well-specific peculiarities in hydrographs of groundwater head monitoring networks. The only information required is a set of time series of groundwater heads all measured at the same instants of time. For each well of the monitoring network a reference hydrograph is calculated, describing expected “normal” behaviour at the respective well as is typical for the monitored region. The reference hydrograph is calculated by multiple linear regression of the observed hydrograph with the “stable” principal components (PCs) of a principal component analysis of all groundwater head series of the network as predictor variables. The stable PCs are those PCs which were found in a random subsampling procedure to be rather insensitive to the specific selection of the analysed observation wells, i.e. complete series, and to the specific selection of measurement dates. Hence they can be considered to be representative for the monitored region in the respective period. The residuals of the reference hydrograph describe local deviations from the normal behaviour. Peculiarities in the residuals allow the data to be checked for measurement errors and the wells with a possible anthropogenic influence to be identified. The approach was tested with 141 groundwater head time series from the state authority groundwater monitoring network in northeastern Germany covering the period from 1993 to 2013 at an approximately weekly frequency of measurement.

States in the N=35 and 37 isotopes 55,57Ca have been populated by direct proton-induced nucleon removal reactions from 56,58Sc and 56Ca beams at the RIBF. In addition, the (p,2p) quasi-free single-proton removal reaction from 56Ca was studied. Excited states in 55K, 55Ca, and 57Ca were established for the first time via in-beam γ-ray spectroscopy. Results for the proton and neutron removal reactions from 56Ca to states in 55K and 55Ca for the level energies, excited state lifetimes, and exclusive cross sections agree well with state-of-the-art theoretical calculations using different approaches. The observation of a short-lived state in 57Ca suggests a transition in the calcium isotopic chain from single-particle dominated states at N=35 to collective excitations at N=37.

The proton drip-line nucleus 17Ne is investigated experimentally in order to determine its two-proton halo character. A fully exclusive measurement of the 17Ne(p,2p)16F→15⁎O+p quasi-free one-proton knockout reaction has been performed at GSI at around 500 MeV/nucleon beam energy. All particles resulting from the scattering process have been detected. The relevant reconstructed quantities are the angles of the two protons scattered in quasi-elastic kinematics, the decay of 16F into 15O (including γ decays from excited states) and a proton, as well as the 15O+p relative-energy spectrum and the 16F momentum distributions. The latter two quantities allow an independent and consistent determination of the fractions of l=0 and l=2 motion of the valence protons in 17Ne. With a resulting relatively small l=0 component of only around 35(3)%, it is concluded that 17Ne exhibits a rather modest halo character only. The quantitative agreement of the two values deduced from the energy spectrum and the momentum distributions supports the theoretical treatment of the calculation of momentum distributions after quasi-free knockout reactions at high energies by taking into account distortions based on the Glauber theory. Moreover, the experimental data allow the separation of valence-proton knockout and knockout from the 15O core. The latter process contributes with 11.8(3.1) mb around 40% to the total proton-knockout cross section of 30.3(2.3) mb, which explains previously reported contradicting conclusions derived from inclusive cross sections.

The nuclear structure of 51Ar, an uncharted territory so far, was studied by the (p,2p) reaction using γ-ray spectroscopy for the bound states and the invariant mass method for the unbound states. Two peaks were detected in the γ-ray spectrum and six peaks were observed in the 50Ar+n relative energy spectrum. Comparing the results to our shell-model calculations, two bound and six unbound states were established. Three of the unbound states could only be placed tentatively due to the low number of counts in the relative energy spectrum of events associated with the decay through the first excited state of 50Ar. The low cross sections populating the two bound states of 51Ar could be interpreted as a clear signature for the presence of significant subshell closures at neutron numbers 32 and 34 in argon isotopes. It was also revealed that due to the two valence holes, unbound collective states coexist with individual-particle states in 51Ar.

We report on the first γ-ray spectroscopy of 51,53K produced via the 52,54Ca(p,2p) reactions at ∼250 MeV/nucleon. Unambiguous final-state angular-momentum assignments were achieved for beam intensities down to few particles per second by using a new technique based on reaction vertex tracking combined with a thick liquid-hydrogen target. Through γ-ray spectroscopy and exclusive parallel momentum distribution analysis, 3/2+ ground states and 1/2+ first excited states in 51,53K were established quantifying the natural ordering of the 1d3/2 and 2s1/2 proton-hole states that are restored at N = 32 and 34. State-of-the-art ab initio calculations and shell-model calculations with improved phenomenological effective interactions reproduce the present data and predict consistently the increase of the E(1/21+) - E(3/21+) energy differences towards N = 40. Keywords: Spectroscopy, Shell evolution, 51K, 53K

