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The transcription factor vitamin D receptor (VDR) is the high affinity nuclear target of the biologically active form of vitamin D3 (1,25(OH)2D3). In order to identify pure genomic transcriptional effects of 1,25(OH)2D3, we used VDR cistrome, transcriptome and open chromatin data, obtained from the human monocytic cell line THP-1, for a novel hierarchical analysis applying three bioinformatics approaches. We predicted 75.6% of all early 1,25(OH)2D3-responding (2.5 or 4 h) and 57.4% of the late differentially expressed genes (24 h) to be primary VDR target genes. VDR knockout led to a complete loss of 1,25(OH)2D3–induced genome-wide gene regulation. Thus, there was no indication of any VDR-independent non-genomic actions of 1,25(OH)2D3 modulating its transcriptional response. Among the predicted primary VDR target genes, 47 were coding for transcription factors and thus may mediate secondary 1,25(OH)2D3 responses. CEBPA and ETS1 ChIP-seq data and RNA-seq following CEBPA knockdown were used to validate the predicted regulation of secondary vitamin D target genes by both transcription factors. In conclusion, a directional network containing 47 partly novel primary VDR target transcription factors describes secondary responses in a highly complex vitamin D signaling cascade. The central transcription factor VDR is indispensable for all transcriptome-wide effects of the nuclear hormone.
Angiogenesis, the process by which endothelial cells (ECs) form new blood vessels from existing ones, is intimately linked to the tissue’s metabolic milieu and often occurs at nutrient-deficient sites. However, ECs rely on sufficient metabolic resources to support growth and proliferation. How endothelial nutrient acquisition and usage are regulated is unknown. Here we show that these processes are instructed by Yes-associated protein 1 (YAP)/WW domain-containing transcription regulator 1 (WWTR1/TAZ)-transcriptional enhanced associate domain (TEAD): a transcriptional module whose function is highly responsive to changes in the tissue environment. ECs lacking YAP/TAZ or their transcriptional partners, TEAD1, 2 and 4 fail to divide, resulting in stunted vascular growth in mice. Conversely, activation of TAZ, the more abundant paralogue in ECs, boosts proliferation, leading to vascular hyperplasia. We find that YAP/TAZ promote angiogenesis by fuelling nutrient-dependent mTORC1 signalling. By orchestrating the transcription of a repertoire of cell-surface transporters, including the large neutral amino acid transporter SLC7A5, YAP/TAZ-TEAD stimulate the import of amino acids and other essential nutrients, thereby enabling mTORC1 activation. Dissociating mTORC1 from these nutrient inputs—elicited by the loss of Rag GTPases—inhibits mTORC1 activity and prevents YAP/TAZ-dependent vascular growth. Together, these findings define a pivotal role for YAP/TAZ-TEAD in controlling endothelial mTORC1 and illustrate the essentiality of coordinated nutrient fluxes in the vasculature.
Adhesion of human pathogenic bacteria to endothelial cells is facilitated by fibronectin interaction
(2023)
Human pathogenic bacteria circulating in the bloodstream need to find a way to interact with endothelial cells (ECs) lining the blood vessels to infect and colonise the host. The extracellular matrix (ECM) of ECs might represent an attractive initial target for bacterial interaction, as many bacterial adhesins have reported affinities to ECM proteins, in particular to fibronectin (Fn). Here, we analysed the general role of EC-expressed Fn for bacterial adhesion. For this, we evaluated the expression levels of ECM coding genes in different ECs, revealing that Fn is the highest expressed gene and thereby, it is highly abundant in the ECM environment of ECs. The role of Fn as a mediator in bacterial cell-host adhesion was evaluated in adhesion assays of Acinetobacter baumannii, Bartonella henselae, Borrelia burgdorferi, and Staphylococcus aureus to ECs. The assays demonstrated that bacteria colocalised with Fn fibres, as observed by confocal laser scanning microscopy. Fn removal from the ECM environment (FN1 knockout ECs) diminished bacterial adherence to ECs in both static and dynamic adhesion assays to varying extents, as evaluated via absolute quantification using qPCR. Interactions between adhesins and Fn might represent the crucial step for the adhesion of human-pathogenic Gram-negative and Gram-positive bacteria targeting the ECs as a niche of infection.
Anaphylactic shock is a severe allergic reaction involving multiple organs including the bronchial and cardiovascular system. Most anaphylactic mediators, like platelet-activating factor (PAF), histamine, and others, act through G protein – coupled receptors, which are linked to the heterotrimeric G proteins Gq /G 11 , G12/G13 , and Gi . The role of downstream signaling pathways activated by anaphylactic mediators in defi ned organs during anaphylactic reactions is largely unknown. Using genetic mouse models that allow for the conditional abrogation of G q /G 11 - and G 12 /G 13 -mediated signaling pathways by inducible Cre/loxP-mediated mutagenesis in endothelial cells (ECs), we show that Gq /G11 -mediated signaling in ECs is required for the opening of the endothelial barrier and the stimulation of nitric oxide formation by various infl ammatory mediators as well as by local anaphylaxis. The systemic effects of anaphylactic mediators like histamine and PAF, but not of bacterial lipopolysaccharide (LPS), are blunted in mice with endothelial G alpha q/G alpha 11 deficiency. Mice with endothelium-specific G alpha q /G alpha 11 deficiency, but not with G alpha 12/G alpha 13 deficiency, are protected against the fatal consequences of passive and active systemic anaphylaxis. This identifies endothelial Gq/G11 -mediated signaling as a critical mediator of fatal systemic anaphylaxis and, hence, as a potential new target to prevent or treat anaphylactic reactions.
Aims: Patients with cardiovascular comorbidities have a significantly increased risk for a critical course of COVID-19. As the SARS-CoV2 virus enters cells via the angiotensin-converting enzyme receptor II (ACE2), drugs which interact with the renin angiotensin aldosterone system (RAAS) were suspected to influence disease severity.
