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The U-turn is a classical three-dimensional RNA folding motif first identified in the anticodon and T-loops of tRNAs. It also occurs frequently as a building block in other functional RNA structures in many different sequence and structural contexts. U-turns induce sharp changes in the direction of the RNA backbone and often conform to the 3-nt consensus sequence 5'-UNR-3' (N = any nucleotide, R = purine). The canonical U-turn motif is stabilized by a hydrogen bond between the N3 imino group of the U residue and the 3' phosphate group of the R residue as well as a hydrogen bond between the 2'-hydroxyl group of the uridine and the N7 nitrogen of the R residue. Here, we demonstrate that a protonated cytidine can functionally and structurally replace the uridine at the first position of the canonical U-turn motif in the apical loop of the neomycin riboswitch. Using NMR spectroscopy, we directly show that the N3 imino group of the protonated cytidine forms a hydrogen bond with the backbone phosphate 3' from the third nucleotide of the U-turn analogously to the imino group of the uridine in the canonical motif. In addition, we compare the stability of the hydrogen bonds in the mutant U-turn motif to the wild type and describe the NMR signature of the C+-phosphate interaction. Our results have implications for the prediction of RNA structural motifs and suggest simple approaches for the experimental identification of hydrogen bonds between protonated C-imino groups and the phosphate backbone.
Conjugated vaccines consisting of flagellin and antigen activate TLR5 and induce strong innate and adaptive immune responses. Objective of the present study was to gain further insight into the mechanisms by which flagellin fusion proteins mediate their immune modulating effects. In a mouse model of Ova-induced intestinal allergy a fusion protein of flagellin and Ova (rflaA:Ova) was used for intranasal and intraperitoneal vaccination. Aggregation status of flaA, Ova and flaA:Ova were compared by light scattering, uptake of fluorescence labeled proteins into mDC was analyzed, processing was investigated by microsomal digestion experiments. Mechanism of DC-activation was investigated using proteasome and inflammasome inhibitors. Immune responses of wildtype, IL-10−/−, TLR5−/− mDCs and Ova-transgenic T cells were investigated. Mucosal and i.p.-application of rflaA:Ova were able to prevent allergic sensitization, suppress disease-related symptoms, prevent body weight loss and reduction in food uptake. Intranasal vaccination resulted in strongest suppression of Ova-specific IgE production. These protective effects were associated with increased aggregation of rflaA:Ova and accompanied by tenfold higher uptake rates into mDC compared to the mixture of both proteins. Microsomal digestion showed that stimulation with rflaA:Ova resulted in faster degradation and the generation of different peptides compared to rOva. rflaA:Ova-mediated activation of mDC could be suppressed in a dose-dependent manner by the application of both inflammasome and proteasome inhibitors. Using TLR5−/− mDC the rflaA:Ova induced IL-10 secretion was shown to be TLR5 dependent. In co-cultures of IL-10−/− mDC with DO11.10 T cells the lack of rflaA:Ova-mediated IL-10 secretion resulted in enhanced levels of both TH2 (IL-4, IL-5) and TH1 (IL-2 and IFN-y) cytokines. In summary, mucosal vaccination with flaA:Ova showed strongest preventive effect. Stimulation with rflaA:Ova results in strong immune modulation mediated by enhanced uptake of the aggregated fusion protein, likely resulting in a different processing by DC as well as stronger TLR5 mediated cell activation.
Moderate physical activity improves various cognitive functions, particularly when it is applied simultaneously to the cognitive task. In two psychoneuroendocrinological within-subject experiments, we investigated whether very low-intensity motor activity, i.e. walking, during foreign-language vocabulary encoding improves subsequent recall compared to encoding during physical rest. Furthermore, we examined the kinetics of brain-derived neurotrophic factor (BDNF) in serum and salivary cortisol. Previous research has associated both substances with memory performance.In both experiments, subjects performed better when they were motorically active during encoding compared to being sedentary. BDNF in serum was unrelated to memory performance. In contrast we found a positive correlation between salivary cortisol concentration and the number of correctly recalled items. In summary, even very light physical activity during encoding is beneficial for subsequent recall.
Background: High-intensity focused ultrasound (HIFU) allows to inflict intracorporal thermal lesions without penetrating the skin or damaging the surrounding tissue. This analysis intends to assess the magnitude of HIFU-induced ablations within benign thyroid nodules using scintigraphic imaging with 99mTc.
Methods: Ten cold, hot, or indifferent nodules were treated using multiple pulses of HIFU to induce temperatures of around 85°C within the ablation zone. Pre- and posttreatment, uptake values of 99mTc pertechnetate or 99mTc-MIBI were recorded. The pre-post reduction of nodular uptake was evaluated to assess ablation magnitude.
Results: Relative nodular uptake in relation to total thyroidal uptake decreased after one session of HIFU in all cases. Median 99mTc-MIBI uptake reduction was 35.5% (ranging from 11% to 57%; p < 0.1), while 99mTc-pertechnetate scintigraphy showed a median uptake reduction of 27% (range 10% to 44%; p < 0.1). No major complications were observed.
Conclusions: HIFU appears to be safe and is an easy to perform means of thermal ablation. This study shows that HIFU treatment in thyroidal nodules can be evaluated by scintigraphic means shortly after the intervention. Due to small sample size, the exact magnitude of HIFU ablation efficiency in thyroidal nodules remains a value to beassessed in a larger study.
Highly promising preclinical data obtained in cultured cells and in nude mice bearing xenografts contrast with the rather modest clinical efficacy of Polo-like kinase 1 (Plk1) inhibitors. In the present study, we investigated if Plk1 might be a suitable target in hepatocellular carcinoma (HCC) and if a genetically engineered mouse tumor model that well reflects the tumor cell and micro-environmental features of naturally occurring cancers might be suitable to study anti-Plk1 therapy. Analysis of Plk1 expression in human HCC samples confirmed that HCC express much higher Plk1 levels than the adjacent normal liver tissue. Inhibition of Plk1 by an adenovirus encoding for a short hairpin RNA against Plk1 or by the small-molecule inhibitor BI 2536 reduced the viability of HCC cell lines and inhibited HCC xenograft progression in nude mice. Treatment of transforming growth factor (TGF) α/c-myc bitransgenic mice with BI 2536 during hepatocarcinogenesis reduced the number of dysplastic foci and of Ki-67-positive cells within the foci, indicating diminished tumorigenesis. In contrast, BI 2536 had no significant effect on HCC progression in the transgenic mouse HCC model as revealed by magnetic resonance imaging. Measurement of BI 2536 by mass spectrometry revealed considerably lower BI 2536 levels in HCC compared with the adjacent normal liver tissue. In conclusion, low intratumoral levels are a novel mechanism of resistance to the Plk1 inhibitor BI 2536. Plk1 inhibitors achieving sufficient intratumoral levels are highly promising in HCC treatment.
A survey of spiders of the genus Scytodes Latreille, 1804 in Iran resulted in six species occurring in this country: Scytodes fusca Walckenaer, 1837, S. strandi Spassky, 1941, S. thoracica (Latreille, 1802), S. univittata Simon, 1882 and – recorded for the first time – S. arwa Rheims, Brescovit & van Harten, 2006 and S. makeda Rheims, Brescovit & van Harten, 2006. Illustrations of the newly recorded species and a key to all known Iranian species are presented.
Analysis of whole cell lipid extracts of bacteria by means of ultra-performance (UP)LC-MS allows a comprehensive determination of the lipid molecular species present in the respective organism. The data allow conclusions on its metabolic potential as well as the creation of lipid profiles, which visualize the organism's response to changes in internal and external conditions. Herein, we describe: i) a fast reversed phase UPLC-ESI-MS method suitable for detection and determination of individual lipids from whole cell lipid extracts of all polarities ranging from monoacylglycerophosphoethanolamines to TGs; ii) the first overview of a wide range of lipid molecular species in vegetative Myxococcus xanthus DK1622 cells; iii) changes in their relative composition in selected mutants impaired in the biosynthesis of α-hydroxylated FAs, sphingolipids, and ether lipids; and iv) the first report of ceramide phosphoinositols in M. xanthus, a lipid species previously found only in eukaryotes.
In reply to internal or external danger stimuli, the body orchestrates an inflammatory response. The endogenous triggers of this process are the damage-associated molecular patterns (DAMPs). DAMPs represent a heterogeneous group of molecules that draw their origin either from inside the various compartments of the cell or from the extracellular space. Following interaction with pattern recognition receptors in cross-talk with various non-immune receptors, DAMPs determine the downstream signaling outcome of septic and aseptic inflammatory responses. In this review, the diverse nature, structural characteristics, and signaling pathways elicited by DAMPs will be critically evaluated.
Na(+)/H(+) exchangers are essential for regulation of intracellular proton and sodium concentrations in all living organisms. We examined and experimentally verified a kinetic model for Na(+)/H(+) exchangers, where a single binding site is alternatively occupied by Na(+) or one or two H(+) ions. The proposed transport mechanism inherently down-regulates Na(+)/H(+) exchangers at extreme pH, preventing excessive cytoplasmic acidification or alkalinization. As an experimental test system we present the first electrophysiological investigation of an electroneutral Na(+)/H(+) exchanger, NhaP1 from Methanocaldococcus jannaschii (MjNhaP1), a close homologue of the medically important eukaryotic NHE Na(+)/H(+) exchangers. The kinetic model describes the experimentally observed substrate dependences of MjNhaP1, and the transport mechanism explains alkaline down-regulation of MjNhaP1. Because this model also accounts for acidic down-regulation of the electrogenic NhaA Na(+)/H(+) exchanger from Escherichia coli (EcNhaA, shown in a previous publication) we conclude that it applies generally to all Na(+)/H(+) exchangers, electrogenic as well as electroneutral, and elegantly explains their pH regulation. Furthermore, the electrophysiological analysis allows insight into the electrostatic structure of the translocation complex in electroneutral and electrogenic Na(+)/H(+) exchangers.
While patients with chronic hepatitis C virus (HCV) infection are treated in order to prevent liver-related morbidity and mortality, we rely on sustained virological response (SVR) as a virological biomarker to evaluate treatment efficacy in both clinical practice as well as in drug development. However, conclusive evidence for the clinical benefit of antiviral therapy or validity of SVR as surrogate marker, as derived from trials randomizing patients to a treatment or control arm, is lacking. In fact, the Hepatitis C Antiviral Long-term Treatment Against Cirrhosis (HALT-C) trial recently showed an increased mortality rate among interferon-treated patients compared to untreated controls. Consequently, the recommendation to treat patients with chronic HCV infection was challenged.
Here, we argue that the possible harmful effect of long-term low-dose pegylated interferon mono therapy, as was observed in the HALT-C trial cohort, cannot be extrapolated to potentially curative short-term treatment regimens. Furthermore, we discuss SVR as a surrogate biomarker, based on numerous studies which indicated an association between SVR and improvements in health-related quality of life, hepatic inflammation and fibrosis, and portal pressure as well as a reduced risk for hepatocellular carcinoma (HCC), liver failure and mortality.
Atrial fibrillation (AF) continues to be a leading cause of cerebrovascular morbidity and mortality resulting from cardioembolic stroke. Oral anticoagulation therapy has been shown to decrease the incidence of cardioembolic stroke in patients with AF by more than 50%. Appropriate use of anticoagulation with vitamin K antagonists requires precise adherence and monitoring. A number of factors that potentially induce patients' dissatisfaction reduce quality of patient life. New direct oral anticoagulants, such as the direct factor Xa inhibitors rivaroxaban, apixaban, edoxaban, and the thrombin inhibitor dabigatran, were developed to overcome the limitations of the conventional anticoagulant drugs. However, models to optimize the benefit of therapy and to ensure that therapy can be safely continued are missing for the new oral anticoagulants. This review will briefly describe the new oral anticoagulants dabigatran, rivaroxaban, apixaban, and edoxaban with focus on their use for prevention of embolic events in AF. Moreover, it will discuss the safety, efficacy, cost data, and benefit for patients' quality of life and adherence.
The study of neutron-induced reactions is of high relevance in a wide variety of fields, ranging from stellar nucleosynthesis and fundamental nuclear physics to applications of nuclear technology. In nuclear energy, high accuracy neutron data are needed for the development of Generation IV fast reactors and accelerator driven systems, these last aimed specifically at nuclear waste incineration, as well as for research on innovative fuel cycles. In this context, a high luminosity Neutron Time Of Flight facility, n_TOF, is operating at CERN since more than a decade, with the aim of providing new, high accuracy and high resolution neutron cross-sections. Thanks to the features of the neutron beam, a rich experimental program relevant to nuclear technology has been carried out so far. The program will be further expanded in the near future, thanks in particular to a new high-flux experimental area, now under construction.