Time series of groundwater and stream water quality often exhibit substantial temporal and spatial variability, whereas typical existing monitoring data sets, e.g. from environmental agencies, are usually characterized by relatively low sampling frequency and irregular sampling in space and/or time. This complicates the differentiation between anthropogenic influence and natural variability as well as the detection of changes in water quality which indicate changes in single drivers. We suggest the new term dominant changes for changes in multivariate water quality data which concern (1) multiple variables, (2) multiple sites and (3) long-term patterns and present an exploratory framework for the detection of such dominant changes in data sets with irregular sampling in space and time. Firstly, a non-linear dimension-reduction technique was used to summarize the dominant spatiotemporal dynamics in the multivariate water quality data set in a few components. Those were used to derive hypotheses on the dominant drivers influencing water quality. Secondly, different sampling sites were compared with respect to median component values. Thirdly, time series of the components at single sites were analysed for long-term patterns. We tested the approach with a joint stream water and groundwater data set quality consisting of 1572 samples, each comprising sixteen variables, sampled with a spatially and temporally irregular sampling scheme at 29 sites in northeast Germany from 1998 to 2009. The first four components were interpreted as (1) an agriculturally induced enhancement of the natural background level of solute concentration, (2) a redox sequence from reducing conditions in deep groundwater to post-oxic conditions in shallow groundwater and oxic conditions in stream water, (3) a mixing ratio of deep and shallow groundwater to the streamflow and (4) sporadic events of slurry application in the agricultural practice. Dominant changes were observed for the first two components. The changing intensity of the first component was interpreted as response to the temporal variability of the thickness of the unsaturated zone. A steady increase in the second component at most stream water sites pointed towards progressing depletion of the denitrification capacity of the deep aquifer.

In hydrological models, parameters are used to represent the time-invariant characteristics of catchments and to capture different aspects of hydrological response. Hence, model parameters need to be identified based on their role in controlling the hydrological behaviour. For the identification of meaningful parameter values, multiple and complementary performance criteria are used that compare modelled and measured discharge time series. The reliability of the identification of hydrologically meaningful model parameter values depends on how distinctly a model parameter can be assigned to one of the performance criteria. To investigate this, we introduce the new concept of connective strength between model parameters and performance criteria. The connective strength assesses the intensity in the interrelationship between model parameters and performance criteria in a bijective way. In our analysis of connective strength, model simulations are carried out based on a latin hypercube sampling. Ten performance criteria including Nash–Sutcliffe efficiency (NSE), Kling–Gupta efficiency (KGE) and its three components (alpha, beta and r) as well as RSR (the ratio of the root mean square error to the standard deviation) for different segments of the flow duration curve (FDC) are calculated. With a joint analysis of two regression tree (RT) approaches, we derive how a model parameter is connected to different performance criteria. At first, RTs are constructed using each performance criterion as the target variable to detect the most relevant model parameters for each performance criterion. Secondly, RTs are constructed using each parameter as the target variable to detect which performance criteria are impacted by changes in the values of one distinct model parameter. Based on this, appropriate performance criteria are identified for each model parameter. In this study, a high bijective connective strength between model parameters and performance criteria is found for low- and mid-flow conditions. Moreover, the RT analyses emphasise the benefit of an individual analysis of the three components of KGE and of the FDC segments. Furthermore, the RT analyses highlight under which conditions these performance criteria provide insights into precise parameter identification. Our results show that separate performance criteria are required to identify dominant parameters on low- and mid-flow conditions, whilst the number of required performance criteria for high flows increases with increasing process complexity in the catchment. Overall, the analysis of the connective strength between model parameters and performance criteria using RTs contribute to a more realistic handling of parameters and performance criteria in hydrological modelling.

Excited states in the N=40 isotone 62Ti were populated via the 63V(p,2p)62Ti reaction at ∼200 MeV/nucleon at the Radioactive Isotope Beam Factory and studied using γ-ray spectroscopy. The energies of the 21+→0gs+ and 41+→21+ transitions, observed here for the first time, indicate a deformed 62Ti ground state. These energies are increased compared to the neighboring 64Cr and 66Fe isotones, suggesting a small decrease of quadrupole collectivity. The present measurement is well reproduced by large-scale shell-model calculations based on effective interactions, while ab initio and beyond mean-field calculations do not yet reproduce our findings. The shell-model calculations for 62Ti show a dominant configuration with four neutrons excited across the N=40 gap. Likewise, they indicate that the N=40 island of inversion extends down to Z=20, disfavoring a possible doubly magic character of the elusive 60Ca. Keywords: Shell evolution, Radioactive beams, Gamma-ray spectroscopy

Globally, there have been many extreme weather events in recent decades. A challenge has been to determine whether these extreme weather events have increased in number and intensity compared to the past. This challenge is made more difficult due to the lack of long-term instrumental data, particularly in terms of river discharge, in many regions including Southeast Asia. Thus our main aim in this paper is to develop a river basin scale approach for assessing interannual hydrometeorological and discharge variability on long, palaeological, time scales. For the development of the basin-wide approach, we used the Mekong River basin as a case study area, although the approach is also intended to be applicable to other basins. Firstly, we derived a basin-wide Palmer Drought Severity Index (PDSI) from the Monsoon Asia Drought Atlas (MADA). Secondly, we compared the basin-wide PDSI with measured discharge to validate our approach. Thirdly, we used basin-wide PDSI to analyse the hydrometeorology and discharge of the case study area over the study period of 1300–2005. For the discharge-MADA comparison and hydrometeorological analyses, we used methods such as linear correlations, smoothing, moving window variances, Levene type tests for variances, and wavelet analyses. We found that the developed basin-wide approach based on MADA can be used for assessing long-term average conditions and interannual variability for river basin hydrometeorology and discharge. It provides a tool for studying interannual discharge variability on a palaeological time scale, and therefore the approach contributes to a better understanding of discharge variability during the most recent decades. Our case study revealed that the Mekong has experienced exceptional levels of interannual variability during the post-1950 period, which could not be observed in any other part of the study period. The increased variability was found to be at least partly associated with increased El Niño Southern Oscillation (ENSO) activity.