Methods and results: We analyzed 1946 consecutive patients with cardiovascular comorbidities or hypertension enrolled in one of the largest European COVID-19 registries, the Lean European Open Survey on SARS-CoV-2 (LEOSS) registry. Here, we show that angiotensin II receptor blocker intake is associated with decreased mortality in patients with COVID-19 [OR 0.75 (95% CI 0,59–0.96; p = 0.013)]. This effect was mainly driven by patients, who presented in an early phase of COVID-19 at baseline [OR 0,64 (95% CI 0,43–0,96; p = 0.029)]. Kaplan-Meier analysis revealed a significantly lower incidence of death in patients on an angiotensin receptor blocker (ARB) (n = 33/318;10,4%) compared to patients using an angiotensin-converting enzyme inhibitor (ACEi) (n = 60/348;17,2%) or patients who received neither an ACE-inhibitor nor an ARB at baseline in the uncomplicated phase (n = 90/466; 19,3%; p<0.034). Patients taking an ARB were significantly less frequently reaching the mortality predicting threshold for leukocytes (p<0.001), neutrophils (p = 0.002) and the inflammatory markers CRP (p = 0.021), procalcitonin (p = 0.001) and IL-6 (p = 0.049). ACE2 expression levels in human lung samples were not altered in patients taking RAAS modulators.
Conclusion: These data suggest a beneficial effect of ARBs on disease severity in patients with cardiovascular comorbidities and COVID-19, which is linked to dampened systemic inflammatory activity.
Above 1 MeV of incident neutron energy the fission fragment angular distribution (FFAD) has generally a strong anisotropic behavior due to the combination of the incident orbital momentum and the intrinsic spin of the fissioning nucleus. This effect has to be taken into account for the efficiency estimation of devices used for fission cross section measurements. In addition it bears information on the spin deposition mechanism and on the structure of transitional states. We designed and constructed a detection device, based on Parallel Plate Avalanche Counters (PPAC), for measuring the fission fragment angular distributions of several isotopes, in particular 232Th. The measurement has been performed at n_TOF at CERN taking advantage of the very broad energy spectrum of the neutron beam. Fission events were recognized by back to back detection in coincidence in two position-sensitive detectors surrounding the targets. The detection efficiency, depending mostly on the stopping of fission fragments in backings and electrodes, has been computed with a Geant4 simulation and validated by the comparison to the measured case of 235U below 3 keV where the emission is isotropic. In the case of 232Th, the result is in good agreement with previous data below 10 MeV, with a good reproduction of the structures associated to vibrational states and the opening of second chance fission. In the 14 MeV region our data are much more accurate than previous ones which are broadly scattered.
We present a measurement of inclusive J/ψ production in p-Pb collisions at sNN−−−√ = 5.02 TeV as a function of the centrality of the collision, as estimated from the energy deposited in the Zero Degree Calorimeters. The measurement is performed with the ALICE detector down to zero transverse momentum, pT, in the backward (−4.46<ycms<−2.96) and forward (2.03<ycms<3.53) rapidity intervals in the dimuon decay channel and in the mid-rapidity region (−1.37<ycms<0.43) in the dielectron decay channel. The backward and forward rapidity intervals correspond to the Pb-going and p-going direction, respectively. The pT-differential J/ψ production cross section at backward and forward rapidity is measured for several centrality classes, together with the corresponding average pT and p2T values. The nuclear modification factor, QpPb, is presented as a function of centrality for the three rapidity intervals, and, additionally, at backward and forward rapidity, as a function of pT for several centrality classes. At mid- and forward rapidity, the J/ψ yield is suppressed up to 40% compared to that in pp interactions scaled by the number of binary collisions. The degree of suppression increases towards central p-Pb collisions at forward rapidity, and with decreasing pT of the J/ψ. At backward rapidity, the QpPb is compatible with unity within the total uncertainties, with an increasing trend from peripheral to central p-Pb collisions.
Transverse momentum (pT) spectra of pions, kaons, and protons up to pT=20 GeV/c have been measured in Pb-Pb collisions at sNN−−−√=2.76 TeV using the ALICE detector for six different centrality classes covering 0-80%. The proton-to-pion and the kaon-to-pion ratios both show a distinct peak at pT≈3 GeV/c in central Pb-Pb collisions that decreases towards more peripheral collisions. For pT>10 GeV/c, the nuclear modification factor is found to be the same for all three particle species in each centrality interval within systematic uncertainties of 10-20%. This suggests there is no direct interplay between the energy loss in the medium and the particle species composition in the hard core of the quenched jet. For pT<10 GeV/c, the data provide important constraints for models aimed at describing the transition from soft to hard physics.
Transverse momentum (pT) spectra of pions, kaons, and protons up to pT=20 GeV/c have been measured in Pb-Pb collisions at sNN−−−√=2.76 TeV using the ALICE detector for six different centrality classes covering 0-80%. The proton-to-pion and the kaon-to-pion ratios both show a distinct peak at pT≈3 GeV/c in central Pb-Pb collisions that decreases towards more peripheral collisions. For pT>10 GeV/c, the nuclear modification factor is found to be the same for all three particle species in each centrality interval within systematic uncertainties of 10-20%. This suggests there is no direct interplay between the energy loss in the medium and the particle species composition in the hard core of the quenched jet. For pT<10 GeV/c, the data provide important constraints for models aimed at describing the transition from soft to hard physics.
Transverse momentum (pT) spectra of pions, kaons, and protons up to pT=20 GeV/c have been measured in Pb-Pb collisions at sNN−−−√=2.76 TeV using the ALICE detector for six different centrality classes covering 0-80%. The proton-to-pion and the kaon-to-pion ratios both show a distinct peak at pT≈3 GeV/c in central Pb-Pb collisions that decreases towards more peripheral collisions. For pT>10 GeV/c, the nuclear modification factor is found to be the same for all three particle species in each centrality interval within systematic uncertainties of 10-20%. This suggests there is no direct interplay between the energy loss in the medium and the particle species composition in the hard core of the quenched jet. For pT<10 GeV/c, the data provide important constraints for models aimed at describing the transition from soft to hard physics.
Transverse momentum (pT) spectra of pions, kaons, and protons up to pT=20 GeV/c have been measured in Pb-Pb collisions at sNN−−−√=2.76 TeV using the ALICE detector for six different centrality classes covering 0-80%. The proton-to-pion and the kaon-to-pion ratios both show a distinct peak at pT≈3 GeV/c in central Pb-Pb collisions that decreases towards more peripheral collisions. For pT>10 GeV/c, the nuclear modification factor is found to be the same for all three particle species in each centrality interval within systematic uncertainties of 10-20%. This suggests there is no direct interplay between the energy loss in the medium and the particle species composition in the hard core of the quenched jet. For pT<10 GeV/c, the data provide important constraints for models aimed at describing the transition from soft to hard physics.