The n_TOF facility operates at CERN with the aim of addressing the request of high accuracy nuclear data for advanced nuclear energy systems as well as for nuclear astrophysics. Thanks to the features of the neutron beam, important results have been obtained on neutron induced fission and capture cross sections of U, Pu and minor actinides. Recently the construction of another beam line has started; the new line will be complementary to the first one, allowing to further extend the experimental program foreseen for next measurement campaigns.
The radiative capture cross section of 238U is very important for the developing of new reactor technologies and the safety of existing ones. Here the preliminary results of the 238U(n,γ) cross section measurement performed at n_TOF with C6D6 scintillation detectors are presented, paying particular attention to data reduction and background subtraction.
We report on a polarization measurement of inclusive J/ψ mesons in the di-electron decay channel at mid-rapidity at 2 < pT < 6 GeV/c in p + p collisions at √s = 200 GeV. Data were taken with the STAR detector at RHIC. The J/ψ polarization measurement should help to distinguish between different models of the J/ψ production mechanism since they predict different pT dependences of the J/ψ polarization. In this analysis, J/ψ polarization is studied in the helicity frame. The polarization parameter λθ measured at RHIC becomes smaller towards high pT , indicating more longitudinal J/ψ polarization as pT increases. The result is compared with predictions of presently available models.
The hydrophobic thickness of membranes, which is manly defined by fatty acids, influences the packing of transmembrane domains of proteins and thus can modulate the activity of these proteins. We analyzed the dynamics of the dimerization of Glycophorin A (GpA) by molecular dynamics simulations to describe the fatty acid dependence of the transmembrane region assembly. GpA represents a well-established model for dimerization of single transmembrane helices containing a GxxxG motif in vitro and in silico. We performed simulations of the dynamics of the NMR-derived dimer as well as self-assembly simulations of monomers in membranes composed of different fatty acid chains and monitored the formed interfaces and their transitions. The observed dimeric interfaces, which also include the one known from NMR, are highly dynamic and converted into each other. The frequency of interface formation and the preferred transitions between interfaces similar to the interface observed by NMR analysis strongly depend on the fatty acid used to build the membrane. Molecular dynamic simulations after adaptation of the helix topology parameters to better represent NMR derived structures of single transmembrane helices yielded an enhanced occurrence of the interface determined by NMR in molecular dynamics simulations. Taken together we give insights into the influence of fatty acids and helix conformation on the dynamics of the transmembrane domain of GpA.
Single-pion production in proton-proton collisions at 1.25 GeV: measurements by HADES and a PWA
(2014)
We report on the single-pion production in proton-proton collisions at a kinetic energy of 1.25 GeV based on data measured with HADES. Exclusive channels npπ+ and ppπ0 were studied simultaneously. The parametrization of production cross sections of the one-pion final states by means of the resonance model has been obtained. Independently, the extraction of the leading partial waves in the data were analyzed within the framework of the partial wave analysis (PWA). Contributions for the production of ∆(1232) and N(1440) intermediate states have been deduced.
In the search for novel organic charge transfer salts with variable degrees of charge transfer we have studied the effects of two modifications of the recently synthesized donor–acceptor system [tetramethoxypyrene (TMP)]–[tetracyanoquinodimethane (TCNQ)]. One is of chemical nature by substituting the acceptor TCNQ molecules by F4TCNQ molecules. The second consists in simulating the application of uniaxial pressure along the stacking axis of the system. In order to test the chemical substitution, we have grown single crystals of the TMP–F4TCNQ complex and analyzed its electronic structure via electronic transport measurements, ab initio density functional theory (DFT) calculations and UV/VIS/IR absorption spectroscopy. This system shows an almost ideal geometrical overlap of nearly planar molecules stacked alternately (mixed stack) and this arrangement is echoed by a semiconductor-like transport behavior with an increased conductivity along the stacking direction. This is in contrast to TMP–TCNQ which shows a less pronounced anisotropy and a smaller conductivity response. Our band structure calculations confirm the one-dimensional behavior of TMP–F4TCNQ with pronounced dispersion only along the stacking axis. Infrared measurements illustrating the C[triple bond, length as m-dash]N vibration frequency shift in F4TCNQ suggest however no improvement in the degree of charge transfer in TMP–F4TCNQ with respect to TMP–TCNQ. In both complexes about 0.1e is transferred from TMP to the acceptor. Concerning the pressure effect, our DFT calculations on the designed TMP–TCNQ and TMP–F4TCNQ structures under different pressure conditions show that application of uniaxial pressure along the stacking axis of TMP–TCNQ may be the route to follow in order to obtain a much more pronounced charge transfer.
Neurons of the mammalian neocortex are produced by proliferating cells located in the ventricular zone (VZ) lining the lateral ventricles. This is a complex and sequential process, requiring precise control of cell cycle progression, fate commitment and differentiation. We have analyzed publicly available databases from mouse and human to identify candidate genes that are potentially involved in regulating early neocortical development and neurogenesis. We used a mouse in situ hybridization dataset (The Allen Institute for Brain Science) to identify 13 genes (Cdon, Celsr1, Dbi, E2f5, Eomes, Hmgn2, Neurog2, Notch1, Pcnt, Sox3, Ssrp1, Tead2, Tgif2) with high correlation of expression in the proliferating cells of the VZ of the neocortex at early stages of development (E15.5). We generated a similar human brain network using microarray and RNA-seq data (BrainSpan Atlas) and identified 407 genes with high expression in the developing human VZ and subventricular zone (SVZ) at 8–9 post-conception weeks. Seven of the human genes were also present in the mouse VZ network. The human and mouse networks were extended using available genetic and proteomic datasets through GeneMANIA. A gene ontology search of the mouse and human networks indicated that many of the genes are involved in the cell cycle, DNA replication, mitosis and transcriptional regulation. The reported involvement of Cdon, Celsr1, Dbi, Eomes, Neurog2, Notch1, Pcnt, Sox3, Tead2, and Tgif2 in neural development or diseases resulting from the disruption of neurogenesis validates these candidate genes. Taken together, our knowledge-based discovery method has validated the involvement of many genes already known to be involved in neocortical development and extended the potential number of genes by 100's, many of which are involved in functions related to cell proliferation but others of which are potential candidates for involvement in the regulation of neocortical development.
Pattern recognition applied to whole-brain neuroimaging data, such as functional Magnetic Resonance Imaging (fMRI), has proved successful at discriminating psychiatric patients from healthy participants. However, predictive patterns obtained from whole-brain voxel-based features are difficult to interpret in terms of the underlying neurobiology. Many psychiatric disorders, such as depression and schizophrenia, are thought to be brain connectivity disorders. Therefore, pattern recognition based on network models might provide deeper insights and potentially more powerful predictions than whole-brain voxel-based approaches. Here, we build a novel sparse network-based discriminative modeling framework, based on Gaussian graphical models and L1-norm regularized linear Support Vector Machines (SVM). In addition, the proposed framework is optimized in terms of both predictive power and reproducibility/stability of the patterns. Our approach aims to provide better pattern interpretation than voxel-based whole-brain approaches by yielding stable brain connectivity patterns that underlie discriminative changes in brain function between the groups. We illustrate our technique by classifying patients with major depressive disorder (MDD) and healthy participants, in two (event- and block-related) fMRI datasets acquired while participants performed a gender discrimination and emotional task, respectively, during the visualization of emotional valent faces.
Ribosome heterogeneity is of increasing biological significance and several examples have been described for multicellular and single cells organisms. In here we show for the first time a variation in ribose methylation within the 18S rRNA of Saccharomyces cerevisiae. Using RNA-cleaving DNAzymes, we could specifically demonstrate that a significant amount of S. cerevisiae ribosomes are not methylated at 2′-O-ribose of A100 residue in the 18S rRNA. Furthermore, using LC-UV-MS/MS of a respective 18S rRNA fragment, we could not only corroborate the partial methylation at A100, but could also quantify the methylated versus non-methylated A100 residue. Here, we exhibit that only 68% of A100 in the 18S rRNA of S.cerevisiae are methylated at 2′-O ribose sugar. Polysomes also contain a similar heterogeneity for methylated Am100, which shows that 40S ribosome subunits with and without Am100 participate in translation. Introduction of a multicopy plasmid containing the corresponding methylation guide snoRNA gene SNR51 led to an increased A100 methylation, suggesting the cellular snR51 level to limit the extent of this modification. Partial rRNA modification demonstrates a new level of ribosome heterogeneity in eukaryotic cells that might have substantial impact on regulation and fine-tuning of the translation process.
Background: Health-related and disease-specific quality of life (HRQoL) has been increasingly valued as relevant clinical parameter in cystic fibrosis (CF) clinical care and clinical trials. HRQoL measures should assess – among other domains – daily functioning from a patient’s perspective. However, validation studies for the most frequently used HRQoL questionnaire in CF, the Cystic Fibrosis Questionnaire (CFQ), have not included measures of physical activity or fitness. The objective of this study was, therefore, to determine the cross-sectional and longitudinal relationships between HRQoL, physical activity and fitness in patients with CF.
Methods: Baseline (n = 76) and 6-month follow-up data (n = 70) from patients with CF (age ≥12 years, FEV1 ≥35%) were analysed. Patients participated in two multi-centre exercise intervention studies with identical assessment methodology. Outcome variables included HRQoL (German revised multi-dimensional disease-specific CFQ (CFQ-R)), body composition, pulmonary function, physical activity, short-term muscle power, and aerobic fitness by peak oxygen uptake and aerobic power.
Results: Peak oxygen uptake was positively related to 7 of 13 HRQoL scales cross-sectionally (r = 0.30-0.46). Muscle power (r = 0.25-0.32) and peak aerobic power (r = 0.24-0.35) were positively related to 4 scales each, and reported physical activity to 1 scale (r = 0.29). Changes in HRQoL-scores were directly and significantly related to changes in reported activity (r = 0.35-0.39), peak aerobic power (r = 0.31-0.34), and peak oxygen uptake (r = 0.26-0.37) in 3 scales each. Established associates of HRQoL such as FEV1 or body mass index correlated positively with fewer scales (all 0.24 < r < 0.55).
Conclusions: HRQoL was associated with physical fitness, especially aerobic fitness, and to a lesser extent with reported physical activity. These findings underline the importance of physical fitness for HRQoL in CF and provide an additional rationale for exercise testing in this population.
Trial registration: ClinicalTrials.gov, NCT00231686
There are no European recommendations on issues specifically related to lung transplantation (LTX) in cystic fibrosis (CF). The main goal of this paper is to provide CF care team members with clinically relevant CF-specific information on all aspects of LTX, highlighting areas of consensus and controversy throughout Europe. Bilateral lung transplantation has been shown to be an important therapeutic option for end-stage CF pulmonary disease. Transplant function and patient survival after transplantation are better than in most other indications for this procedure. Attention though has to be paid to pretransplant morbidity, time for referral, evaluation, indication, and contraindication in children and in adults. This review makes extensive use of specific evidence in the field of lung transplantation in CF patients and addresses all issues of practical importance. The requirements of pre-, peri-, and postoperative management are discussed in detail including bridging to transplant and postoperative complications, immune suppression, chronic allograft dysfunction, infection, and malignancies being the most important. Among the contributors to this guiding information are 19 members of the ECORN-CF project and other experts. The document is endorsed by the European Cystic Fibrosis Society and sponsored by the Christiane Herzog Foundation.
5-Lipoxygenase (5LO) is a key enzyme in biosynthesis of leukotrienes (LTs), lipid mediators of inflammation. To study the roles of the 5LO accessory proteins coactosin-like protein (CLP) and 5LO-activating protein (FLAP), we knocked down these proteins in human monocytic cells. Our results show that expression of CLP was required for full cellular 5LO activity when cells were activated with Ca2+ ionophore, as well as with a physiological stimulus (lipopolysaccharide followed by N-formylmethionyl-leucyl-phenylalanine). During LT biosynthesis in stimulated cells, 5LO typically translocates to the nuclear membrane. This redistribution, from cytosolic to perinuclear, was clearly compromised in both CLP- and FLAP-deficient cells. Our results suggest that the CLP–5LO interaction may be a target for reduced LT production.