Jews who immigrated to the Canadian prairies before 1914 mostly gravitated to urban areas. Those who chose to farm usually located in Jewish agricultural colonies where a full Jewish life was possible. A minority voluntarily settled in small farming communities among non-Jews. Jewish merchants in prairie towns also became involved in agriculture both as farmers and as agricultural traders and dealers. Few Jews chose to settle on homesteads where they were isolated from Jewish social and religious life. In the interwar period, attempts to circumvent restrictions placed on Jewish immigration led Jewish philanthropic agencies to place Jewish refugee immigrants on scattered farms, often isolated from Jewish communities. Although economically unsuccessful the strategy achieved its humanitarian objectives.

Background: Cancer-associated thrombosis is a frequent complication in patients with malignancies. While factor XI (FXI)/FXIa inhibition is efficacious in preventing postoperative venous thromboembolism, its role in tumor cell-induced coagulation is less defined., Objectives: We thus aimed to provide mechanistic insights into FXI/FXIa inhibition in tumor cell-induced coagulation activation., Methods: Procoagulant activity (PCA) of 4 different tissue factor (TF) expressing tumor cell lines was analyzed by single-stage clotting and thrombin generation assay in the presence of a FXIa inhibitor, BMS-262084 (BMS), an inhibitory FXI antibody (anti-FXI), or peak and trough concentrations of rivaroxaban or tinzaparin. Further, tumor cell-induced platelet aggregation was recorded. Recombinant human TF served as positive control., Results: Although BMS and anti-FXI potently inhibited FXIa amidolytic activity, both inhibitors efficiently mitigated recombinant human TF- and tumor cell-induced fibrin clot formation and platelet aggregation only in the presence of low TF PCA. The anticoagulant effects showed an inverse correlation with the magnitude of cellular TF PCA expression. Similarly, BMS markedly interfered with tumor cell-induced thrombin generation, with the most prominent effects on peak and total thrombin. In addition, anticoagulant effects of FXIa inhibition by 10 μM BMS were in a similar range to those obtained by 600 nM rivaroxaban and 1.6 μM tinzaparin at low TF PCA levels. However, rivaroxaban and tinzaparin also exerted marked anticoagulant activity at high TF PCA levels., Conclusion: Our findings indicate that FXI/FXIa inhibition interferes with tumor cell-induced coagulation activation only at low TF PCA expression levels, a finding with potential implications for future in vivo studies., Competing Interests: Declaration of competing interests J.M., A.S., C.L., J.R., and L.B. declare no conflicts of interest relevant to the content of this article. C.C.R. has received travel support from Pfizer. M.V. declares personal fees for lectures from Bristol-Myers Squibb and travel support from Bayer, Bristol-Myers Squibb, and LEO Pharma. C.B. has received personal fees for consultancy, research support, and/or travel support from Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Novartis, Pfizer, Roche, and Sanofi. F.L. has received personal fees for lectures or consultancy and/or research support from Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, LEO Pharma, Pfizer, Sanofi, and Viatris., (Copyright © 2023 International Society on Thrombosis and Haemostasis. Published by Elsevier Inc. All rights reserved.)

The neural mechanisms that unfold when humans form a large group defined by an overarching context, such as audiences in theater or sports, are largely unknown and unexplored. This is mainly due to the lack of availability of a scalable system that can record the brain activity from a significantly large portion of such an audience simultaneously. Although the technology for such a system has been readily available for a long time, the high cost as well as the large overhead in human resources and logistic planning have prohibited the development of such a system. However, during the recent years reduction in technology costs and size have led to the emergence of low-cost, consumer-oriented EEG systems, developed primarily for recreational use. Here by combining such a low-cost EEG system with other off-the-shelve hardware and tailor-made software, we develop in the lab and test in a cinema such a scalable EEG hyper-scanning system. The system has a robust and stable performance and achieves accurate unambiguous alignment of the recorded data of the different EEG headsets. These characteristics combined with small preparation time and low-cost make it an ideal candidate for recording large portions of audiences., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Authors. Published by Elsevier Ltd.)