We have has performed the first measurement of the coherent ψ(2S) photo-production cross section in ultra-peripheral Pb-Pb collisions at the LHC. This charmonium excited state is reconstructed via the ψ(2S) →l+l− and ψ(2S) → J/ψπ+π− decays, where the J/ψ decays into two leptons. The analysis is based on an event sample corresponding to an integrated luminosity of about 22 μb−1. The cross section for coherent ψ(2S) production in the rapidity interval −0.9<y<0.9 is dσcohψ(2S)/dy=0.83±0.19(stat+syst) mb. The ψ(2S) to J/ψ coherent cross section ratio is 0.34+0.08−0.07(stat+syst). The obtained results are compared to predictions from theoretical models.
We have has performed the first measurement of the coherent ψ(2S) photo-production cross section in ultra-peripheral Pb-Pb collisions at the LHC. This charmonium excited state is reconstructed via the ψ(2S) →l+l− and ψ(2S) → J/ψπ+π− decays, where the J/ψ decays into two leptons. The analysis is based on an event sample corresponding to an integrated luminosity of about 22 μb−1. The cross section for coherent ψ(2S) production in the rapidity interval −0.9<y<0.9 is dσcohψ(2S)/dy=0.83±0.19(stat+syst) mb. The ψ(2S) to J/ψ coherent cross section ratio is 0.34+0.08−0.07(stat+syst). The obtained results are compared to predictions from theoretical models.
Background: Previously, we used inhibitors blocking BET bromodomain binding proteins (BRDs) in Ewing sarcoma (EwS) and observed that long term treatment resulted in the development of resistance. Here, we analyze the possible interaction of BRD4 with cyclin-dependent kinase (CDK) 9. Methods: Co-immunoprecipitation experiments (CoIP) to characterize BRD4 interaction and functional consequences of inhibiting transcriptional elongation were assessed using drugs targeting of BRD4 or CDK9, either alone or in combination. Results: CoIP revealed an interaction of BRD4 with EWS-FLI1 and CDK9 in EwS. Treatment of EwS cells with CDKI-73, a specific CDK9 inhibitor (CDK9i), induced a rapid downregulation of EWS-FLI1 expression and block of contact-dependent growth. CDKI-73 induced apoptosis in EwS, as depicted by cleavage of Caspase 7 (CASP7), PARP and increased CASP3 activity, similar to JQ1. Microarray analysis following CDKI-73 treatment uncovered a transcriptional program that was only partially comparable to BRD inhibition. Strikingly, combined treatment of EwS with BRD- and CDK9-inhibitors re-sensitized cells, and was overall more effective than individual drugs not only in vitro but also in a preclinical mouse model in vivo. Conclusion: Treatment with BRD inhibitors in combination with CDK9i offers a new treatment option that significantly blocks the pathognomonic EWS-ETS transcriptional program and malignant phenotype of EwS.
Our study provides evidence on the share price reactions to the announcement of equity issues in Germany, where capital market is characterized by institutional features distinct from the U.S. market. German seasoned equity issues yield a positive market reaction which contrasts to the significant negative abnormal returns reported for the U.S. We provide evidence that these results are due to differences in both issuing characteristics and floatation methods, and in the corporate governance and ownership structures of the two countries. Our study explains much of the empirical puzzle of different market reactions to seemingly similar events across financial markets.
Die Einteilung der Pneumonien richtet sich neben klinischen und pathologischen vor allem nach ätiologischen Gesichtspunkten. Es werden diesbezüglich die respirato- bzw. pneumotropen Viren vorgestellt, daneben differentialdiagnostisch wichtige andere Infektionserreger der "Viruspneumonie" (M. pneumoniae, Chlamydia psittaci, Coxiella burnetii) beschrieben und ihre klinischen Aspekte, labordiagnostischen Möglichkeiten sowie die Aussagekraft der verschiedenen Nachweisverfahren diskutiert. Die Letalität der primär virusbedingten Pneumonien ist zwar niedrig, der respiratotrope Virusbefall kann aber Schrittmacher für schwerebakterielle Superinfektionen sein.
The production of J/ψ and ψ(2S) was measured with the ALICE detector in Pb-Pb collisions at the LHC. The measurement was performed at forward rapidity (2.5<y<4) down to zero transverse momentum (pT) in the dimuon decay channel. Inclusive J/ψ yields were extracted in different centrality classes and the centrality dependence of the average pT is presented. The J/ψ suppression, quantified with the nuclear modification factor (RAA), was studied as a function of centrality, transverse momentum and rapidity. Comparisons with similar measurements at lower collision energy and theoretical models indicate that the J/ψ production is the result of an interplay between color screening and recombination mechanisms in a deconfined partonic medium, or at its hadronization. Results on the ψ(2S) suppression are provided via the ratio of ψ(2S) over J/ψ measured in pp and Pb-Pb collisions.
The directed and elliptic flow of protons and charged pions has been observed from the semi-central collisions of a 158 GeV/nucleon Pb beam with a Pb target. The rapidity and transverse momentum dependence of the flow has been measured. The directed flow of the pions is opposite to that of the protons but both exhibit negative flow at low pt. The elliptic flow of both is fairly independent of rapidity but rises with pt. PACS numbers: 25.75.-q, 25.75.Ld
Directed and elliptic flow of charged pions and protons in Pb + Pb collisions at 40 and 158 A GeV
(2003)
Directed and elliptic flow measurements for charged pions and protons are reported as a function of transverse momentum, rapidity, and centrality for 40 and 158A GeV Pb + Pb collisions as recorded by the NA49 detector. Both the standard method of correlating particles with an event plane, and the cumulant method of studying multiparticle correlations are used. In the standard method the directed flow is corrected for conservation of momentum. In the cumulant method elliptic flow is reconstructed from genuine 4, 6, and 8-particle correlations, showing the first unequivocal evidence for collective motion in A+A collisions at SPS energies.