The phase diagram of the square lattice bilayer Hubbard model: a variational Monte Carlo study
(2014)
We investigate the phase diagram of the square lattice bilayer Hubbard model at half-filling with the variational Monte Carlo method for both the magnetic and the paramagnetic case as a function of the interlayer hopping and on-site Coulomb repulsion U. With this study we resolve some discrepancies in previous calculations based on the dynamical mean-field theory, and we are able to determine the nature of the phase transitions between metal, Mott insulator and band insulator. In the magnetic case we find only two phases: an antiferromagnetic Mott insulator at small for any value of U and a band insulator at large . At large U values we approach the Heisenberg limit. The paramagnetic phase diagram shows at small a metal to Mott insulator transition at moderate U values and a Mott to band insulator transition at larger U values. We also observe a re-entrant Mott insulator to metal transition and metal to band insulator transition for increasing in the range of . Finally, we discuss the phase diagrams obtained in relation to findings from previous studies based on different many-body approaches.
The traffic AAA-ATPase PilF is essential for pilus biogenesis and natural transformation of Thermus thermophilus HB27. Recently, we showed that PilF forms hexameric complexes containing six zinc atoms coordinated by conserved tetracysteine motifs. Here we report that zinc binding is essential for complex stability. However, zinc binding is neither required for pilus biogenesis nor natural transformation. A number of the mutants did not exhibit any pili during growth at 64 °C but still were transformable. This leads to the conclusion that type 4 pili and the DNA translocator are distinct systems. At lower growth temperatures (55 °C) the zinc-depleted multiple cysteine mutants were hyperpiliated but defective in pilus-mediated twitching motility. This provides evidence that zinc binding is essential for the role of PilF in pilus dynamics. Moreover, we found that zinc binding is essential for complex stability but dispensable for ATPase activity. In contrast to many polymerization ATPases from mesophilic bacteria, ATP binding is not required for PilF complex formation; however, it significantly increases complex stability. These data suggest that zinc and ATP binding increase complex stability that is important for functionality of PilF under extreme environmental conditions.
Several microRNAs (miRNAs) are associated with the molecular pathogenesis of hepatocellular carcinoma (HCC). However, previous studies analyzing the dysregulation of miRNAs in HCC show heterogeneous results. We hypothesized that part of this heterogeneity might be attributable to variations of miRNA expression deriving from the HCC capsule or the fibrotic septa within the peritumoral tissue used as controls. Tissue from surgically resected hepatitis C–associated HCC from six well-matched patients was microdissected using laser microdissection and pressure catapulting technique. Four distinct histologic compartments were isolated: tumor parenchyma (TP), fibrous capsule of the tumor (TC), tumor-adjacent liver parenchyma (LP), and cirrhotic septa of the tumor-adjacent liver (LC). MiRNA expression profiling analysis of 1105 mature miRNAs and precursors was performed using miRNA microarray. Principal component analysis and consecutive pairwise supervised comparisons demonstrated distinct patterns of expressed miRNAs not only for TP versus LP (e.g., intratumoral down-regulation of miR-214, miR-199a, miR-146a, and miR-125a; P< .05) but also for TC versus LC (including down-regulation within TC of miR-126, miR-99a/100, miR-26a, and miR-125b; P< .05). The tumor capsule therefore demonstrates a tumor-like phenotype with down-regulation of well-known tumor-suppressive miRNAs. Variations of co-analyzed fibrotic tissue within the tumor or in controls may have profound influence on miRNA expression analyses in HCC. Several miRNAs, which are proposed to be HCC specific, may indeed be rather associated to the tumor capsule. As miRNAs evolve to be important biomarkers in liver tumors, the presented data have important translational implications on diagnostics and treatment in patients with HCC.
Electromagnetic calorimeter (ECAL) is being developed to complement dilepton spectrometer HADES. ECAL will enable the HADES@FAIR experiment to measure data on neutral meson production in heavy ion collisions at the energy range of 2-10 AGeV on the beam of future accelerator SIS100@FAIR. We will report results of the last beam test with quasi-monoenergetic photons carried out in MAMI facility at Johannes Gutenberg Universität Mainz.
Background: Simple peak-picking algorithms, such as those based on lineshape fitting, perform well when peaks are completely resolved in multidimensional NMR spectra, but often produce wrong intensities and frequencies for overlapping peak clusters. For example, NOESY-type spectra have considerable overlaps leading to significant peak-picking intensity errors, which can result in erroneous structural restraints. Precise frequencies are critical for unambiguous resonance assignments.
Results: To alleviate this problem, a more sophisticated peaks decomposition algorithm, based on non-negative matrix factorization (NMF), was developed. We produce peak shapes from Fourier-transformed NMR spectra. Apart from its main goal of deriving components from spectra and producing peak lists automatically, the NMF approach can also be applied if the positions of some peaks are known a priori, e.g. from consistently referenced spectral dimensions of other experiments.
Conclusions: Application of the NMF algorithm to a three-dimensional peak list of the 23 kDa bi-domain section of the RcsD protein (RcsD-ABL-HPt, residues 688-890) as well as to synthetic HSQC data shows that peaks can be picked accurately also in spectral regions with strong overlap.
Background: Influenza vaccination of healthcare workers (HCWs) is recommended to prevent the transmission of influenza to vulnerable patients. Nevertheless, vaccination coverage rates of HCWs in European countries have been low.
Aim: To investigate the relative and combined strength of sociocognitive variables, from past research, theory and a qualitative study, in explaining the motivation of HCWs to receive the influenza vaccine.
Methods: An anonymous, online questionnaire was distributed among HCWs in hospital settings in Belgium, Germany and the Netherlands between February and April 2013.
Findings: Attitude and past vaccination uptake explained a considerable amount of variance in the intention of HCWs to receive the influenza vaccine. Moreover, low perceived social norms, omission bias, low moral norms, being older, having no patient contact, and being Belgian or Dutch (compared with German) increased the probability of having no intention to receive the influenza vaccine compared with being undecided about vaccination. High intention to receive the influenza vaccine was shown to be more likely than being undecided about vaccination when HCWs had high perceived susceptibility of contracting influenza, low naturalistic views, and lower motivation to receive the vaccine solely for self-protection.
Conclusion: Country-specific interventions and a focus on different sociocognitive variables depending on the intention/lack of intention of HCWs to receive the influenza vaccine may be beneficial to promote vaccination uptake.
MTO1-deficient mouse model mirrors the human phenotype showing complex I defect and cardiomyopathy
(2014)
Recently, mutations in the mitochondrial translation optimization factor 1 gene (MTO1) were identified as causative in children with hypertrophic cardiomyopathy, lactic acidosis and respiratory chain defect. Here, we describe an MTO1-deficient mouse model generated by gene trap mutagenesis that mirrors the human phenotype remarkably well. As in patients, the most prominent signs and symptoms were cardiovascular and included bradycardia and cardiomyopathy. In addition, the mutant mice showed a marked worsening of arrhythmias during induction and reversal of anaesthesia. The detailed morphological and biochemical workup of murine hearts indicated that the myocardial damage was due to complex I deficiency and mitochondrial dysfunction. In contrast, neurological examination was largely normal in Mto1-deficient mice. A translational consequence of this mouse model may be to caution against anaesthesia-related cardiac arrhythmias which may be fatal in patients.
The diagnosis of drug induced liver injury (DILI) is based primarily on the exclusion of alternative causes. To assess the frequency of alternative causes in initially suspected DILI cases, we searched the Medline database with the following terms: drug hepatotoxicity, drug induced liver injury, and hepatotoxic drugs. For each term, we used the first 100 publications. We reviewed references, selected those reports relevant to our study, and retrieved finally 15 publications related to DILI and alternative causes. A total of 2,906 cases of initially assumed DILI were analyzed in these 15 publications, with diagnoses missed in 14% of the cases due to overt alternative causes. In another 11%, the diagnosis of DILI could not be established because of confounding variables. Alternative diagnoses included hepatitis B, C, and E, CMV, EBV, ischemic hepatitis, autoimmune hepatitis, primary biliary cirrhosis, primary sclerosing cholangitis, hemochromatosis, Wilson’s disease, Gilbert’s syndrome, fatty liver, non alcoholic steatohepatitis, alcoholic liver diseases, cardiac and thyroid causes, rhabdomyolysis, polymyositis, postictal state, tumors, lymphomas, chlamydial and HIV infections. Causality assessment methods applied in these 15 publications were the CIOMS (Council for International Organizations of Medical Sciences) scale alone (n = 5) or combined with the Maria and Victorino (MV) scale (n = 1), the DILIN (Drug-Induced Liver Injury Network) method (n = 4), or the Naranjo scale (n = 1); the qualitative CIOMS method alone (n = 3) or combined with the MV scale (n = 1). In conclusion, alternative diagnoses are common in primarily suspected DILI cases and should be excluded early in future cases, requiring a thorough clinical and causality assessment.
We present a simultaneous calculation of heavy single-Λ hypernuclei and compact stars containing hypernuclear core within a relativistic density functional theory based on a Lagrangian which includes the hyperon octet and lightest isoscalar-isovector mesons which couple to baryons with density-dependent couplings. The corresponding density functional allows for SU(6) symmetry breaking and mixing in the isoscalar sector, whereby the departures in the σ–Λ and σ–Σ couplings away from their values implied by the SU(3) symmetric model are used to adjust the theory to the laboratory and astronomical data. We fix σ–Λ coupling using the data on the single-Λ hypernuclei and derive an upper bound on the σ–Σ from the requirement that the lower bound on the maximum mass of a compact star is 2M⊙.
Autophagy plays an essential role in maintaining an intricate balance between nutrient demands and energetic requirements during normal homeostasis. Autophagy recycles metabolic substrates from nonspecific bulk degradation of proteins and excess or damaged organelles. Recent work posits an active and dynamic signaling role for extracellular matrix-evoked autophagic regulation, that is, allosteric and independent of prevailing nutrient conditions. Several candidates, representing a diverse repertoire of matrix constituents (decorin, collagen VI, laminin α2, endostatin, endorepellin, and kringle V), can modulate autophagic signaling pathways. Importantly, a novel principle indicates that matrix constituents can differentially modulate autophagic induction and repression via interaction with specific receptors. Most of the matrix-derived factors described here appear to control autophagy in a canonical manner but independent of nutrient deprivation. Because the molecular composition and structure of the extracellular matrix are dynamically remodeled during various physiological and pathological conditions, we propose that matrix-regulated autophagy is key for maintaining proper tissue homeostasis and disease prevention, such as cancer progression and muscular dystrophies.
We study vacuum masses of charmonia and the charm-quark diffusion coefficient in the quark-gluon plasma based on the spectral representation for meson correlators. To calculate the correlators, we solve the quark gap equation and the inhomogeneous Bethe–Salpeter equation in the rainbow-ladder approximation. It is found that the ground-state masses of charmonia in the pseudoscalar, scalar, and vector channels can be well described. For 1.5Tc<T<3.0Tc, the value of the diffusion coefficient D is comparable with that obtained by lattice QCD and experiments: 3.4<2πTD<5.9. Relating the diffusion coefficient with the ratio of shear viscosity to entropy density η/s of the quark-gluon plasma, we obtain values in the range 0.09<η/s<0.16.
We study the phase structure of QCD at finite temperature within a Polyakov-loop extended quark–meson model. Such a model describes the chiral as well as the confinement-deconfinement dynamics. In the present investigation, based on the approach and results put forward in [1], [2], [3], [4], both matter and glue fluctuations are included. We present results for the order parameters as well as some thermodynamic observables and find very good agreement with recent results from lattice QCD.
The colour-singlet axial-vector vertex plays a pivotal role in understanding dynamical chiral symmetry breaking and numerous hadronic weak interactions, yet scant model-independent information is available. We therefore use longitudinal and transverse Ward–Green–Takahashi (WGT) identities, together with kinematic constraints, in order to ameliorate this situation and expose novel features of the axial vertex: amongst them, Ward-like identities for elements in the transverse piece of the vertex, which complement and shed new light on identities determined previously for components in its longitudinal part. Such algebraic results are verified via solutions of the Bethe–Salpeter equation for the axial vertex obtained using two materially different kernels for the relevant Dyson–Schwinger equations. The solutions also provide insights that suggest a practical Ansatz for the axial-vector vertex.