Introduction: Patients with acute myeloid leukemia (AML) are at increased risk of thrombohemorrhagic complications. Overexpressed tissue factor (TF) on AML blasts contributes to systemic coagulation activation. We have recently shown that the heme enzyme myeloperoxidase (MPO) negatively regulates TF procoagulant activity (PCA) on myelomonocytic cells in vitro. We now aimed to further characterize the functional interaction of MPO and TF in AML in vivo., Methods: We prospectively recruited 66 patients with newly diagnosed AML. TF PCA of isolated peripheral blood mononuclear cells (PBMC) was assessed by single-stage clotting assay in the presence or absence of inhibitors against MPO catalytic activity (ABAH) or against MPO-binding integrins (anti-CD18). MPO in plasma and in AML blasts was measured by ELISA, and plasma D-dimers and prothrombin fragment F1+2 were quantified by automated immunoturbidimetric and chemiluminescence assays, respectively., Results: Patients with AML had significantly higher MPO plasma levels compared to healthy controls and exhibited increased levels of D-dimers and F1+2. In vivo thrombin generation was mediated by TF PCA on circulating PBMC. Ex vivo incubation of isolated PBMC with ABAH or anti-CD18 antibody resulted in either increased or decreased TF PCA. The strong and robust correlation of F1+2 with TF PCA of circulating PBMC was abrogated at MPO plasma levels higher than 150 ng/mL, indicating a modulatory role for MPO on TF-mediated in vivo thrombin generation above this threshold., Conclusion: Our study indicates that catalytically active MPO released by circulating myeloblasts regulates TF-dependent coagulation in patients with newly diagnosed AML in a CD18-dependent manner., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Aims: Pulmonary hypertension (PH) management is dependent on cardiac output (CO) assessment. The gold standard Fick method for CO and cardiac index (CI) measurement is not widely available. An accessible and reliable method for CO/CI estimation is needed not only in catheterization labs but also in other environments such as the intensive care unit, where pulmonary artery catheters are less likely to be used. We hypothesized that veno-arterial carbon dioxide gradient (PvaCO2) is a reliable surrogate for Fick CI in patients with PH., Methods and Results: A single-centre retrospective analysis of patients with PH who underwent direct Fick CI (DFCI) measurement during right heart catheterization. The primary outcome was correlation between PvaCO2 and DFCI. To assess the agreement between central and mixed venous CO2 values, a separate prospective cohort of patients was analysed. Data from 186 patients with all haemodynamic types of PH were analysed. PvaCO2 moderately correlated with Fick CI, R = -0.51 [95% confidence interval (CI): -0.61, -0.39]. A higher PvaCO2 was associated with an increased risk of CI < 2.5 L/min/m2 (odds ratio: 1.88, 95% CI: 1.55, 2.35). Low thermodilution CI with normal veno-arterial carbon dioxide gradient values was associated with a thermodilution underestimation of Fick CI. In the prospective analysis of 32 patients, central venous CO2 overestimated mixed venous values (mean difference 3.3, 95% CI: 2.5, 4.0) and there was poor agreement overall (limits of agreement -1.10, 7.59)., Conclusion: Veno-arterial carbon dioxide gradient moderately correlates with Fick CI and may be useful to identify patients with low CI. Central and mixed venous CO2 values should not be used interchangeably in PH., Competing Interests: Conflict of interest: None declared., (© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

The one-neutron knockout from ^{52}Ca in inverse kinematics onto a proton target was performed at ∼230  MeV/nucleon combined with prompt γ spectroscopy. Exclusive quasifree scattering cross sections to bound states in ^{51}Ca and the momentum distributions corresponding to the removal of 1f&#95;{7/2} and 2p&#95;{3/2} neutrons were measured. The cross sections, interpreted within the distorted-wave impulse approximation reaction framework, are consistent with a shell closure at the neutron number N=32, found as strong as at N=28 and N=34 in Ca isotopes from the same observables. The analysis of the momentum distributions leads to a difference of the root-mean-square radii of the neutron 1f&#95;{7/2} and 2p&#95;{3/2} orbitals of 0.61(23) fm, in agreement with the modified-shell-model prediction of 0.7 fm suggesting that the large root-mean-square radius of the 2p&#95;{3/2} orbital in neutron-rich Ca isotopes is responsible for the unexpected linear increase of the charge radius with the neutron number.

Introduction: Protein disulfide isomerase (PDI) contributes to tissue factor (TF) regulation in monocytes. While bacitracin and quercetin-3-rutinoside mitigate myeloid TF production, the effect of PACMA-31, a more specific PDI inhibitor with distinct pharmacologic properties, remains unclear., Materials and Methods: Lipopolysaccharide (LPS) stimulation of peripheral blood mononuclear cells (PBMCs) or citrate-anticoagulated whole blood was carried out in the presence of PACMA-31 or DMSO vehicle before monocytes were analyzed for TF expression, including antigen, procoagulant activity (PCA) and mRNA, release of IL-6 and TNFα, and LPS-induced signaling pathways., Results: While PACMA-31 alone had no effect, coincubation with LPS and PACMA-31 (25 μM) enhanced LPS-induced monocyte TF production in whole blood. The effect was at least partially regulated on the transcriptional level and could not be explained by increased phosphatidylserine membrane exposure. In contrast, the same PACMA-31 concentrations were cytotoxic in isolated PBMCs. A lower dose of PACMA-31, however, restored the stimulating effect by enhancing IκB-NFκB signaling that also increased the release of IL-6 and TNFα. The protease-activated receptor 2 (PAR2) inhibitor ENMD 547 but not TF antibody 10H10 or factor Xa inhibitor rivaroxaban prevented the stimulatory effect of PACMA-31 on inflammatory monocytes. In sharp contrast, short time incubation of LPS-stimulated PBMCs with 25 μM PACMA-31 was non-cytotoxic and significantly inhibited cellular TF PCA but not surface antigen expression., Conclusions: PACMA-31 regulates monocyte TF in a concentration-dependent manner by opposing transcriptional and posttranscriptional mechanisms. While low concentrations of PACMA-31 augment monocyte TF production by amplifying LPS-dependent PAR2 signaling, high concentrations convert monocyte TF into its non-coagulant state., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