The transcription factor hypoxia-inducible factor 1 (HIF1) is an important driver of cancer and is therefore an attractive drug target. Acriflavine (ACF) has been suggested to inhibit HIF1, but its mechanism of action is unknown. Here we investigated the interaction of ACF with DNA and long non-coding RNAs (lncRNAs) and its function in human endothelial cells. ACF promoted apoptosis and reduced proliferation, network formation, and angiogenic capacity. It also induced changes in gene expression, as determined by RNA sequencing (RNA-seq), which could not be attributed to specific inhibition of HIF1. A similar response was observed in murine lung endothelial cells. Although ACF increased and decreased a similar number of protein-coding genes, lncRNAs were preferentially upregulated under normoxic and hypoxic conditions. An assay for transposase accessibility with subsequent DNA sequencing (ATAC-seq) demonstrated that ACF induced strong changes in chromatin accessibility at lncRNA promoters. Immunofluorescence showed displacement of DNA:RNA hybrids. Such effects might be due to ACF-mediated topoisomerase inhibition, which was indeed the case, as reflected by DNA unwinding assays. Comparison with other acridine derivatives and topoisomerase inhibitors suggested that the specific function of ACF is an effect of acridinium-class compounds. This study demonstrates that ACF inhibits topoisomerases rather than HIF specifically and that it elicits a unique expression response of lncRNAs.
Dryopteris lacunosa – eine neue Art des Dryopteris-affinis-Aggregats (Dryopteridaceae, Pteridophyta)
(2011)
Eine weitere Sippe des Dryopteris-affinis-Aggregats wird als Art, D. lacunosa S. JESS., ZENNER, CH. STARK & BUJNOCH beschrieben. Sie lässt sich morphologisch von den anderen bisher beschriebenen Taxa des Aggregats unterscheiden, ist triploid und zeigt spezifische Phloroglucid- und RAPD- Bandenmuster. Bisher sind Funde aus Norditalien, Österreich, der Schweiz, Frankreich, Deutschland, Großbritannien und Irland belegt.
Macrophages are plastic and heterogeneous immune cells that adapt pro- or anti-inflammatory phenotypes upon exposure to different stimuli. Even though there has been evidence supporting a crosstalk between coagulation and innate immunity, the way in which protein components of the hemostasis pathway influence macrophages remains unclear. We investigated the effect of thrombin on macrophage polarization. On the basis of gene expression and cytokine secretion, our results suggest that polarization with thrombin induces an anti-inflammatory, M2-like phenotype. In functional studies, thrombin polarization promoted oxLDL phagocytosis by macrophages, and conditioned medium from the same cells increased endothelial cell proliferation. There were, however, clear differences between the classical M2a polarization and the effects of thrombin on gene expression. Finally, the deletion and inactivation of secreted modular Ca2+-binding protein 1 (SMOC1) attenuated phagocytosis by thrombin-stimulated macrophages, a phenomenon revered by the addition of recombinant SMOC1. Manipulation of SMOC1 levels also had a pronounced impact on the expression of TGF-β-signaling-related genes. Taken together, our results show that thrombin induces an anti-inflammatory macrophage phenotype with similarities as well as differences to the classical alternatively activated M2 polarization states, highlighting the importance of tissue levels of SMOC1 in modifying thrombin-induced macrophage polarization.
Eine fachübergreifende Zusammenarbeit von Fachleuten aus den Bereichen Makrophyten, Makrozoobenthos und Ornithologie hat am Bodensee zum ersten Mal das Beziehungsgefüge zwischen limnischen Nahrungsressourcen der Flachwasserzone und deren Hauptprädatoren, den Wasservögeln, aufgezeigt und die hohe Dynamik in diesem Ökosystem beleuchtet. Hierfür wurden bei dieser Untersuchung Stellen am Bodensee ausgewählt, die geeignet waren, um den Einfluss der Wasservögel auf Makrophyten beziehungsweise auf Dreikantmuscheln (Dreissena polymorpha PALLAS) zu untersuchen. Wasservögel wurden in halbmo-natlichem Abstand zwischen September und März quantifiziert und deren Aktivität abge-schätzt. Diese Erfassung wurde tags und nachts mit einem Infrarotgerät oder einem Restlichtverstärker durchgeführt. Die Beprobung von Makrophyten erfolgte über das gesamte Winterhalbjahr in 3 Tiefenstufen (-1, -1,5 und -2 m) bezogen auf die Mittelwasserlinie (MW, Pegel Konstanz = 361 cm) und wurde am Bodensee zum ersten Mal durchge-führt. Die Characeen-Vegetation im flacheren Litoralbereich des Zeller Sees war bis Dezember schon stark von Wasservögeln genutzt worden, während die tieferen Zonen erst nach der Vereisungsperiode im Februar und März abgeweidet wurden. Ferner zeigte die zum Ende des Winters noch vorhandene Biomasse in Fraßschutzkäfigen, dass der Seneszenzpro-zess am Biomasseverlust offensichtlich nur einen geringen Anteil hat. Bis in -2 m Wasser-tiefe wurde die vorhandene Characeen-Biomasse von den Wasservögeln fast vollständig als Nahrungsressource genutzt. In Iznang verknappten die Ressourcen in -1 m Tiefe frü-her als in Gundholzen. Die Vögel wichen aber nicht nach Gundholzen aus, wo noch genügend Nahrung in dieser Tiefenstufe vorhanden war, sondern sie erschlossen zunächst am selben Ort die tieferen Bereiche. Dies belegt eine Bevorzugung bestimmter Nahrungsgründe. Während der Untersuchungen im Dezem-ber 2001 wurden hier 10.000 Kolbenenten festgestellt, die wesentlich zur Reduktion der dortigen Chara-Bestände beitrugen. Aber im Gegensatz zu den Kolbenenten, die im Februar zahlenmäßig gering vertreten waren, schöpften die Blässhühner die aufgrund des gefallenen Wasserstandes leicht erreichbaren Chara-Rasen noch weiter ab. Die limnologischen Untersuchungen der Dreikantmuscheln erfolgten in vier Tiefenstufen (-1, -3, -7 und -11 m) unter dem Mittleren Niedrigwasserstand (MNW, Pegel Konstanz = 264 cm). Die Probennahmen fanden an allen Stellen vor (September), während (Januar) und nach der Prädation (März) durch Wasservögel statt.
Results are presented on event-by-event electric charge fluctuations in central Pb+Pb collisions at 20, 30, 40, 80 and 158 AGeV. The observed fluctuations are close to those expected for a gas of pions correlated by global charge conservation only. These fluctuations are considerably larger than those calculated for an ideal gas of deconfined quarks and gluons. The present measurements do not necessarily exclude reduced fluctuations from a quark-gluon plasma because these might be masked by contributions from resonance decays.