Large herbivores are significant vectors for the long distance dispersal of seeds in various habitats, both attached to animals (epizoochory) and via gut passage (endozoochory). The majority of studies on epizoochory have examined dispersal in the fur of domesticated ungulates. Studies on wild ungulates are important to understand dispersal processes in many habitats, but rare due to methodological constraints. We studied epizoochory of seeds by European bison in an open-forest-mosaic (nutrient poor grassland and heathland, mixed forest) in NW Germany, where bison had been introduced for the purpose of nature conservation. At the study site it was possible to apply a method by which hoof material of freeranging bison was non-invasively collected. We identified a total of 1082 seeds from 32 plant species in the hoof material. The three most abundant species were Polygonum aviculare, Agrostis capillaris and Betula spp. Seed species originated from various habitat types of the study area, while the majority of seeds derived from trampled areas. Compared to the non-dispersed plant species of the study area, dispersed plant species had a higher seed longevity index, suggesting that many seeds were picked up from the soil seed bank. Epizoochory ranking indices of dispersed seed species, classifying the importance of epizoochory, revealed that transport in the fur may be of minor importance for many species, i.e. epizoochory by the hooves turned out to be negatively correlated to epizoochory in the fur. We conclude that European bison disperses a considerable number of seed species through trampling. Further research should consider epizoochory via the hooves and include integrative approaches to understand the different dispersal mechanisms by ungulates and their longterm synergetic effect on plant communities.
The Cueva del Azufre in Tabasco, Mexico, is a nutrient-rich cave and its inhabitants need to cope with high levels of dissolved hydrogen sulfide and extreme hypoxia. One of the successful colonizers of this cave is the poeciliid fish Poecilia mexicana, which has received considerable attention as a model organism to examine evolutionary adaptations to extreme environmental conditions. Nonetheless, basic ecological data on the endemic cave molly population are still missing; here we aim to provide data on population densities, size class compositions and use of different microhabitats. We found high overall densities in the cave and highest densities at the middle part of the cave with more than 200 individuals per square meter. These sites have lower H2S concentrations compared to the inner parts where most large sulfide sources are located, but they are annually exposed to a religious harvesting ceremony of local Zoque people called La Pesca. We found a marked shift in size/age compositions towards an overabundance of smaller, juvenile fish at those sites. We discuss these findings in relation to several environmental gradients within the cave (i.e., differences in toxicity and lighting conditions), but we also tentatively argue that the annual fish harvest during a religious ceremony (La Pesca) locally diminishes competition (and possibly, cannibalism by large adults), which is followed by a phase of overcompensation of fish densities.
Background: Different parameters have been determined for prediction of treatment outcome in hepatitis c virus genotype 1 infected patients undergoing pegylated interferon, ribavirin combination therapy. Results on the importance of vitamin D levels are conflicting. In the present study, a comprehensive analysis of vitamin D levels before and during therapy together with single nucleotide polymorphisms involved in vitamin D metabolism in the context of other known treatment predictors has been performed.
Methods: In a well characterized prospective cohort of 398 genotype 1 infected patients treated with pegylated interferon-α and ribavirin for 24–72 weeks (INDIV-2 study) 25-OH-vitamin D levels and different single nucleotide polymorphisms were analyzed together with known biochemical parameters for a correlation with virologic treatment outcome.
Results: Fluctuations of more than 5 (10) ng/ml in 25-OH-vitamin D-levels have been observed in 66 (39) % of patients during the course of antiviral therapy and neither pretreatment nor under treatment 25-OH-vitamin D-levels were associated with treatment outcome. The DHCR7-TT-polymorphism within the 7-dehydrocholesterol-reductase showed a significant association (P = 0.031) to sustained viral response in univariate analysis. Among numerous further parameters analyzed we found that age (OR = 1.028, CI = 1.002–1.056, P = 0.035), cholesterol (OR = 0.983, CI = 0.975–0.991, P<0.001), ferritin (OR = 1.002, CI = 1.000–1.004, P = 0.033), gGT (OR = 1.467, CI = 1.073–2.006, P = 0.016) and IL28B-genotype (OR = 2.442, CI = 1.271–4.695, P = 0.007) constituted the strongest predictors of treatment response.
Conclusions: While 25-OH-vitamin D-levels levels show considerable variations during the long-lasting course of antiviral therapy they do not show any significant association to treatment outcome in genotype 1 infected patients.
Background: Alzheimer's disease is a common debilitating dementia with known heritability, for which 20 late onset susceptibility loci have been identified, but more remain to be discovered. This study sought to identify new susceptibility genes, using an alternative gene-wide analytical approach which tests for patterns of association within genes, in the powerful genome-wide association dataset of the International Genomics of Alzheimer's Project Consortium, comprising over 7 m genotypes from 25,580 Alzheimer's cases and 48,466 controls.
Principal findings: In addition to earlier reported genes, we detected genome-wide significant loci on chromosomes 8 (TP53INP1, p = 1.4×10−6) and 14 (IGHV1-67 p = 7.9×10−8) which indexed novel susceptibility loci.
Significance: The additional genes identified in this study, have an array of functions previously implicated in Alzheimer's disease, including aspects of energy metabolism, protein degradation and the immune system and add further weight to these pathways as potential therapeutic targets in Alzheimer's disease.
The ability to delay gratification, to wait for a larger but delayed reward in the presence of a smaller but constantly available reward, has been shown to be predictive for various aspects of everyday life. For instance, preschool children who were better able to delay gratification achieved better school grades, a higher education, a better ability to cope with stress, as well as a reduced risk for being overweight or consume drugs up to 30 years later (Mischel et al., 2011). However, despite the importance of delay of gratification cognitive factors underlying individual differences are only poorly understood. Wittmann and Paulus (2008) suggested that individuals who overestimate the duration of time intervals experience waiting times as more costly and are, therefore, less likely to delay gratification. Furthermore, a recent study revealed an association between less accurate internal clock speed and a behavioral choice delay task (Corvi, Juergensen, Weaver, & Demaree, 2012). Further evidence for an association between temporal processing and delay of gratification can be derived from studies using clinical samples. For instance, children with attention-deficit/hyperactivity disorder (ADHD) consistently prefer smaller, immediate rewards over larger, delayed rewards and show impaired temporal processing (Sonuga-Barke, Bitsakou, & Thompson, 2010). However, no study has directly tested an association between a measure of temporal processing and a classical delay of gratification task in children with and without ADHD so far.
As part of a larger study, 64 children (29 with ADHD) aged between 8 to 12 years performed a version of an auditory duration discrimination task and a delay of gratification task. In the duration discrimination task, the children were presented with two unfilled intervals indicated by two brief tones each. The baseline interval lasted for 400 ms, while the comparison interval was always longer and adjusted up or down in 10 ms steps securing an accuracy of 80%. In the delay of gratification task, the children were instructed that they could either opt for one chocolate bar immediately or that they could wait to receive two chocolate bars. Unbeknownst to the children, the waiting time lasted 25 minutes but children were told that they could decide for the immediate chocolate bar at any time by ringing a bell.
Children with ADHD did not differ in their performance from children without ADHD in the duration discrimination task or the delay of gratification task. However, in the whole sample of children with and without ADHD, children who waited for the additional chocolate bar showed a better duration discrimination than children who failed to wait for the additional chocolate bar [t(62) = -2.52, p = .01].
We demonstrated an association between temporal processing ability and the ability to delay gratification. These results need to be replicated in further studies with larger sample sizes. Moreover, different tasks measuring temporal processing and delay of gratification should be used to further clarify the relationship of temporal processing, delay of gratification, and ADHD.
Recent density functional theory (DFT) calculations for KFe2As2 have been shown to be insufficient to satisfactorily describe angle-resolved photoemission (ARPES) measurements as well as observed de Haas–van Alphen (dHvA) frequencies. In the present work, we extend DFT calculations based on the full-potential linear augmented plane-wave method by dynamical mean field theory (DFT+DMFT) to include correlation effects beyond the local density approximation. We present results for two sets of reported crystal structures. Our calculations indicate that KFe2As2 is a moderately correlated metal with a mass renormalization factor of the Fe $3{\rm d}$ orbitals between 1.6 and 2.7. Furthermore, the obtained shape and size of the Fermi surface are in good agreement with ARPES measurements and we observe some topological changes with respect to DFT calculations such as the opening of an inner hole cylinder at the Z point. As a result, our calculated dHvA frequencies differ greatly from existing DFT results and qualitatively agree with experimental data. On this basis, we argue that correlation effects are important to understand the -presently under debate- nature of the superconducting state in KFe2As2.
Rare copy-number variation (CNV) is an important source of risk for autism spectrum disorders (ASDs). We analyzed 2,446 ASD-affected families and confirmed an excess of genic deletions and duplications in affected versus control groups (1.41-fold, p = 1.0 × 10(-5)) and an increase in affected subjects carrying exonic pathogenic CNVs overlapping known loci associated with dominant or X-linked ASD and intellectual disability (odds ratio = 12.62, p = 2.7 × 10(-15), ∼3% of ASD subjects). Pathogenic CNVs, often showing variable expressivity, included rare de novo and inherited events at 36 loci, implicating ASD-associated genes (CHD2, HDAC4, and GDI1) previously linked to other neurodevelopmental disorders, as well as other genes such as SETD5, MIR137, and HDAC9. Consistent with hypothesized gender-specific modulators, females with ASD were more likely to have highly penetrant CNVs (p = 0.017) and were also overrepresented among subjects with fragile X syndrome protein targets (p = 0.02). Genes affected by de novo CNVs and/or loss-of-function single-nucleotide variants converged on networks related to neuronal signaling and development, synapse function, and chromatin regulation.
Protein signatures of oxidative stress response in a patient specific cell line model for autism
(2014)
Background: Known genetic variants can account for 10% to 20% of all cases with autism spectrum disorders (ASD). Overlapping cellular pathomechanisms common to neurons of the central nervous system (CNS) and in tissues of peripheral organs, such as immune dysregulation, oxidative stress and dysfunctions in mitochondrial and protein synthesis metabolism, were suggested to support the wide spectrum of ASD on unifying disease phenotype. Here, we studied in patient-derived lymphoblastoid cell lines (LCLs) how an ASD-specific mutation in ribosomal protein RPL10 (RPL10[H213Q]) generates a distinct protein signature. We compared the RPL10[H213Q] expression pattern to expression patterns derived from unrelated ASD patients without RPL10[H213Q] mutation. In addition, a yeast rpl10 deficiency model served in a proof-of-principle study to test for alterations in protein patterns in response to oxidative stress.
Methods: Protein extracts of LCLs from patients, relatives and controls, as well as diploid yeast cells hemizygous for rpl10, were subjected to two-dimensional gel electrophoresis and differentially regulated spots were identified by mass spectrometry. Subsequently, Gene Ontology database (GO)-term enrichment and network analysis was performed to map the identified proteins into cellular pathways.
Results: The protein signature generated by RPL10[H213Q] is a functionally related subset of the ASD-specific protein signature, sharing redox-sensitive elements in energy-, protein- and redox-metabolism. In yeast, rpl10 deficiency generates a specific protein signature, harboring components of pathways identified in both the RPL10[H213Q] subjects' and the ASD patients' set. Importantly, the rpl10 deficiency signature is a subset of the signature resulting from response of wild-type yeast to oxidative stress.
Conclusions: Redox-sensitive protein signatures mapping into cellular pathways with pathophysiology in ASD have been identified in both LCLs carrying the ASD-specific mutation RPL10[H213Q] and LCLs from ASD patients without this mutation. At pathway levels, this redox-sensitive protein signature has also been identified in a yeast rpl10 deficiency and an oxidative stress model. These observations point to a common molecular pathomechanism in ASD, characterized in our study by dysregulation of redox balance. Importantly, this can be triggered by the known ASD-RPL10[H213Q] mutation or by yet unknown mutations of the ASD cohort that act upstream of RPL10 in differential expression of redox-sensitive proteins.
Global warming, changes in the hydrological cycle and enhanced marine primary productivity all have been invoked to have contributed to the occurrence of widespread ocean anoxia during the Cenomanian-Turonian Oceanic Anoxic Event (OAE2; ~ 94 Ma), but disentangling these factors on a regional scale has remained problematic. We generated palynological and organic geochemical records that allow the separation of these forcing factors in a core spanning the OAE2 from Wunstorf, Lower Saxony Basin (LSB; North Gemany), which exhibits cyclic black shale–marl alternations related to the orbital precession cycle.
Despite the widely varying depositional conditions complicating the interpretation of the obtained records, TEX86H indicates that sea-surface temperature (SST) evolution in the LSB during OAE2 resembles that of previously studied sites throughout the proto-North Atlantic. Cooling during the so-called Plenus Cold Event interrupted black shale deposition during the early stages of OAE2. However, TEX86 does not vary significantly across marl–black shale alternations, suggesting that temperature variations did not force the formation of the cyclic black shale horizons. Relative (i.e., with respect to marine palynomorphs) and absolute abundances of pollen and spores are elevated during phases of black shale deposition, indicative of enhanced precipitation and run-off. High abundances of cysts from inferred heterotrophic and euryhaline dinoflagellates supports high run-off, which likely introduced additional nutrients to the epicontinental shelf resulting in elevated marine primary productivity.