A long-standing question in nuclear physics is whether chargeless nuclear systems can exist. To our knowledge, only neutron stars represent near-pure neutron systems, where neutrons are squeezed together by the gravitational force to very high densities. The experimental search for isolated multi-neutron systems has been an ongoing quest for several decades 1 , with a particular focus on the four-neutron system called the tetraneutron, resulting in only a few indications of its existence so far 2-4 , leaving the tetraneutron an elusive nuclear system for six decades. Here we report on the observation of a resonance-like structure near threshold in the four-neutron system that is consistent with a quasi-bound tetraneutron state existing for a very short time. The measured energy and width of this state provide a key benchmark for our understanding of the nuclear force. The use of an experimental approach based on a knockout reaction at large momentum transfer with a radioactive high-energy 8 He beam was key., (© 2022. The Author(s).)

Aberrant expression of tissue factor (TF) by transformed myeloblasts and inflammatory monocytes drives coagulation activation in acute myeloid leukemia (AML). Although regulation of TF procoagulant activity (PCA) involves thiol-disulfide exchange reactions, the specific role of protein disulfide isomerase (PDI) and other thiol isomerases in AML-associated TF biology is unclear. THP1 cells and peripheral blood mononuclear cells (PBMCs) from healthy controls or AML patients were analyzed for thiol isomerase-dependent TF production under various experimental conditions. Total cellular and membrane TF antigen, TF PCA and TF mRNA were analyzed by ELISA, flow cytometry, clotting or Xa generation assay and qPCR, respectively. PBMCs and THP1 cells showed significant insulin reductase activity, which was inhibited by bacitracin or rutin. Co-incubation with these thiol isomerase inhibitors prevented LPS-induced TF production by CD14-positive monocytes and constitutive TF expression by THP1 cells and AML blasts. Downregulation of the TF antigen was mainly restricted to the cryptic pool of TF, efficiently preventing phosphatidylserine-dependent TF activation by daunorubicin, and at least partially regulated on the mRNA level in LPS-stimulated monocytes. Our study thus delineates a complex role of thiol isomerases in the regulation of myeloid TF PCA, with PDI being a promising therapeutic target in the management of AML-associated coagulopathies.

Direct proton-knockout reactions of ^{55}Sc at ∼220  MeV/nucleon were studied at the RIKEN Radioactive Isotope Beam Factory. Populated states of ^{54}Ca were investigated through γ-ray and invariant-mass spectroscopy. Level energies were calculated from the nuclear shell model employing a phenomenological internucleon interaction. Theoretical cross sections to states were calculated from distorted-wave impulse approximation estimates multiplied by the shell model spectroscopic factors, which describe the wave function overlap of the ^{55}Sc ground state with states in ^{54}Ca. Despite the calculations showing a significant amplitude of excited neutron configurations in the ground-state of ^{55}Sc, valence proton removals populated predominantly the ground state of ^{54}Ca. This counterintuitive result is attributed to pairing effects leading to a dominance of the ground-state spectroscopic factor. Owing to the ubiquity of the pairing interaction, this argument should be generally applicable to direct knockout reactions from odd-even to even-even nuclei.

Exclusive cross sections and momentum distributions have been measured for quasifree one-neutron knockout reactions from a ^{54}Ca beam striking on a liquid hydrogen target at ∼200  MeV/u. A significantly larger cross section to the p&#95;{3/2} state compared to the f&#95;{5/2} state observed in the excitation of ^{53}Ca provides direct evidence for the nature of the N=34 shell closure. This finding corroborates the arising of a new shell closure in neutron-rich calcium isotopes. The distorted-wave impulse approximation reaction formalism with shell model calculations using the effective GXPF1Bs interaction and ab initio calculations concur our experimental findings. Obtained transverse and parallel momentum distributions demonstrate the sensitivity of quasifree one-neutron knockout in inverse kinematics on a thick liquid hydrogen target with the reaction vertex reconstructed to final state spin-parity assignments.

The first γ-ray spectroscopy of ^{52}Ar, with the neutron number N=34, was measured using the ^{53}K(p,2p) one-proton removal reaction at ∼210  MeV/u at the RIBF facility. The 2&#95;{1}^{+} excitation energy is found at 1656(18) keV, the highest among the Ar isotopes with N>20. This result is the first experimental signature of the persistence of the N=34 subshell closure beyond ^{54}Ca, i.e., below the magic proton number Z=20. Shell-model calculations with phenomenological and chiral-effective-field-theory interactions both reproduce the measured 2&#95;{1}^{+} systematics of neutron-rich Ar isotopes, and support a N=34 subshell closure in ^{52}Ar.