The energy dependence of multiplicity fluctuations was studied for the most central Pb+Pb collisions at 20A, 30A, 40A, 80A and 158A GeV by the NA49 experiment at the CERN SPS. The multiplicity distribution for negatively and positively charged hadrons is significantly narrower than Poisson one for all energies. No significant structure in energy dependence of the scaled variance of multiplicity fluctuations is observed. The measured scaled variance is lower than the one predicted by the grand-canonical formulation of the hadron-resonance gas model. The results for scaled variance are in approximate agreement with the string-hadronic model UrQMD.
In this study, we develop a technique for estimating a firm’s expected cost of equity capital derived from analyst consensus forecasts and stock prices. Building on the work of Gebhardt/Lee/-Swaminathan (2001) and Easton/Taylor/Shroff/Sougiannis (2002), our approach allows daily estimation, using only publicly available information at that date. We then estimate the expected cost of equity capital at the market, industry and individual firm level using historical German data from 1989-2002 and examine firm characteristics which are systematically related to these estimates. Finally, we demonstrate the applicability of the concept in a contemporary case study for DaimlerChrysler and the European automobile industry.
We report on results obtained with the Event Shape Engineering technique applied to Pb-Pb collisions at sNN−−−√=2.76 TeV. By selecting events in the same centrality interval, but with very different average flow, different initial state conditions can be studied. We find the effect of the event-shape selection on the elliptic flow coefficient v2 to be almost independent of transverse momentum pT, as expected if this effect is due to fluctuations in the initial geometry of the system. Charged hadron, pion, kaon, and proton transverse momentum distributions are found to be harder in events with higher-than-average elliptic flow, indicating an interplay between radial and elliptic flow.
Event-by-event fluctuations of particle ratios in central Pb + Pb collisions at 20 to 158 AGeV
(2004)
In the vicinity of the QCD phase transition, critical fluctuations have been predicted to lead to non-statistical fluctuations of particle ratios, depending on the nature of the phase transition. Recent results of the NA49 energy scan program show a sharp maximum of the ratio of K+ to Pi+ yields in central Pb+Pb collisions at beam energies of 20-30 AGeV. This observation has been interpreted as an indication of a phase transition at low SPS energies. We present first results on event-by-event fluctuations of the kaon to pion and proton to pion ratios at beam energies close to this maximum.
Evidence for an exotic S=-2, Q=-2 baryon resonance in proton-proton collisions at the CERN SPS
(2004)
Results of resonance searches in the Xi - pi -, Xi - pi +, Xi -bar+ pi -, and Xi -bar+ pi + invariant mass spectra in proton-proton collisions at sqrt[s]=17.2 GeV are presented. Evidence is shown for the existence of a narrow Xi - pi - baryon resonance with mass of 1.862±0.002 GeV/c2 and width below the detector resolution of about 0.018 GeV/c2. The significance is estimated to be above 4.2 sigma . This state is a candidate for the hypothetical exotic Xi --3/2 baryon with S=-2, I=3 / 2, and a quark content of (dsdsu-bar). At the same mass, a peak is observed in the Xi - pi + spectrum which is a candidate for the Xi 03/2 member of this isospin quartet with a quark content of (dsusd-bar). The corresponding antibaryon spectra also show enhancements at the same invariant mass.
Two-particle angular correlations between trigger particles in the forward pseudorapidity range (2.5<|η|<4.0) and associated particles in the central range (|η|<1.0) are measured with the ALICE detector in p-Pb collisions at a nucleon-nucleon centre-of-mass energy of 5.02 TeV. The trigger particles are reconstructed using the muon spectrometer, and the associated particles by the central barrel tracking detectors. In high-multiplicity events, the double-ridge structure, previously discovered in two-particle angular correlations at midrapidity, is found to persist to the pseudorapidity ranges studied in this Letter. The second-order Fourier coefficients for muons in high-multiplicity events are extracted after jet-like correlations from low-multiplicity events have been subtracted. The coefficients are found to have a similar transverse momentum (pT) dependence in p-going (p-Pb) and Pb-going (Pb-p) configurations, with the Pb-going coefficients larger by about 16±6%, rather independent of pT within the uncertainties of the measurement. The data are compared with calculations using the AMPT model, which predicts a different pT and η dependence than observed in the data. The results are sensitive to the parent particle v2 and composition of reconstructed muon tracks, where the contribution from heavy flavour decays are expected to dominate at pT>2 GeV/c.
Two-particle angular correlations between trigger particles in the forward pseudorapidity range (2.5<|η|<4.0) and associated particles in the central range (|η|<1.0) are measured with the ALICE detector in p-Pb collisions at a nucleon-nucleon centre-of-mass energy of 5.02 TeV. The trigger particles are reconstructed using the muon spectrometer, and the associated particles by the central barrel tracking detectors. In high-multiplicity events, the double-ridge structure, previously discovered in two-particle angular correlations at midrapidity, is found to persist to the pseudorapidity ranges studied in this Letter. The second-order Fourier coefficients for muons in high-multiplicity events are extracted after jet-like correlations from low-multiplicity events have been subtracted. The coefficients are found to have a similar transverse momentum (pT) dependence in p-going (p-Pb) and Pb-going (Pb-p) configurations, with the Pb-going coefficients larger by about 16±6%, rather independent of pT within the uncertainties of the measurement. The data are compared with calculations using the AMPT model, which predicts a different pT and η dependence than observed in the data. The results are sensitive to the parent particle v2 and composition of reconstructed muon tracks, where the contribution from heavy flavour decays are expected to dominate at pT>2 GeV/c.
Two-particle angular correlations between trigger particles in the forward pseudorapidity range (2.5<|η|<4.0) and associated particles in the central range (|η|<1.0) are measured with the ALICE detector in p-Pb collisions at a nucleon-nucleon centre-of-mass energy of 5.02 TeV. The trigger particles are reconstructed using the muon spectrometer, and the associated particles by the central barrel tracking detectors. In high-multiplicity events, the double-ridge structure, previously discovered in two-particle angular correlations at midrapidity, is found to persist to the pseudorapidity ranges studied in this Letter. The second-order Fourier coefficients for muons in high-multiplicity events are extracted after jet-like correlations from low-multiplicity events have been subtracted. The coefficients are found to have a similar transverse momentum (pT) dependence in p-going (p-Pb) and Pb-going (Pb-p) configurations, with the Pb-going coefficients larger by about 16±6%, rather independent of pT within the uncertainties of the measurement. The data are compared with calculations using the AMPT model, which predicts a different pT and η dependence than observed in the data. The results are sensitive to the parent particle v2 and composition of reconstructed muon tracks, where the contribution from heavy flavour decays are expected to dominate at pT>2 GeV/c.