We conclude that orbitally-forced enhanced precipitation and run-off, in tandem with elevated marine primary productivity, were critical in cyclic black shale formation on the northwest European epicontinental shelf and potentially for other OAE2 sections in the proto-Atlantic and Western Interior Seaway at similar latitudes as well.
Global warming, changes in the hydrological cycle and enhanced marine primary productivity all have been invoked to have contributed to the occurrence of widespread ocean anoxia during the Cenomanian-Turonian Oceanic Anoxic Event (OAE2; ~ 94 Ma), but disentangling these factors on a regional scale has remained problematic. We generated palynological and organic geochemical records that allow the separation of these forcing factors in a core spanning the OAE2 from Wunstorf, Lower Saxony Basin (LSB; North Gemany), which exhibits cyclic black shale–marl alternations related to the orbital precession cycle.
Despite the widely varying depositional conditions complicating the interpretation of the obtained records, TEX86H indicates that sea-surface temperature (SST) evolution in the LSB during OAE2 resembles that of previously studied sites throughout the proto-North Atlantic. Cooling during the so-called Plenus Cold Event interrupted black shale deposition during the early stages of OAE2. However, TEX86 does not vary significantly across marl–black shale alternations, suggesting that temperature variations did not force the formation of the cyclic black shale horizons. Relative (i.e., with respect to marine palynomorphs) and absolute abundances of pollen and spores are elevated during phases of black shale deposition, indicative of enhanced precipitation and run-off. High abundances of cysts from inferred heterotrophic and euryhaline dinoflagellates supports high run-off, which likely introduced additional nutrients to the epicontinental shelf resulting in elevated marine primary productivity.
We conclude that orbitally-forced enhanced precipitation and run-off, in tandem with elevated marine primary productivity, were critical in cyclic black shale formation on the northwest European epicontinental shelf and potentially for other OAE2 sections in the proto-Atlantic and Western Interior Seaway at similar latitudes as well.
Reconstructing the early Paleogene climate dynamics of terrestrial settings in the high southern latitudes is important to assess the role of high-latitude physical and biogeochemical processes in the global climate system. However, whereas a number of high-quality Paleogene climate records has become available for the marine realm of the high southern latitudes over the recent past, the long-term evolution of coeval terrestrial climates and ecosystems is yet poorly known. We here explore the climate and vegetation dynamics on Tasmania from the middle Paleocene to the early Eocene (60.7–54.2 Ma) based on a sporomorph record from Ocean Drilling Program (ODP) Site 1172 on the East Tasman Plateau. Our results show that three distinctly different vegetation types thrived on Tasmania under a high-precipitation regime during the middle Paleocene to early Eocene, with each type representing different temperature conditions: (i) warm-temperate forests dominated by gymnosperms that were dominant during the middle and late Paleocene; (ii) cool-temperate forests dominated by southern beech (Nothofagus) and araucarians across the middle/late Paleocene transition interval (~59.5 to ~59.0 Ma); and (iii) paratropical forests rich in ferns that were established during and in the wake of the Paleocene–Eocene Thermal Maximum (PETM). The transient establishment of cool-temperate forests lacking any frost-sensitive elements (i.e., palms and cycads) across the middle/late Paleocene transition interval indicates markedly cooler conditions, with the occurrence of frosts in winter, on Tasmania during that time. The integration of our sporomorph data with previously published TEX86-based sea-surface temperatures from ODP Site 1172 documents that the vegetation dynamics on Tasmania were closely linked with the temperature evolution in the Tasman sector of the Southwest Pacific region. Moreover, the comparison of our season-specific climate estimates for the sporomorph assemblages from ODP Site 1172 with the TEX86L- and TEX86H-based temperature data suggests a warm-season bias of both calibrations for the early Paleogene of the high southern latitudes.
While it is extraordinarily difficult to theoretically specify privacy, in the last 100 years or so (social) psychology, philosophy, communication studies, economics, and, to a lesser degree, also sociology and anthropology, provided attempts to conceptualize its meaning. Be that as it may, from the 1960s onwards privacy discourse has focused upon data, understood as “personal information”, to a certain extent because of the advent of huge databases and information and communication technologies (ICTs). Influential scholarship at the present time tends to conceive of ICT-related privacy in terms of the “sociotechnical”, thus highlighting the interlocking of human and technical agency. Although having developed a manifold of instruments to research sociotechnical phenomena, STS engagement with sociotechnical privacy, so far, has been rather low-key. In our contribution we therefore provide a mapping of the research landscape, identify connecting factors between STS and sociotechnical privacy research, and calling for further STS contributions.
Coevolution of viruses and their hosts represents a dynamic molecular battle between the immune system and viral factors that mediate immune evasion. After the abandonment of smallpox vaccination, cowpox virus infections are an emerging zoonotic health threat, especially for immunocompromised patients. Here we delineate the mechanistic basis of how cowpox viral CPXV012 interferes with MHC class I antigen processing. This type II membrane protein inhibits the coreTAP complex at the step after peptide binding and peptide-induced conformational change, in blocking ATP binding and hydrolysis. Distinct from other immune evasion mechanisms, TAP inhibition is mediated by a short ER-lumenal fragment of CPXV012, which results from a frameshift in the cowpox virus genome. Tethered to the ER membrane, this fragment mimics a high ER-lumenal peptide concentration, thus provoking a trans-inhibition of antigen translocation as supply for MHC I loading. These findings illuminate the evolution of viral immune modulators and the basis of a fine-balanced regulation of antigen processing.
Background: The aim of this study was to compare outcome of patients with previous cardiac surgery undergoing transapical aortic valve implantation (Redo-TAVI) to those undergoing classic aortic valve replacement (Redo-AVR) by using propensity analysis.
Methods: From January 2005 through May 2012, 52 high-risk patients underwent Redo-TAVI using a pericardial xenograft fixed within a stainless steel, balloon-expandable stent (Edwards SAPIEN™). During the same period of time 167 patients underwent classic Redo-AVR. Logistic regression analysis was used to identify covariates among 11 baseline patient variables including the type of initial surgery. Using the significant regression coefficients, each patient’s propensity score was calculated, allowing selectively matched subgroups of 40 patients each. Initial surgery included coronary artery bypass grafting in 30 patients, aortic valve replacement in 7 patients and mitral valve reconstruction in 3 patients in each group. Follow-up was 4 ± 2 years and was 100% complete.
Results: Postoperative chest tube drainage (163 ± 214 vs. 562 ± 332 ml/24 h, p = 0.02) and incidence of early permanent neurologic deficit (0 vs. 13%, p = 0.04) was lower in patients with Redo-TAVI and there was a trend towards improved 30-day survival (p = 0.06). Also we detected a decreased ventilation time (p = 0.04) and lower transfusion rate of allogenic blood products (p ≤ 0.05) in the Redo-TAVI group. At late follow up differences regarding incidence of major adverse events, including death and permanent neurologic deficits (25% vs. 43%, p = 0.01) statistically supported early postoperative findings.
Conclusion: The encouraging results regarding early and long-term outcomes following TAVI in patients with previous cardiac surgery show, that this evolving approach may be particularly beneficial in this patient cohort.
Background: Targeted therapies have improved therapeutic options of treating renal cell carcinoma (RCC). However, drug response is temporary due to resistance development.
Methods: Functional and molecular changes in RCC Caki-1 cells, after acquired resistance to the mammalian target of rapamycin (mTOR)-inhibitor everolimus (Cakires), were investigated with and without additional application of the histone deacetylase (HDAC)-inhibitor valproic acid (VPA). Cell growth was evaluated by MTT assay, cell cycle progression and apoptosis by flow cytometry. Target molecules of everolimus and VPA, apoptotic and cell cycle regulating proteins were investigated by western blotting. siRNA blockade was performed to evaluate the functional relevance of the proteins.
Results: Everolimus resistance was accompanied by significant increases in the percentage of G2/M-phase cells and in the IC50. Akt and p70S6K, targets of everolimus, were activated in Cakires compared to drug sensitive cells. The most prominent change in Cakires cells was an increase in the cell cycle activating proteins cdk2 and cyclin A. Knock-down of cdk2 and cyclin A caused significant growth inhibition in the Cakires cells. The HDAC-inhibitor, VPA, counteracted everolimus resistance in Cakires, evidenced by a significant decrease in tumor growth and cdk2/cyclin A.
Conclusion: It is concluded that non-response to everolimus is characterized by increased cdk2/cyclin A, driving RCC cells into the G2/M-phase. VPA hinders everolimus non-response by diminishing cdk2/cyclin A. Therefore, treatment with HDAC-inhibitors might be an option for patients with advanced renal cell carcinoma and acquired everolimus resistance.
Amygdalin, a natural compound, has been used by many cancer patients as an alternative approach to treat their illness. However, whether or not this substance truly exerts an anti-tumor effect has never been settled. An in vitro study was initiated to investigate the influence of amygdalin (1.25–10 mg/ml) on the growth of a panel of bladder cancer cell lines (UMUC-3, RT112 and TCCSUP). Tumor growth, proliferation, clonal growth and cell cycle progression were investigated. The cell cycle regulating proteins cdk1, cdk2, cdk4, cyclin A, cyclin B, cyclin D1, p19, p27 as well as the mammalian target of rapamycin (mTOR) related signals phosphoAkt, phosphoRaptor and phosphoRictor were examined. Amygdalin dose-dependently reduced growth and proliferation in all three bladder cancer cell lines, reflected in a significant delay in cell cycle progression and G0/G1 arrest. Molecular evaluation revealed diminished phosphoAkt, phosphoRictor and loss of Cdk and cyclin components. Since the most outstanding effects of amygdalin were observed on the cdk2-cyclin A axis, siRNA knock down studies were carried out, revealing a positive correlation between cdk2/cyclin A expression level and tumor growth. Amygdalin, therefore, may block tumor growth by down-modulating cdk2 and cyclin A. In vivo investigation must follow to assess amygdalin's practical value as an anti-tumor drug.
Molecular tumour targeting has significantly improved anti-cancer protocols. Still, the addition of molecular targeting to the treatment regime has not led to a curative breakthrough. Combined mammalian target of Rapamycin (mTOR) and histone deacetylase (HDAC) inhibition has been shown not only to enhance anti-tumour potential, but also to prevent resistance development seen under mono-drug therapy. This investigation was designed to evaluate whether cross-communication exists between mTOR signalling and epigenetic events regulated by HDAC. DU-145 prostate cancer cells were treated with insulin-like growth factor (IGF) to activate the Akt-mTOR cascade or with the HDAC-inhibitor valproic acid (VPA) to induce histone H3 and H4 acetylation (aH3, aH4). Subsequently, mTOR, Rictor, Raptor, p70s6k, Akt (all: total and phosphorylated), H3 and H4 (total and acetylated) were analysed by western blotting. Both techniques revealed a link between mTOR and the epigenetic machinery. IGF activated mTOR, Rictor, Raptor, p70s6k and Akt, but also enhanced aH3 and aH4. Inversely, IGFr blockade and knock-down blocked the Akt-mTOR axis, but simultaneously diminished aH3 and aH4. VPA treatment up-regulated histone acetylation, but also activated mTOR-Akt signalling. HDAC1 and 2 knock-down revealed that the interaction with the mTOR system is initiated by histone H3 acetylation. HDAC-mTOR communication, therefore, is apparent whereby tumour-promoting (Akt/mTORhigh, aH3/aH4low) and tumour-suppressing signals (Akt/mTORlow, aH3/aH4high) are activated in parallel. Combined use of an HDAC- and mTOR inhibitor might then diminish pro-tumour effects triggered by the HDAC- (Akt/mTORhigh) or mTOR inhibitor (aH3/aH4low) alone.
Purpose: Prostate specific antigen is not reliable in diagnosing prostate cancer (PCa), making the identification of novel, precise diagnostic biomarkers important. Since chemokines are associated with more aggressive disease and poor prognosis in diverse malignancies, we aimed to investigate the diagnostic relevance of chemokines in PCa.
Materials and methods: Preoperative and early postoperative serum samples were obtained from 39 consecutive PCa patients undergoing radical prostatectomy. Serum from 15 healthy volunteers served as controls. Concentrations of CXCL12, CXCL13, CX3CL1, CCL2, CCL5, and CCL20 were measured in serum by Luminex. The expression activity of CXCR3, CXCR4, CXCR5, CXCR7, CXCL12, CXCL13, CX3CR1, CXCL1, CCR2, CCR5, CCR6, CCR7, CCL2, and CCL5 mRNA was assessed in tumor and adjacent normal tissue of prostatectomy specimens by quantitative real-time polymerase chain reaction. The associations of these chemokines with clinical and histological parameters were tested.