Myeloperoxidase (MPO) is a cationic heme enzyme stored in neutrophilic polymorphonuclear leukocytes (PMNs) that has recently been implicated in inflammatory cell signaling and tissue damage. Although PMNs play a critical role in both innate immunity and vascular thrombosis, no previous study has systematically investigated the effect of MPO on blood coagulation. Here, we show that PMN-derived MPO inhibits the procoagulant activity (PCA) of lipidated recombinant human tissue factor (rhTF) in a time- and concentration-dependent manner that involves, but is not entirely dependent on the enzyme's catalytic activity. Similarly, MPO together with its substrate, H2O2, inhibited the PCA of plasma microvesicles isolated from lipopolysaccharide (LPS)-stimulated whole blood, an effect additive to that of a function blocking TF antibody. Treatment of whole blood with LPS or phorbol-myristate-acetate dramatically increased MPO plasma levels, and co-incubation with 4-ABAH, a specific MPO inhibitor, significantly enhanced the PCA in plasma supernatants. MPO and MPO/H2O2 also inhibited the PCA of activated platelets and purified phospholipids (PLs), suggesting that modulation of negatively charged PLs, i.e., phosphatidylserine, rather than direct interference with the TF/FVIIa initiation complex was involved. Consistently, pretreatment of activated platelets with MPO or MPO/H2O2 attenuated the subsequent binding of lactadherin, which specifically recognizes procoagulant PS on cell membranes. Finally, endogenously released MPO regulated the PCA of THP1 cells in an autocrine manner dependent on the binding to CD11b/CD18 integrins. Collectively, these findings indicate that MPO is a negative regulator of PL-dependent coagulation and suggest a more complex role of activated PMNs in haemostasis and thrombosis., Competing Interests: Conflict of Interest: The authors declare no competing financial interests.

Adipic acid is a high-value compound used primarily as a precursor for the synthesis of nylon, coatings, and plastics. Today it is produced mainly in chemical processes from petrochemicals like benzene. Because of the strong environmental impact of the production processes and the dependence on fossil resources, biotechnological production processes would provide an interesting alternative. Here we describe the first engineered Saccharomyces cerevisiae strain expressing a heterologous biosynthetic pathway converting the intermediate 3-dehydroshikimate of the aromatic amino acid biosynthesis pathway via protocatechuic acid and catechol into cis,cis-muconic acid, which can be chemically dehydrogenated to adipic acid. The pathway consists of three heterologous microbial enzymes, 3-dehydroshikimate dehydratase, protocatechuic acid decarboxylase composed of three different subunits, and catechol 1,2-dioxygenase. For each heterologous reaction step, we analyzed several potential candidates for their expression and activity in yeast to compose a functional cis,cis-muconic acid synthesis pathway. Carbon flow into the heterologous pathway was optimized by increasing the flux through selected steps of the common aromatic amino acid biosynthesis pathway and by blocking the conversion of 3-dehydroshikimate into shikimate. The recombinant yeast cells finally produced about 1.56 mg/liter cis,cis-muconic acid.

Background: Previous studies have demonstrated that nociceptin/orphanin FQ (N/OFQ), the endogenous peptide ligand for the G-protein-coupled NOP receptor, inhibits cough in experimental models. SCH 225288 is a nonpeptide, orally active NOP agonist that may provide the foundation for the development of novel treatments for cough., Methods: First we characterized the selectivity of SCH 225288 in human receptor binding assays. Afterwards, the antitussive activity of SCH 225288 was studied in three mechanistically distinct cough models. Specifically, we observed the cough-suppressant effect of SCH 225288 in a guinea pig capsaicin irritant-evoked cough model, a feline mechanically induced cough model and finally in a canine Bordetella bronchiseptica disease model., Results: SCH 225288 selectively binds human NOP receptor (K(i) = 0.38 +/- 0.02 nmol/l) over classical opioid receptors (COR). In a guinea pig capsaicin cough model, SCH 225288 (0.1-1 mg/kg) suppressed cough at 2, 4, and 6 h after oral administration. The antitussive effect of SCH 225288 (3.0 mg/kg, p.o.) was blocked by the NOP antagonist J113397 (12 mg/kg, i.p.) but not by the classical opioid receptor (COR) antagonist, naltrexone (3.0 mg/kg, i.p.). In the anesthetized cat, we evaluated the effects of SCH 225288 given either intravenously or via the intravertebral artery against the increases in cough number and respiratory expiratory and inspiratory muscle (rectus abdominis and parasternal) electromyographic (EMG) activities due to perturbations of the intrathoracic trachea. SCH 225288 (0.03-3.0 mg/kg, i.v.) inhibited both cough number and abdominal EMG amplitudes. Similarly, SCH 225288 (0.001-0.3 mg/kg) administered intra-arterially also diminished cough number and abdominal EMG amplitudes. No significant effect of the drug was noted on parasternal EMG activity. Finally, we studied the antitussive actions of SCH 225288 (1.0 mg/kg) in a canine B. bronchiseptica disease model. In this model, dogs were challenged intranasally with B. bronchiseptica. Comparisons were made between a vehicle group, an SCH 225288 (1.0 mg/kg, p.o., q.d.) and a butorphanol (0.6 mg/kg, p.o., b.i.d.) group on the mean change in cough scores from baseline values and days 6-9 after B. bronchiseptica challenge. SCH 225288 (1.0 mg/kg, p.o., q.d.) displayed a positive antitussive tendency (p = 0.06) to inhibit B. bronchiseptica cough whereas butorphanol (0.6 mg/kg, p.o., b.i.d.) was devoid of antitussive activity., Conclusions: Taken together, the present data show that SCH 225288 is a potent and effective antitussive agent in animal models of cough. Furthermore, these findings indicate that NOP agonists represent a promising new therapeutic approach for the treatment of cough without the side effect liabilities associated with opioid antitussives., (Copyright 2009 S. Karger AG, Basel.)