Two-particle angular correlations between trigger particles in the forward pseudorapidity range (2.5<|η|<4.0) and associated particles in the central range (|η|<1.0) are measured with the ALICE detector in p-Pb collisions at a nucleon-nucleon centre-of-mass energy of 5.02 TeV. The trigger particles are reconstructed using the muon spectrometer, and the associated particles by the central barrel tracking detectors. In high-multiplicity events, the double-ridge structure, previously discovered in two-particle angular correlations at midrapidity, is found to persist to the pseudorapidity ranges studied in this Letter. The second-order Fourier coefficients for muons in high-multiplicity events are extracted after jet-like correlations from low-multiplicity events have been subtracted. The coefficients are found to have a similar transverse momentum (pT) dependence in p-going (p-Pb) and Pb-going (Pb-p) configurations, with the Pb-going coefficients larger by about 16±6%, rather independent of pT within the uncertainties of the measurement. The data are compared with calculations using the AMPT model, which predicts a different pT and η dependence than observed in the data. The results are sensitive to the parent particle v2 and composition of reconstructed muon tracks, where the contribution from heavy flavour decays are expected to dominate at pT>2 GeV/c.
With increasing distribution of endovascular stroke therapies, transient middle cerebral artery occlusion (tMCAO) in mice now more than ever depicts a relevant patient population with recanalized M1 occlusion. In this case, the desired therapeutic effect of blood flow restauration is accompanied by breakdown of the blood-brain barrier (BBB) and secondary reperfusion injury. The aim of this study was to elucidate short and intermediate-term transcriptional patterns and the involved pathways covering the different cellular players at the neurovascular unit after transient large vessel occlusion. To achieve this, male C57Bl/6J mice were treated according to an intensive post-stroke care protocol after 60 min occlusion of the middle cerebral artery or sham surgery to allow a high survival rate. After 24 h or 7 days, RNA from microvessel fragments from the ipsilateral and the contralateral hemispheres was isolated and used for mRNA sequencing. Bioinformatic analyses allowed us to depict gene expression changes at two timepoints of neurovascular post-stroke injury and regeneration. We validated our dataset by quantitative real time PCR of BBB-associated targets with well-characterized post-stroke dynamics. Hence, this study provides a well-controlled transcriptome dataset of a translationally relevant mouse model 24 h and 7 days after stroke which might help to discover future therapeutic targets in cerebral ischemia/reperfusion injury.
Two-particle correlation functions of negative hadrons over wide phase space, and transverse mass spectra of negative hadrons and deuterons near mid-rapidity have been measured in central Pb+Pb collisions at 158 GeV per nucleon by the NA49 experiment at the CERN SPS. A novel Coulomb correction procedure for the negative two-particle correlations is employed making use of the measured oppositely charged particle correlation. Within an expanding source scenario these results are used to extract the dynamic characteristics of the hadronic source, resolving the ambiguities between the temperature and transverse expansion velocity of the source, that are unavoidable when single and two particle spectra are analysed separately. The source shape, the total duration of the source expansion, the duration of particle emission, the freeze-out temperature and the longitudinal and transverse expansion velocities are deduced.
The large acceptance TPCs of the NA49 spectrometer allow for a systematic multidimensional study of two-particle correlations in different part of phase space. Results from Bertsch-Pratt and Yano-Koonin-Podgoretskii parametrizations are presented differentially in transverse pair momentum and pair rapidity. These studies give an insight into the dynamical space-time evolution of relativistic Pb+Pb collisions, which is dominated by longitudinal expansion.
The hadronic final state of central Pb+Pb collisions at 20, 30, 40, 80, and 158 AGeV has been measured by the CERN NA49 collaboration. The mean transverse mass of pions and kaons at midrapidity stays nearly constant in this energy range, whereas at lower energies, at the AGS, a steep increase with beam energy was measured. Compared to p+p collisions as well as to model calculations, anomalies in the energy dependence of pion and kaon production at lower SPS energies are observed. These findings can be explained, assuming that the energy density reached in central A+A collisions at lower SPS energies is sufficient to force the hot and dense nuclear matter into a deconfined phase.
The hadronic final state of central Pb+Pb collisions at 20, 30, 40, 80, and 158 AGeV has been measured by the CERN NA49 collaboration. The mean transverse mass of pions and kaons at midrapidity stays nearly constant in this energy range, whereas at lower energies, at the AGS, a steep increase with beam energy was measured. Compared to p+p collisions as well as to model calculations, anomalies in the energy dependence of pion and kaon production at lower SPS energies are observed. These findings can be explained, assuming that the energy density reached in central A+A collisions at lower SPS energies is sufficient to transform the hot and dense nuclear matter into a deconfined phase.
Particle production in central Pb+Pb collisions was studied with the NA49 large acceptance spectrometer at the CERN SPS at beam energies of 20, 30, 40, 80, and 158 GeV per nucleon. A change of the energy dependence is observed around 30A GeV for the yields of pions and strange particles as well as for the shapes of the transverse mass spectra. At present only a reaction scenario with onset of deconfinement is able to reproduce the measurements.
Transcription factors can serve as links between tumor microenvironment signaling and oncogenesis. Interferon regulatory factor 9 (IRF9) is recruited and expressed upon interferon stimulation and is dependent on cofactors that exert in tumor-suppressing or oncogenic functions via the JAK-STAT pathway. IRF9 is frequently overexpressed in human lung cancer and is associated with decreased patient survival; however, the underlying mechanisms remain to be elucidated. Here, we used stably transduced lung adenocarcinoma cell lines (A549 and A427) to overexpress or knockdown IRF9. Overexpression led to increased oncogenic behavior in vitro, including enhanced proliferation and migration, whereas knockdown reduced these effects. These findings were confirmed in vivo using lung tumor xenografts in nude mice, and effects on both tumor growth and tumor mass were observed. Using RNA sequencing, we identified versican (VCAN) as a novel downstream target of IRF9. Indeed, IRF9 and VCAN expression levels were found to be correlated. We showed for the first time that IRF9 binds at a newly identified response element in the promoter region of VCAN to regulate its transcription. Using an siRNA approach, VCAN was found to enable the oncogenic properties (proliferation and migration) of IRF9 transduced cells, perhaps with CDKN1A involvement. The targeted inhibition of IRF9 in lung cancer could therefore be used as a new treatment option without multimodal interference in microenvironment JAK-STAT signaling.