Results: The gene expression activity of CCL2 and CCR6 was significantly higher in tumor tissue compared to adjacent normal tissue. CCL2 was also significantly higher in the blood samples of PCa patients, compared to controls. CCL5, CCL20, and CX3CL1 were lower in patient serum, compared to controls. CCR2 tissue mRNA was negatively correlated with the Gleason score and grading.
Conclusion: Chemokines are significantly modified during tumorigenesis of PCa, and CCL2 is a promising diagnostic biomarker.
Background: In cystic fibrosis, highly variable glucose tolerance is suspected. However, no study provided within-patient coefficients of variation. The main objective of this short report was to evaluate within-patient variability of oral glucose tolerance.
Methods: In total, 4,643 standardized oral glucose tolerance tests of 1,128 cystic fibrosis patients (median age at first test: 15.5 [11.5; 21.5] years, 48.8% females) were studied. Patients included were clinically stable, non-pregnant, and had at least two oral glucose tolerance tests, with no prior lung transplantation or systemic steroid therapy. Transition frequency from any one test to the subsequent test was analyzed and within-patient coefficients of variation were calculated for fasting and two hour blood glucose values. All statistical analysis was implemented with SAS 9.4.
Results: A diabetic glucose tolerance was confirmed in 41.2% by the subsequent test. A regression to normal glucose tolerance at the subsequent test was observed in 21.7% and to impaired fasting glucose, impaired glucose tolerance or both in 15.2%, 12.0% or 9.9%. The average within-patient coefficient of variation for fasting blood glucose was 11.1% and for two hour blood glucose 25.3%.
Conclusion: In the cystic fibrosis patients studied, a highly variable glucose tolerance was observed. Compared to the general population, variability of two hour blood glucose was 1.5 to 1.8-fold higher.
Glioblastoma multiforme (GBM) is a deadly primary brain malignancy. Glioblastoma stem cells (GSC), which have the ability to self-renew and differentiate into tumor lineages, are believed to cause tumor recurrence due to their resistance to current therapies. A subset of GSCs is marked by cell surface expression of CD133, a glycosylated pentaspan transmembrane protein. The study of CD133-expressing GSCs has been limited by the relative paucity of genetic tools that specifically target them. Here, we present CD133-LV, a lentiviral vector presenting a single chain antibody against CD133 on its envelope, as a vehicle for the selective transduction of CD133-expressing GSCs. We show that CD133-LV selectively transduces CD133+ human GSCs in dose-dependent manner and that transduced cells maintain their stem-like properties. The transduction efficiency of CD133-LV is reduced by an antibody that recognizes the same epitope on CD133 as the viral envelope and by shRNA-mediated knockdown of CD133. Conversely, the rate of transduction by CD133-LV is augmented by overexpression of CD133 in primary human GBM cultures. CD133-LV selectively transduces CD133-expressing cells in intracranial human GBM xenografts in NOD.SCID mice, but spares normal mouse brain tissue, neurons derived from human embryonic stem cells and primary human astrocytes. Our findings indicate that CD133-LV represents a novel tool for the selective genetic manipulation of CD133-expressing GSCs, and can be used to answer important questions about how these cells contribute to tumor biology and therapy resistance.
Gene transfer vectors such as lentiviral vectors offer versatile possibilities to express transgenic antigens for vaccination purposes. However, viral vaccines leading to broad transduction and transgene expression in vivo, are undesirable. Therefore, strategies capable of directing gene transfer only to professional antigen-presenting cells would increase the specific activity and safety of genetic vaccines. A lentiviral vector pseudotype specific for murine major histocompatibilty complex class II (LV-MHCII) was recently developed and the present study aims to characterize the in vivo biodistribution profile and immunization potential of this vector in mice. Whereas the systemic administration of a vector pseudotyped with a ubiquitously-interacting envelope led to prominent detection of vector copies in the liver of animals, the injection of an equivalent amount of LV-MHCII resulted in a more specific biodistribution of vector and transgene. Copies of LV-MHCII were found only in secondary lymphoid organs, essentially in CD11c+ dendritic cells expressing the transgene whereas B cells were not efficiently targeted in vivo, contrary to expectations based on in vitro testing. Upon a single injection of LV-MHCII, naive mice mounted specific effector CD4 and CD8 T cell responses against the intracelllular transgene product with the generation of Th1 cytokines, development of in vivo cytotoxic activity and establishment of T cell immune memory. The targeting of dendritic cells by recombinant viral vaccines must therefore be assessed in vivo but this strategy is feasible, effective for immunization and cross-presentation and constitutes a potentially safe alternative to limit off-target gene expression in gene-based vaccination strategies with integrative vectors.
Structure and regulatory interactions of the cytoplasmic terminal domains of serotonin transporter
(2014)
Uptake of neurotransmitters by sodium-coupled monoamine transporters of the NSS family is required for termination of synaptic transmission. Transport is tightly regulated by protein–protein interactions involving the small cytoplasmic segments at the amino- and carboxy-terminal ends of the transporter. Although structures of homologues provide information about the transmembrane regions of these transporters, the structural arrangement of the terminal domains remains largely unknown. Here, we combined molecular modeling, biochemical, and biophysical approaches in an iterative manner to investigate the structure of the 82-residue N-terminal and 30-residue C-terminal domains of human serotonin transporter (SERT). Several secondary structures were predicted in these domains, and structural models were built using the Rosetta fragment-based methodology. One-dimensional 1H nuclear magnetic resonance and circular dichroism spectroscopy supported the presence of helical elements in the isolated SERT N-terminal domain. Moreover, introducing helix-breaking residues within those elements altered the fluorescence resonance energy transfer signal between terminal cyan fluorescent protein and yellow fluorescent protein tags attached to full-length SERT, consistent with the notion that the fold of the terminal domains is relatively well-defined. Full-length models of SERT that are consistent with these and published experimental data were generated. The resultant models predict confined loci for the terminal domains and predict that they move apart during the transport-related conformational cycle, as predicted by structures of homologues and by the “rocking bundle” hypothesis, which is consistent with spectroscopic measurements. The models also suggest the nature of binding to regulatory interaction partners. This study provides a structural context for functional and regulatory mechanisms involving SERT terminal domains.
Objective: Advanced or recurrent endometrial cancer (EC) no longer amenable to surgery or radiotherapy is a life-threatening disease with limited therapeutic options left. Eighty percent of ECs express receptors for luteinizing hormone-releasing hormone (LHRH), which can be targeted by AEZS-108 (zoptarelin doxorubicin acetate). This phase 2 trial was performed to assess the efficacy and safety of AEZS-108 in this group of patients.
Methods: Patients had FIGO (Fédération Internationale de Gynécologie et d'Obstétrique) III or IV or recurrent EC, LHRH receptor-positive tumor status, and at least had 1 measurable lesion (Response Evaluation Criteria in Solid Tumors). Prior anthracycline therapy was not allowed. Patients received AEZS-108 as a 2-hour infusion on day 1 of a 21-day cycle. The treatment was continued for a maximum of 6 to 8 cycles. The primary end point was the response rate determined by the Response Evaluation Criteria in Solid Tumors.
Results: From April 2008 to November 2009, 44 patients were included in the study at 8 centers in Germany (AGO) and 3 centers in Bulgaria. Forty-three of these patients were eligible. Two (5%) patients had a complete remission, and 8 (18%) achieved a partial remission. Stable disease for at least 6 weeks was observed in 44%. The median time to progression was 7 months, and the median overall survival was 15 months. The most frequently reported grade 3 or 4 adverse effects were neutropenia (12%) and leucopenia (9%).
Conclusions: AEZS-108, an LHRH-agonist coupled to doxorubicin, has significant activity and low toxicity in women with advanced or recurrent LHRH receptor-positive EC, supporting the principle of receptor-mediated targeted chemotherapy.
Inhibitors of the mammalian target of rapamycin (mTOR) have improved the treatment of renal cell carcinoma (RCC). However, chronic drug exposure may trigger resistance, limiting the utility of these agents. The metastatic behavior of RCC cells, susceptible (RCC(par)) or resistant (RCC(res)) to the mTOR inhibitor temsirolimus, was investigated. Adhesion to vascular endothelium or immobilized collagen and fibronectin was quantified. Chemotactic motility was evaluated with a modified Boyden chamber assay. Integrin α and β subtype receptors were analyzed by flow cytometry and Western blot analysis. The physiological relevance of the integrins was then determined by blocking studies and small interfering RNA knockdown. Adhesion to endothelial cells and to fibronectin (not to collagen) and chemotaxis were enhanced in RCC(res) compared to RCC(par). RCC(res) detached from fibronectin and motile activity further increased under retreatment with low-dosed temsirolimus. α5 integrin was diminished inside the cell and at the cell surface, whereas the β3 subtype was reduced intracellularly but elevated at the plasma membrane. In RCC(par), blocking α5 surface receptors enhanced RCC-collagen but reduced RCC-fibronectin interaction, whereas the opposite was true for RCC(res). Chemotaxis of RCC(par) but not of RCC(res) was strongly diminished by the α5 antibody. Blocking β3 significantly lowered chemotaxis with stronger effects on RCC(res), compared to RCC(par). Importantly, β3 knockdown reduced chemotaxis of RCC(par) but upregulated the motile behavior of RCC(res). Temsirolimus resistance is characterized by quantitative alterations of integrin α5 and β3 expression, coupled to functional changes of the integrin molecules, and forces a switch from RCC adhesion to RCC migration.
Consequences of a human TRPA1 genetic variant on the perception of nociceptive and olfactory stimuli
(2014)
Background: TRPA1 ion channels are involved in nociception and are also excited by pungent odorous substances. Based on reported associations of TRPA1 genetics with increased sensitivity to thermal pain stimuli, we therefore hypothesized that this association also exists for increased olfactory sensitivity.
Methods: Olfactory function and nociception was compared between carriers (n = 38) and non-carriers (n = 43) of TRPA1 variant rs11988795 G.A, a variant known to enhance cold pain perception. Olfactory function was quantified by assessing the odor threshold, odor discrimination and odor identification, and by applying 200-ms pulses of H2S intranasal. Nociception was assessed by measuring pain thresholds to experimental nociceptive stimuli (blunt pressure, electrical stimuli, cold and heat stimuli, and 200-ms intranasal pulses of CO2).
Results: Among the 11 subjects with moderate hyposmia, carriers of the minor A allele (n = 2) were underrepresented (34 carriers among the 70 normosmic subjects; p = 0.049). Moreover, carriers of the A allele discriminated odors significantly better than non-carriers (13.161.5 versus 12.361.6 correct discriminations) and indicated a higher intensity of the H2S stimuli (29.2613.2 versus 21612.8 mm VAS, p = 0.006), which, however, could not be excluded to have involved a trigeminal component during stimulation. Finally, the increased sensitivity to thermal pain could be reproduced.
Conclusions: The findings are in line with a previous association of a human TRPA1 variant with nociceptive parameters and extend the association to the perception of odorants. However, this addresses mainly those stimulants that involve a trigeminal component whereas a pure olfactory effect may remain disputable. Nevertheless, findings suggest that future TRPA1 modulating drugs may modify the perception of odorants.
Antigen presentation to cytotoxic T lymphocytes via major histocompatibility complex class I (MHC I) molecules depends on the heterodimeric transporter associated with antigen processing (TAP). For efficient antigen supply to MHC I molecules in the ER, TAP assembles a macromolecular peptide-loading complex (PLC) by recruiting tapasin. In evolution, TAP appeared together with effector cells of adaptive immunity at the transition from jawless to jawed vertebrates and diversified further within the jawed vertebrates. Here, we compared TAP function and interaction with tapasin of a range of species within two classes of jawed vertebrates. We found that avian and mammalian TAP1 and TAP2 form heterodimeric complexes across taxa. Moreover, the extra N-terminal domain TMD0 of mammalian TAP1 and TAP2 as well as avian TAP2 recruits tapasin. Strikingly, however, only TAP1 and TAP2 from the same taxon can form a functional heterodimeric translocation complex. These data demonstrate that the dimerization interface between TAP1 and TAP2 and the tapasin docking sites for PLC assembly are conserved in evolution, whereas elements of antigen translocation diverged later in evolution and are thus taxon specific.