Injuries of the penis are uncommon but represent urological emergencies. We report 3 cases of penile trauma illustrating the diversity of penile injury presentation. Radiological investigations are only mandatory if there is any suspicion of a urethral injury. Primary surgical approach is recommended in cases of penile fracture or local wound infection. An immediate operative exploration with removal of hematoma and primary defect closure should be done in every case. Surgical management should not be delayed to avoid late complications., (2008 S. Karger AG, Basel)

Healthy dogs with low antibody titer to Bordetella bronchiseptica were vaccinated intranasally with an avirulent live vaccine, subcutaneously with an antigen extract vaccine, or subcutaneously and intranasally with a placebo. Intranasally vaccinated dogs developed B. bronchiseptica-specific IgA titers in nasal secretions that remained at high levels until the end of the study; dogs vaccinated subcutaneously with the antigen extract or placebo did not develop measurable antigen-specific IgA titers in nasal secretions. Dogs were challenged with virulent live B. bronchiseptica 63 days after vaccination. Intranasally vaccinated dogs had significantly lower cough scores (P < or =.0058) and shed significantly fewer challenge organisms (P <.0001) than dogs in either of the other groups. Cough scores of subcutaneously vaccinated dogs were not significantly different from placebo-vaccinated dogs.

Transposon Tn5-B22 mutagenesis was used to identify genetic determinants required for arsenite [As(III)] oxidation in an Agrobacterium tumefaciens soil isolate, strain 5A. In one mutant, the transposon interrupted modB, which codes for the permease component of a high-affinity molybdate transporter. In a second mutant, the transposon insertion occurred in mrpB, which is part of a seven-gene operon encoding an Mrp-type Na+:H+ antiporter complex. Complementation experiments with mod and mrp operons PCR cloned from the genome-sequenced A. tumefaciens strain C58 resulted in complementation back to an As(III)-oxidizing phenotype, confirming that these genes encode activities essential for As(III) oxidation in this strain of A. tumefaciens. As expected, the mrp mutant was extremely sensitive to NaCl and LiCl, indicating that the Mrp complex in A. tumefaciens is involved in Na+ circulation across the membrane. Gene expression studies (lacZ reporter and reverse transcriptase PCR experiments) failed to show evidence of transcriptional regulation of the mrp operon in response to As(III) exposure, whereas expression of the mod operon was found to be up-regulated by As(III) exposure. In each mutant, the loss of As(III)-oxidizing capacity resulted in conversion to an arsenate [As(V)]-reducing phenotype. Neither mutant was more sensitive to As(III) than the parental strain.

The fruit fly Tephritis bardanae infests flower heads of two burdock hosts, Arctium tomentosum and A. minus. Observations suggest host-associated mating and behavioural differences at oviposition indicating host-race status. Previously, flies from each host plant were found to differ slightly in allozyme allele frequencies, but these differences could as well be explained by geographical separation of host plants. In the present study, we explicitly test whether genetic and morphological variance among T. bardanae are explained best by host-plant association or by geographical location, and if this pattern is stable over a 10-year period. Populations of A. tomentosum flies differed significantly from those of A. minus flies in (i) allozyme allele frequencies at the loci Pep-A and Pgd, (ii) mtDNA haplotype frequencies and (iii) wing size. In contrast, geographical location had no significant influence on the variance estimates. While it remains uncertain whether morphometric differentiation reflects genotypic variability or phenotypic plasticity, allozyme and mtDNA differentiation is genetically determined. This provides strong evidence for host-race formation in T. bardanae. However, the levels of differentiation are relatively low indicating that the system is in an early stage of divergence. This might be due to a lack of time (i.e. the host shift occurred recently) or due to relatively high gene flow preventing much differentiation at loci not experiencing selection.

Complex coacervation has been investigated on mixtures of beta-lactoglobulin (beta-lg) and acacia gum (AG) at pH 4.2 where these two macromolecules interact electrostatically. Changes in beta-lg/AG complex coacervation induced by the presence of beta-lg aggregates were considered. The nature and structure of particles resulting from complex coacervation were determined by using confocal scanning laser microscopy (CSLM). CSLM revealed fundamental differences in the structure of each of the studied dispersions (at 1 wt.% total concentration). Spherical vesicular coacervates and precipitates (based on beta-lg aggregates) were the hallmark of BLG/AG dispersions (beta-lg dispersion containing insoluble aggregates). Only coacervates were visible in AF-BLG/AG dispersions (beta-lg dispersion free of insoluble aggregates). The latter were characterised by the presence of large foam-like coacervates induced by partial coalescence of single coacervates, especially at the 2:1 protein to polysaccharide (Pr:Ps) ratio. Diffusing wave spectroscopy (DWS) was used to study the stability of dispersions as a function of time. Depending on the Pr:Ps ratio and the presence of beta-lg aggregates, the intensity correlation function (g(2)(t)) shifted to lower correlation times rapidly after mixing of both macromolecules. This revealed the formation of a large number of small particles, characterised by faster Brownian motion. At 1 and 5 wt.% total concentration, the 8:1 Pr:Ps ratio exhibited a rapid decrease of the backscattered intensity in time, both for BLG/AG and AF-BLG/AG mixtures, revealing rapid sedimentation/coalescence of particles. This precluded the achievement of a stable correlation function. For the 2:1 Pr:Ps ratio, mixtures exhibited both coalescence and sedimentation phenomena as confirmed by shifts in the g(2)(t) towards larger correlation times and the decrease of the initial value of g(2)(t) with time. Mixtures obtained for the 1:1 Pr:Ps ratio were characterised by small variations in the DWS signal, emphasising the stability of produced particles. The increase of the total biopolymer concentration reduced the effect of both Pr:Ps ratio and presence of protein aggregates. From CSLM and DWS observations, possible differences in the complex coacervation mechanism in both types of mixtures were highlighted. The use of protein aggregates to control complex coacervation was underlined.