Lambda and Antilambda reconstruction in central Pb+Pb collisions using a time projection chamber
(1997)
The large acceptance time projection chambers of the NA49 experiment are used to record the trajectory of charged particles from Pb + Pb collisions at 158 GeV per nucleon. Neutral strange hadrons have been reconstructed from their charged decay products. To obtain distributions of Λ, and Ks0 in discrete bins of rapidity, y, and transverse momentum, pT, calculations have been performed to determine the acceptance of the detector and the efficiency of the reconstruction software as a function of both variables. The lifetime distributions obtained give values of cτ = 7.8 ± 0.6 cm for Λ and cτ = 2.5 ± 0.3 cm for Ks0, consistent with data book values.
Background: The angiogenic function of endothelial cells is regulated by numerous mechanisms, but the impact of long noncoding RNAs (lncRNAs) has hardly been studied. We set out to identify novel and functionally important endothelial lncRNAs.
Methods: Epigenetically controlled lncRNAs in human umbilical vein endothelial cells were searched by exon-array analysis after knockdown of the histone demethylase JARID1B. Molecular mechanisms were investigated by RNA pulldown and immunoprecipitation, mass spectrometry, microarray, several knockdown approaches, CRISPR-Cas9, assay for transposase-accessible chromatin sequencing, and chromatin immunoprecipitation in human umbilical vein endothelial cells. Patient samples from lung and tumors were studied for MANTIS expression.
Results: A search for epigenetically controlled endothelial lncRNAs yielded lncRNA n342419, here termed MANTIS, as the most strongly regulated lncRNA. Controlled by the histone demethylase JARID1B, MANTIS was downregulated in patients with idiopathic pulmonary arterial hypertension and in rats treated with monocrotaline, whereas it was upregulated in carotid arteries of Macaca fascicularis subjected to atherosclerosis regression diet, and in endothelial cells isolated from human glioblastoma patients. CRISPR/Cas9-mediated deletion or silencing of MANTIS with small interfering RNAs or GapmeRs inhibited angiogenic sprouting and alignment of endothelial cells in response to shear stress. Mechanistically, the nuclear-localized MANTIS lncRNA interacted with BRG1, the catalytic subunit of the switch/sucrose nonfermentable chromatin-remodeling complex. This interaction was required for nucleosome remodeling by keeping the ATPase function of BRG1 active. Thereby, the transcription of key endothelial genes such as SOX18, SMAD6, and COUP-TFII was regulated by ensuring efficient RNA polymerase II machinery binding.
Conclusion: MANTIS is a differentially regulated novel lncRNA facilitating endothelial angiogenic function.
Long-range angular correlations on the near and away side in p–Pb collisions at √sNN=5.02 TeV
(2013)
Angular correlations between charged trigger and associated particles are measured by the ALICE detector in p–Pb collisions at a nucleon–nucleon centre-of-mass energy of 5.02 TeV for transverse momentum ranges within 0.5<pT,assoc<pT,trig<4 GeV/c. The correlations are measured over two units of pseudorapidity and full azimuthal angle in different intervals of event multiplicity, and expressed as associated yield per trigger particle. Two long-range ridge-like structures, one on the near side and one on the away side, are observed when the per-trigger yield obtained in low-multiplicity events is subtracted from the one in high-multiplicity events. The excess on the near-side is qualitatively similar to that recently reported by the CMS Collaboration, while the excess on the away-side is reported for the first time. The two-ridge structure projected onto azimuthal angle is quantified with the second and third Fourier coefficients as well as by near-side and away-side yields and widths. The yields on the near side and on the away side are equal within the uncertainties for all studied event multiplicity and pT bins, and the widths show no significant evolution with event multiplicity or pT. These findings suggest that the near-side ridge is accompanied by an essentially identical away-side ridge.
The metastasis-associated lung adenocarcinoma transcript 1, MALAT1, is a long non-coding RNA (lncRNA) that has been discovered as a marker for lung cancer metastasis. It is highly abundant, its expression is strongly regulated in many tumor entities including lung adenocarcinoma and hepatocellular carcinoma as well as physiological processes, and it is associated with many RNA binding proteins and highly conserved throughout evolution. The nuclear transcript MALAT-1 has been functionally associated with gene regulation and alternative splicing and its regulation has been shown to impact proliferation, apoptosis, migration and invasion.
Here, we have developed a human and a mouse knockout system to study the loss-of-function phenotypes of this important ncRNA. In human tumor cells, MALAT1 expression was abrogated using Zinc Finger Nucleases. Unexpectedly, the quantitative loss of MALAT1 did neither affect proliferation nor cell cycle progression nor nuclear architecture in human lung or liver cancer cells. Moreover, genetic loss of Malat1 in a knockout mouse model did not give rise to any obvious phenotype or histological abnormalities in Malat1-null compared with wild-type animals. Thus, loss of the abundant nuclear long ncRNA MALAT1 is compatible with cell viability and normal development.
The mouse bitter taste receptors Tas2r143, Tas2r135, and Tas2r126 are encoded by genes that cluster on chromosome 6 and have been suggested to be expressed under common regulatory elements. Previous studies indicated that the Tas2r143/Tas2r135/Tas2r126 cluster is expressed in the heart, but other organs had not been systematically analyzed. In order to investigate the expression of this bitter taste receptor gene cluster in non-gustatory tissues, we generated a BAC (bacterial artificial chromosome) based transgenic mouse line, expressing CreERT2 under the control of the Tas2r143 promoter. After crossing this line with a mouse line expressing EGFP after Cre-mediated recombination, we were able to validate the Tas2r143-CreERT2 transgenic mouse line and monitor the expression of Tas2r143. EGFP-positive cells, indicating expression of members of the cluster, were found in about 47% of taste buds, and could also be found in several other organs. A population of EGFP-positive cells was identified in thymic epithelial cells, in the lamina propria of the intestine and in vascular smooth muscle cells of cardiac blood vessels. EGFP-positive cells were also identified in the epithelium of organs readily exposed to pathogens including lower airways, the gastrointestinal tract, urethra, vagina, and cervix. With respect to the function of cells expressing this bitter taste receptor cluster, RNA-seq analysis in EGFP-positive cells isolated from the epithelium of trachea and stomach showed expression of genes related to innate immunity. These data further support the concept that bitter taste receptors serve functions outside the gustatory system.