Neoadjuvant systemic chemotherapy is a possible therapeutic approach for the treatment of locally advanced operable, primarily non-operable or inflammatory breast cancer. Neoadjuvant systemic chemotherapy is an option for breast cancer patients who would require adjuvant chemotherapy otherwise based on clinical and histological examination and imaging. The use of neoadjuvant systemic therapy in operable breast cancer is currently increasing because of its advantages that include higher rates of breast conserving surgery and the possibility of measuring early in-vivo response to systemic treatment. The timing of axillary sentinel lymph node diagnosis (i.e. before or after neoadjuvant chemotherapy) is critical in that it may influence the likelihood of axillary preservation. It is not yet clear if neoadjuvant therapy might improve outcomes in certain subgroups of breast cancer patients. Neoadjuvant treatment modalities require a close collaboration between oncology professionals, including surgeons, gynecologists, medical oncologists, radiation oncologists, radiologists and pathologists. The most important parameter for treatment success and improved overall survival is the achievement of a pathologic complete response (pCR), although the role of pCR in patients with luminal A like tumours might be less informative. Identification of patient subgroups with high pCR rates may allow less invasive surgical or radiological interventions. Patients not achieving a pCR may be candidates for postoperative clinical trials exploring novel systemic treatments.
The ALICE Zero Degree Calorimeter system (ZDC) is composed of two identical sets of calorimeters, placed at opposite sides with respect to the interaction point, 114 meters away from it, complemented by two small forward electromagnetic calorimeters (ZEM). Each set of detectors consists of a neutron (ZN) and a proton (ZP) ZDC. They are placed at zero degrees with respect to the LHC axis and allow to detect particles emitted close to beam direction, in particular neutrons and protons emerging from hadronic heavy-ion collisions (spectator nucleons) and those emitted from electromagnetic processes. For neutrons emitted by these two processes, the ZN calorimeters have nearly 100% acceptance.
During the √sNN = 2.76 TeV Pb-Pb data-taking, the ALICE Collaboration studied forward neutron emission with a dedicated trigger, requiring a minimum energy deposition in at least one of the two ZN. By exploiting also the information of the two ZEM calorimeters it has been possible to separate the contributions of electromagnetic and hadronic processes and to study single neutron vs. multiple neutron emission.
The measured cross sections of single and mutual electromagnetic dissociation of Pb nuclei at √sNN = 2.76 TeV, with neutron emission, are σsingle EMD = 187:4 ± 0.2 (stat.)−11.2+13.2 (syst.) b and σmutual EMD = 5.7 ± 0.1 (stat.) ±0.4 (syst.) b, respectively [1]. This is the first measurement of electromagnetic dissociation of 208Pb nuclei at the LHC energies, allowing a test of electromagnetic dissociation theory in a new energy regime. The experimental results are compared to the predictions from a relativistic electromagnetic dissociation model.
Background: Since sorafenib has shown activity in different tumour types and gemcitabine regimens improved the outcome for biliary tract cancer (BTC) patients, we evaluated first-line gemcitabine plus sorafenib in a double-blind phase II study.
Patients and methods: 102 unresectable or metastatic BTC patients with histologically proven adenocarcinoma of gallbladder or intrahepatic bile ducts, Eastern Cooperative Oncology Group (ECOG) 0–2 were randomised to gemcitabine (1000 mg/m2 once weekly, first 7-weeks + 1-week rest followed by once 3-weeks + 1-week rest) plus sorafenib (400 mg twice daily) or placebo. Treatment continued until progression or unacceptable toxicity. Tumour samples were prospectively stained for sorafenib targets and potential biomarkers. Serum samples (first two cycles) were measured for vascular endothelial growth factors (VEGFs), vascular endothelial growth factor receptor 2 (VEGFR-2) and stromal cell-derived factor 1 (SDF1)α by enzyme-linked immunosorbent assay (ELISA).
Results: Gemcitabine plus sorafenib was generally well tolerated. Four and three patients achieved partial responses in the sorafenib and placebo groups, respectively. There was no difference in the primary end-point, median progression-free survival (PFS) for gemcitabine plus sorafenib versus gemcitabine plus placebo (3.0 versus 4.9 months, P = 0.859), and no difference for median overall survival (OS) (8.4 versus 11.2 months, P = 0.775). Patients with liver metastasis after resection of primary BTC survived longer with sorafenib (P = 0.019) compared to placebo. Patients who developed hand-foot syndrome (HFS) showed longer PFS and OS than patients without HFS. Two sorafenib targets, VEGFR-2 and c-kit, were not expressed in BTC samples. VEGFR-3 and Hif1α were associated with lymph node metastases and T stage. Absence of PDGFRβ expression correlated with longer PFS.
Conclusion: The addition of sorafenib to gemcitabine did not demonstrate improved efficacy in advanced BTC patients. Biomarker subgroup analysis suggested that some patients might benefit from combined treatment.
Cytochrome P450 (CYP) epoxygenases generate bioactive lipid epoxides which can be further metabolized to supposedly less active diols by the soluble epoxide hydrolase (sEH). As the role of epoxides and diols in angiogenesis is unclear, we compared retinal vasculature development in wild-type and sEH−/− mice. Deletion of the sEH significantly delayed angiogenesis, tip cell, and filopodia formation, a phenomenon associated with activation of the Notch signaling pathway. In the retina, sEH was localized in Müller glia cells, and Müller cell–specific sEH deletion reproduced the sEH−/− retinal phenotype. Lipid profiling revealed that sEH deletion decreased retinal and Müller cell levels of 19,20–dihydroxydocosapentaenoic acid (DHDP), a diol of docosahexenoic acid (DHA). 19,20-DHDP suppressed endothelial Notch signaling in vitro via inhibition of the γ-secretase and the redistribution of presenilin 1 from lipid rafts. Moreover, 19,20-DHDP, but not the parent epoxide, was able to rescue the defective angiogenesis in sEH−/− mice as well as in animals lacking the Fbxw7 ubiquitin ligase, which demonstrate strong basal activity of the Notch signaling cascade. These studies demonstrate that retinal angiogenesis is regulated by a novel form of neuroretina–vascular interaction involving the sEH-dependent generation of a diol of DHA in Müller cells.
Fibrous tissue growth and loss of residual hearing after cochlear implantation can be reduced by application of the glucocorticoid dexamethasone-21-phosphate-disodium-salt (DEX). To date, sustained delivery of this agent to the cochlea using a number of pharmaceutical technologies has not been entirely successful. In this study we examine a novel way of continuous local drug application into the inner ear using a refillable hydrogel functionalized silicone reservoir. A PEG-based hydrogel made of reactive NCO-sP(EO-stat-PO) prepolymers was evaluated as a drug conveying and delivery system in vitro and in vivo. Encapsulating the free form hydrogel into a silicone tube with a small opening for the drug diffusion resulted in delayed drug release but unaffected diffusion of DEX through the gel compared to the free form hydrogel. Additionally, controlled DEX release over several weeks could be demonstrated using the hydrogel filled reservoir. Using a guinea-pig cochlear trauma model the reservoir delivery of DEX significantly protected residual hearing and reduced fibrosis. As well as being used as a device in its own right or in combination with cochlear implants, the hydrogel-filled reservoir represents a new drug delivery system that feasibly could be replenished with therapeutic agents to provide sustained treatment of the inner ear.
Event-by-event fluctuations of the mean transverse momentum of charged particles produced in pp collisions at s√ = 0.9, 2.76 and 7 TeV, and Pb-Pb collisions at sNN−−−−√ = 2.76 TeV are studied as a function of the charged-particle multiplicity using the ALICE detector at the LHC. Dynamical fluctuations indicative of correlated particle emission are observed in all systems. The results in pp collisions show little dependence on collision energy. The Monte Carlo event generators PYTHIA and PHOJET are in qualitative agreement with the data. Peripheral Pb-Pb data exhibit a similar multiplicity dependence as that observed in pp. In central Pb-Pb, the results deviate from this trend, featuring a significant reduction of the fluctuation strength. The results in Pb--Pb are in qualitative agreement with previous measurements in Au-Au at lower collision energies and with expectations from models that incorporate collective phenomena.
Species distributed across vast continental areas and across major biomes provide unique model systems for studies of biotic diversification, yet also constitute daunting financial, logistic and political challenges for data collection across such regions. The tree frog Dendropsophus minutus (Anura: Hylidae) is a nominal species, continentally distributed in South America, that may represent a complex of multiple species, each with a more limited distribution. To understand the spatial pattern of molecular diversity throughout the range of this species complex, we obtained DNA sequence data from two mitochondrial genes, cytochrome oxidase I (COI) and the 16S rhibosomal gene (16S) for 407 samples of D. minutus and closely related species distributed across eleven countries, effectively comprising the entire range of the group. We performed phylogenetic and spatially explicit phylogeographic analyses to assess the genetic structure of lineages and infer ancestral areas. We found 43 statistically supported, deep mitochondrial lineages, several of which may represent currently unrecognized distinct species. One major clade, containing 25 divergent lineages, includes samples from the type locality of D. minutus. We defined that clade as the D. minutus complex. The remaining lineages together with the D. minutus complex constitute the D. minutus species group. Historical analyses support an Amazonian origin for the D. minutus species group with a subsequent dispersal to eastern Brazil where the D. minutus complex originated. According to our dataset, a total of eight mtDNA lineages have ranges >100,000 km2. One of them occupies an area of almost one million km2 encompassing multiple biomes. Our results, at a spatial scale and resolution unprecedented for a Neotropical vertebrate, confirm that widespread amphibian species occur in lowland South America, yet at the same time a large proportion of cryptic diversity still remains to be discovered.
Background: In Germany, about 20% of the total population have a migration background. Differences exist between migrants and non-migrants in terms of health care access and utilisation. Colorectal cancer is the second most common malignant tumour in Germany, and incidence, staging and survival chances depend, amongst other things, on ethnicity and lifestyle. The current study investigates whether stage at diagnosis differs between migrants and non-migrants with colorectal cancer in an area of high migration and attempts to identify factors that can explain any differences.
Methods/Design: Data on tumour and migration status will be collected for 1,200 consecutive patients that have received a new, histologically verified diagnosis of colorectal cancer in a high migration area in Germany in the previous three months. The recruitment process is expected to take 16 months and will include gastroenterological private practices and certified centres for intestinal diseases. Descriptive and analytical analysis will be performed: the distribution of variables for migrants versus non-migrants and participants versus non-participants will be analysed using appropriate χ2-, t-, F- or Wilcoxon tests. Multivariable, logistic regression models will be performed, with the dependent variable being the dichotomized stage of the tumour (UICC stage I versus more advanced than UICC stage I). Odds ratios and associated 95%-confidence intervals will be calculated. Furthermore, ordered logistic regression models will be estimated, with the exact stage of the tumour at diagnosis as the dependent variable. Predictors used in the ordered logistic regression will be patient characteristics that are specific to migrants as well as patient characteristics that are not. Interaction models will be estimated in order to investigate whether the effects of patient characteristics on stage of tumour at the time of the initial diagnosis is different in migrants, compared to non-migrants.
Discussion: An association of migration status or other socioeconomic variables with stage at diagnosis of colorectal cancer would be an important finding with respect to equal health care access among migrants. It would point to access barriers or different symptom appraisal and, in the long term, could contribute to the development of new health care concepts for migrants.
Trial registration: German Clinical Trials Register DRKS00005056.
Autism spectrum disorder and schizophrenia share a substantial number of etiologic and phenotypic characteristics. Still, no direct comparison of both disorders has been performed to identify differences and commonalities in brain structure. In this voxel based morphometry study, 34 patients with autism spectrum disorder, 21 patients with schizophrenia and 26 typically developed control subjects were included to identify global and regional brain volume alterations. No global gray matter or white matter differences were found between groups. In regional data, patients with autism spectrum disorder compared to typically developed control subjects showed smaller gray matter volume in the amygdala, insula, and anterior medial prefrontal cortex. Compared to patients with schizophrenia, patients with autism spectrum disorder displayed smaller gray matter volume in the left insula. Disorder specific positive correlations were found between mentalizing ability and left amygdala volume in autism spectrum disorder, and hallucinatory behavior and insula volume in schizophrenia. Results suggest the involvement of social brain areas in both disorders. Further studies are needed to replicate these findings and to quantify the amount of distinct and overlapping neural correlates in autism spectrum disorder and schizophrenia.