The preparation of nanoparticles (NP) as an improved colloidal carrier system for proteins was investigated. Bovine serum albumin (BSA) was used as model drug. Owing to the high solubility of the protein in water, the double emulsion technique has been chosen as one of the most appropriate method. In order to both reaching submicron size as well as increasing the grade of monodispersity compared to previous preparation techniques, a microfluidizer as homogenization device was used. All experiments were performed using two biodegradable polymers, poly[D,L-lactic-co-glycolic acid] 50/50 (PLGA) and poly[epsilon-caprolactone] (PCL). The homogenization procedure has been optimized with regard to particle size and monodispersity by studying the influence of the homogenization time as well as the amount of polymer and surfactant in the external aqueous phase. The drug loading has been improved by varying the concentration of the protein in the inner aqueous phase. By increasing the protein concentration in the inner aqueous phase the polydispersity was slightly higher, while the particle size was not influenced significantly. The BSA encapsulation efficiency decreased with higher protein concentration in the inner aqueous phase. All release profiles were characterized by a initial burst effect, a higher release rate was obtained after 4 weeks for PLGA NP (60%) compared with PCL NP (47%).

The potential of confocal laser scanning microscope (CLSM) has been evaluated for characterizing microcapsules. The aim was to visualize the polymer distribution within the particle wall, and to localize and to quantify the encapsulated oil phase. Microcapsules were prepared by complex coacervation: the oil phase, gelatine, and arabic gum were labelled with fluorescent markers. For all compounds it was proved that fluorescence labelling did not alter physico-chemical properties critical to the encapsulation process. Labelling of the inner oil phase allowed us to identify and to localize, three-dimensionally, the encapsulated compound. A homogeneous distribution for both gelatine and arabic gum throughout the capsule wall was observed. The addition of fluorescently labelled casein as a macromolecular model compound to the coacervate resulted in an inhomogeneous distribution of casein within the wall material, the highest concentration of casein was found at the oil-wall interface. To determine the encapsulation rate, CLSM pictures of the microcapsule samples were acquired using different fluorescence labels for the microcapsule wall polymers and the incorporated oil phase, respectively. By applying computational image analysis, the volumes of the different phases were calculated. Comparing the results of non-destructive image analysis with those obtained by degradation, extraction and chemical analysis, a linear relation was found with correlation coefficients better than 0.980.

The aim of the present work was to investigate the preparation of nanoparticles (NP) as potential drug carriers for proteins. The hydrophilic protein bovine serum albumin (BSA) was chosen as the model drug to be incorporated within NP. Owing to the high solubility of the protein in water, the double emulsion technique has been chosen as one of the most appropriate method. In order to reach submicron size we used a microfluidizer as a homogenization device with a view to obtaining NP with a very high grade of monodispersity. Two different biodegradable polymers, poly[D, L-lactic-co-glycolic acid] 50/50 (PLGA) and poly[epsilon-caprolactone] (PCL) has been used for the preparation of the NP. The drug loading has been optimized by varying the concentration of the protein in the inner aqueous phase, the polymer in the organic phase, the surfactant in the external aqueous phase, as well as the volume of the external aqueous phase. The BSA encapsulation efficiency was high (>80%) and release profiles were characterized by a substantial initial burst release for both PLGA and PCL NP. A higher release was obtained at the end of the dissolution study for PLGA NP (92%) compared with PCL NP (72%)., (Copyright.)

Two cases of scleroderma and carcinoma of the lung are reported. The 16 previously reported cases in the English literature are reviewed and tabulated in an attempt to determine the pathological and clinical presentation of carcinoma of the lung superimposed on the sclerodermal lung. When patients with scleroderma develop a change in pulmonary symptoms, a superimposed cancer of the lung should be suspected. The relationship between interstitial pulmonary inflammatory disease and cancer of the lung is discussed.

Forty-two patients with various abdominal wall hernias and five patients with inguinal hernias were studied with ultrasonography. Thirteen patients were studied by CT. Although hernias are usually apparent on physical examination, difficulty in diagnosis may be encountered in some patients. Ultrasonography and CT are not only capable of diagnosing hernia in such instances, they are also helpful in the clinical management of the patients by demonstrating the precise location and extent of the muscular defect. However, the hernia may simulate a mass or cyst in the ultrasonograph and CT scan and one should carefully demonstrate intraperitoneal communication through a muscular defect or a herniated bowl loop within the hernia in order to avoid misdiagnosis. Pseudohernias due to localized thinning or thickening of the rectus muscle were also observed in five patients.