Individual adult ventricular cardiomyocytes are either mono- or multi-nucleated and undergo morphological changes during cardiac hypertrophy. However, corresponding transcriptional signatures, reflecting potentially different functions or the ability for cell-cycle entry, are not known. The aim of this study was to determine the transcriptional profile of mono- and multi-nucleated adult cardiomyocytes by single-cell RNA-sequencing (scRNA-seq) and to investigate heterogeneity among cardiomyocytes under baseline conditions and in pressure-induced cardiac hypertrophy. We developed an array-based approach for scRNA-seq of rod-shaped multi-nucleated cardiomyocytes from both healthy and hypertrophic hearts. Single-cell transcriptomes of mono- or multi-nucleated cardiomyocytes were highly similar, although a certain degree of variation was noted across both populations. Non-image-based quality control allowing inclusion of damaged cardiomyocytes generated artificial cell clusters demonstrating the need for strict exclusion criteria. In contrast, cardiomyocytes isolated from hypertrophic heart after transverse aortic constriction showed heterogeneous transcriptional signatures, characteristic for hypoxia-induced responses. Immunofluorescence analysis revealed an inverse correlation between HIF1α+ cells and CD31-stained vessels, suggesting that imbalanced vascular growth in the hypertrophied heart induces cellular heterogeneity. Our study demonstrates that individual mono- and multi-nucleated cardiomyocytes express nearly identical sets of genes. Homogeneity among cardiomyocytes was lost after induction of hypertrophy due to differential HIF1α-dependent responses most likely caused by none-homogenous vessel growth.
System size dependence of multiplicity fluctuations of charged particles produced in nuclear collisions at 158 A GeV was studied in the NA49 CERN experiment. Results indicate a non-monotonic dependence of the scaled variance of the multiplicity distribution with a maximum for semi-peripheral Pb+Pb interactions with number of projectile participants of about 35. This effect is not observed in a string-hadronic model of nuclear collision HIJING.
A non-monotonic energy dependence of the K + / pi + ratio with a sharp maximum close to 30 A GeV is observed in central Pb+Pb collisions. Within a statistical model of the early stage, this is interpreted as a sign of the phase transition to a QGP, which causes a sharp change in the energy dependence of the strangeness to entropy ratio. This observation naturally motivates us to study the production of multistrange hyperons (Xi, Omega) as a function of the beam energy. Furthermore it was suggested that the kinematic freeze-out of Omega takes place directly at QGP hadronization. If this is indeed the case, the transverse momentum spectra of the Omega directly reflect the transverse expansion velocity of a hadronizing QGP. In this report we show preliminary NA49 results on Omega - and Omega + production in central Pb+Pb collisions at 40 and 158 A GeV and compare them to measurements of Xi - and Xi + production in central Pb+Pb collisions at 30, 40, 80 and 158 A GeV.
Impaired alveolar formation and maintenance are features of many pulmonary diseases that are associated with significant morbidity and mortality. In a forward genetic screen for modulators of mouse lung development, we identified the non-muscle myosin II heavy chain gene, Myh10. Myh10 mutant pups exhibit cyanosis and respiratory distress, and die shortly after birth from differentiation defects in alveolar epithelium and mesenchyme. From omics analyses and follow up studies, we find decreased Thrombospondin expression accompanied with increased matrix metalloproteinase activity in both mutant lungs and cultured mutant fibroblasts, as well as disrupted extracellular matrix (ECM) remodeling. Loss of Myh10 specifically in mesenchymal cells results in ECM deposition defects and alveolar simplification. Notably, MYH10 expression is downregulated in the lung of emphysema patients. Altogether, our findings reveal critical roles for Myh10 in alveologenesis at least in part via the regulation of ECM remodeling, which may contribute to the pathogenesis of emphysema.
Highlights
• NCoR1 is the most highly expressed endothelial corepressor.
• Loss of NCoR1 promotes angiogenic function in endothelial cells.
• Loss of NCoR1 promotes a tip cell position during angiogenic sprouting.
Abstract
Corepressors negatively regulate gene expression by chromatin compaction. Targeted regulation of gene expression could provide a means to control endothelial cell phenotype. We hypothesize that by targeting corepressor proteins, endothelial angiogenic function can be improved. To study this, the expression and function of nuclear corepressors in human umbilical vein endothelial cells (HUVEC) and in murine organ culture was studied. RNA-seq revealed that nuclear receptor corepressor 1 (NCoR1), silencing mediator of retinoid and thyroid hormone receptors (SMRT) and repressor element-1 silencing transcription factor (REST) are the highest expressed corepressors in HUVECs. Knockout and knockdown strategies demonstrated that the depletion of NCoR1 increased the angiogenic capacity of endothelial cells, whereas depletion of SMRT or REST did not. Interestingly, the effect was VEGF signaling independent. NCoR1 depletion significantly upregulated angiogenesis-associated genes, especially tip cell genes, including ESM1, DLL4 and NOTCH4, as observed by RNA- and ATAC-seq. Confrontation assays comparing cells with and without NCoR1-deficiency revealed that loss of NCoR1 promotes a tip-cell position during spheroid sprouting. Moreover, a proximity ligation assay identified NCoR1 as a direct binding partner of the Notch-signaling-related transcription factor RBPJk. Luciferase assays showed that siRNA-mediated knockdown of NCOR1 promotes RBPJk activity. Furthermore, NCoR1 depletion prompts upregulation of several elements in the Notch signaling cascade. Downregulation of NOTCH4, but not NOTCH1, prevented the positive effect of NCOR1 knockdown on spheroid outgrowth. Collectively, these data indicate that decreasing NCOR1 expression is an attractive approach to promote angiogenic function.