Attention-deficit/hyperactivity disorder (ADHD) is often accompanied by problems in social behaviour, which are sometimes similar to some symptoms of autism-spectrum disorders (ASD). However, neuronal mechanisms of ASD-like deficits in ADHD have rarely been studied. The processing of biological motion–recently discussed as a marker of social cognition–was found to be disrupted in ASD in several studies. Thus in the present study we tested if biological motion processing is disrupted in ADHD. We used 64-channel EEG and spatio-temporal source analysis to assess event-related potentials associated with human motion processing in 21 children and adolescents with ADHD and 21 matched typically developing controls. On the behavioural level, all subjects were able to differentiate between human and scrambled motion. But in response to both scrambled and biological motion, the N200 amplitude was decreased in subjects with ADHD. After a spatio-temporal dipole analysis, a human motion specific activation was observable in occipital-temporal regions with a reduced and more diffuse activation in ADHD subjects. These results point towards neuronal determined alterations in the processing of biological motion in ADHD.
Background: Acute leukemia in early age (EAL) is characterized by acquired genetic alterations such as MLL rearrangements (MLL-r). The aim of this case-controlled study was to investigate whether single nucleotide polymorphisms (SNPs) of IKZF1, ARID5B, and CEBPE could be related to the onset of EAL cases (<24 months-old at diagnosis).
Methods: The SNPs (IKZF1 rs11978267, ARID5B rs10821936 and rs10994982, CEBPE rs2239633) were genotyped in 265 cases [169 acute lymphoblastic leukemia (ALL) and 96 acute myeloid leukaemia (AML)] and 505 controls by Taqman allelic discrimination assay. Logistic regression was used to evaluate the association between SNPs of cases and controls, adjusted on skin color and/or age. The risk was determined by calculating odds ratios (ORs) with 95% confidence interval (CI).
Results: Children with the IKZF1 SNP had an increased risk of developing MLL-germline ALL in white children. The heterozygous/mutant genotype in ARID5B rs10994982 significantly increased the risk for MLL-germline leukemia in white and non-white children (OR 2.60, 95% CI: 1.09-6.18 and OR 3.55, 95% CI: 1.57-8.68, respectively). The heterozygous genotype in ARID5B rs10821936 increased the risk for MLL-r leukemia in both white and non-white (OR 2.06, 95% CI: 1.12-3.79 and OR 2.36, 95% CI: 1.09-5.10, respectively). Furthermore, ARID5B rs10821936 conferred increased risk for MLL-MLLT3 positive cases (OR 7.10, 95% CI:1.54-32.68). Our data do not show evidence that CEBPE rs2239633 confers increased genetic susceptibility to EAL.
Conclusions: IKZF1 and CEBPE variants seem to play a minor role in genetic susceptibility to EAL, while ARID5B rs10821936 increased the risk of MLL-MLLT3. This result shows that genetic susceptibility could be associated with the differences regarding MLL breakpoints and partner genes.
Ultraviolet-B (UVB)-induced inflammation produces a dose-dependent mechanical and thermal hyperalgesia in both humans and rats, most likely via inflammatory mediators acting at the site of injury. Previous work has shown that the gene expression of cytokines and chemokines is positively correlated between species and that these factors can contribute to UVB-induced pain. In order to investigate other potential pain mediators in this model we used RNA-seq to perform genome-wide transcriptional profiling in both human and rat skin at the peak of hyperalgesia. In addition we have also measured transcriptional changes in the L4 and L5 DRG of the rat model. Our data show that UVB irradiation produces a large number of transcriptional changes in the skin: 2186 and 3888 genes are significantly dysregulated in human and rat skin, respectively. The most highly up-regulated genes in human skin feature those encoding cytokines (IL6 and IL24), chemokines (CCL3, CCL20, CXCL1, CXCL2, CXCL3 and CXCL5), the prostanoid synthesising enzyme COX-2 and members of the keratin gene family. Overall there was a strong positive and significant correlation in gene expression between the human and rat (R = 0.8022). In contrast to the skin, only 39 genes were significantly dysregulated in the rat L4 and L5 DRGs, the majority of which had small fold change values. Amongst the most up-regulated genes in DRG were REG3B, CCL2 and VGF. Overall, our data shows that numerous genes were up-regulated in UVB irradiated skin at the peak of hyperalgesia in both human and rats. Many of the top up-regulated genes were cytokines and chemokines, highlighting again their potential as pain mediators. However many other genes were also up-regulated and might play a role in UVB-induced hyperalgesia. In addition, the strong gene expression correlation between species re-emphasises the value of the UVB model as translational tool to study inflammatory pain.
Caspase-2 represents the most conserved member of the caspase family, which exhibits features of both initiator and effector caspases. Using ribonucleoprotein (RNP)-immunoprecipitation assay, we identified the proapoptotic caspase-2L encoding mRNA as a novel target of the ubiquitous RNA-binding protein HuR in DLD-1 colon carcinoma cells. Unexpectedly, crosslinking-RNP and RNA probe pull-down experiments revealed that HuR binds exclusively to the caspase-2-5' untranslated region (UTR) despite that the 3' UTR of the mRNA bears several adenylate- and uridylate-rich elements representing the prototypical HuR binding sites. By using RNAi-mediated loss-of-function approach, we observed that HuR regulates the mRNA and in turn the protein levels of caspase-2 in a negative manner. Silencing of HuR did not affect the stability of caspase-2 mRNA but resulted in an increased redistribution of caspase-2 transcripts from RNP particles to translational active polysomes implicating that HuR exerts a direct repressive effect on caspase-2 translation. Consistently, in vitro translation of a luciferase reporter gene under the control of an upstream caspase-2-5'UTR was strongly impaired after the addition of recombinant HuR, whereas translation of caspase-2 coding region without the 5'UTR is not affected by HuR confirming the functional role of the caspase-2-5'UTR. Functionally, an elevation in caspase-2 level by HuR knockdown correlated with an increased sensitivity of cells to apoptosis induced by staurosporine- and pore-forming toxins as implicated by their significant accumulation in the sub G1 phase and an increase in caspase-2, -3 and poly ADP-ribose polymerase cleavage, respectively. Importantly, HuR knockdown cells remained insensitive toward STS-induced apoptosis if cells were additionally transfected with caspase-2-specific siRNAs. Collectively, our findings support the hypothesis that HuR by acting as an endogenous inhibitor of caspase-2-driven apoptosis may essentially contribute to the antiapoptotic program of adenocarcinoma cells by HuR.
miRNA let-7e is involved in stem cell differentiation, and metalloproteinases are among its potential target genes. We hypothesized that the inhibitory action of let-7e on regulation of MMP9 expression could represent a crucial mechanism during differentiation of adipose-derived stem cells (ASCs). ASCs were differentiated with all-trans retinoic acid (ATRA) to promote differentiation, and the effect of let-7 silencing during differentiation was tested. Results indicate that ASCs cultured with ATRA differentiated into cells of the epithelial lineage. We found that ASCs cultured with ATRA or transfected with miRNA let-7e expressed epithelial markers such as cytokeratin-18 and early renal organogenesis markers such as Pax2, Wt1, Wnt4 and megalin. Conversely, the specific knockdown of miRNA let-7e in ASCs significantly decreased the expression of these genes, indicating its vital role during the differentiation process. Using luciferase reporter assays, we also showed that MMP9 is a direct target of miRNA let-7e. Thus, our results suggest that miRNA let-7e acts as a matrix metalloproteinase-9 (MMP9) inhibitor and differentiation inducer in ASCs.
Dendritic cells (DCs) are the cutting edge in innate and adaptive immunity. The major functions of these antigen-presenting cells are the capture, endosomal processing and presentation of antigens, providing them an exclusive ability to provoke adaptive immune responses and to induce and control tolerance. Immature DCs capture and process antigens, migrate towards secondary lymphoid organs where they present antigens to naive T cells in a well-synchronized sequence of procedures referred to as maturation. Indeed, recent research indicated that sphingolipids are modulators of essential steps in DC homeostasis. It has been recognized that sphingolipids not only modulate the development of DC subtypes from precursor cells but also influence functional activities of DCs such as antigen capture, and cytokine profiling. Thus, it is not astonishing that sphingolipids and sphingolipid metabolism play a substantial role in inflammatory diseases that are modulated by DCs. Here we highlight the function of sphingosine 1-phosphate (S1P) on DC homeostasis and the role of S1P and S1P metabolism in inflammatory diseases.
Resveratrol shows beneficial effects in inflammation-based diseases like cancer, cardiovascular and chronic inflammatory diseases. Therefore, the molecular mechanisms of the anti-inflammatory resveratrol effects deserve more attention. In human epithelial DLD-1 and monocytic Mono Mac 6 cells resveratrol decreased the expression of iNOS, IL-8 and TNF-α by reducing mRNA stability without inhibition of the promoter activity. Shown by pharmacological and siRNA-mediated inhibition, the observed effects are SIRT1-independent. Target-fishing and drug responsive target stability experiments showed selective binding of resveratrol to the RNA-binding protein KSRP, a central post-transcriptional regulator of pro-inflammatory gene expression. Knockdown of KSRP expression prevented resveratrol-induced mRNA destabilization in human and murine cells. Resveratrol did not change KSRP expression, but immunoprecipitation experiments indicated that resveratrol reduces the p38 MAPK-related inhibitory KSRP threonine phosphorylation, without blocking p38 MAPK activation or activity. Mutation of the p38 MAPK target site in KSRP blocked the resveratrol effect on pro-inflammatory gene expression. In addition, resveratrol incubation enhanced KSRP-exosome interaction, which is important for mRNA degradation. Finally, resveratrol incubation enhanced its intra-cellular binding to the IL-8, iNOS and TNF-α mRNA. Therefore, modulation of KSRP mRNA binding activity and, thereby, enhancement of mRNA degradation seems to be the common denominator of many anti-inflammatory effects of resveratrol.
Background: Hypoxia-inducible factor-1α (HIF-1α) and NF-κB play important roles in the inflammatory response after hemorrhagic shock and resuscitation (H/R). Here, the role of myeloid HIF-1α in liver hypoxia, injury, and inflammation after H/R with special regard to NF-κB activation was studied.
Methods: Mice with a conditional HIF-1α knockout (KO) in myeloid cell-line and wild-type (WT) controls were hemorrhaged for 90 min ( mm Hg) and resuscitated. Controls underwent only surgical procedures.
Results: After six hours, H/R enhanced the expression of HIF-1α-induced genes vascular endothelial growth factor (VEGF) and adrenomedullin (ADM). In KO mice, this was not observed. H/R-induced liver injury in HIF-1α KO was comparable to WT. Elevated plasma interleukin-6 (IL-6) levels after H/R were not reduced by HIF-1α KO. Local hepatic hypoxia was not significantly reduced in HIF-1α KO compared to controls after H/R. H/R-induced NF-κB phosphorylation in liver did not significantly differ between WT and KO.
Conclusions: Here, deleting HIF-1α in myeloid cells and thereby in Kupffer cells was not protective after H/R. This data indicates that other factors, such as NF-κB, due to its upregulated phosphorylation in WT and KO mice, contrary to HIF-1α, are rather key modulators of inflammation after H/R in our model.
Background: Autotaxin (ATX) and its product lysophosphatidic acid (LPA) are considered to be involved in the development of liver fibrosis and elevated levels of serum ATX have been found in patients with hepatitis C virus associated liver fibrosis. However, the clinical role of systemic ATX in the stages of liver cirrhosis was unknown. Here we investigated the relation of ATX serum levels and severity of cirrhosis as well as prognosis of cirrhotic patients.
Methods: Patients with liver cirrhosis were prospectively enrolled and followed until death, liver transplantation or last contact. Blood samples drawn at the day of inclusion in the study were assessed for ATX content by an enzyme-linked immunosorbent assay. ATX levels were correlated with the stage as well as complications of cirrhosis. The prognostic value of ATX was investigated by uni- and multivariate Cox regression analyses. LPA concentration was determined by liquid chromatography-tandem mass spectrometry.
Results: 270 patients were enrolled. Subjects with liver cirrhosis showed elevated serum levels of ATX as compared to healthy subjects (0.814±0.42 mg/l vs. 0.258±0.40 mg/l, P<0.001). Serum ATX levels correlated with the Child-Pugh stage and the MELD (model of end stage liver disease) score and LPA levels (r = 0.493, P = 0.027). Patients with hepatic encephalopathy (P = 0.006), esophageal varices (P = 0.002) and portal hypertensive gastropathy (P = 0.008) had higher ATX levels than patients without these complications. Low ATX levels were a parameter independently associated with longer overall survival (hazard ratio 0.575, 95% confidence interval 0.365–0.905, P = 0.017).
Conclusion: Serum ATX is an indicator for the severity of liver disease and the prognosis of cirrhotic patients.