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Leukemia cells reciprocally interact with their surrounding bone marrow microenvironment (BMM), rendering it hospitable to leukemia cell survival, for instance through the release of small extracellular vesicles (sEVs). In contrast, we show here that BMM deficiency of pleckstrin homology domain family M member 1 (PLEKHM1), which serves as a hub between fusion and secretion of intracellular vesicles and is important for vesicular secretion in osteoclasts, accelerates murine BCR-ABL1+ B-cell acute lymphoblastic leukemia (B-ALL) via regulation of the cargo of sEVs released by BMM-derived mesenchymal stromal cells (MSCs). PLEKHM1-deficient MSCs and their sEVs carry increased amounts of syntenin and syndecan-1, resulting in a more immature B-cell phenotype and an increased number/function of leukemia-initiating cells (LICs) via focal adhesion kinase and AKT signaling in B-ALL cells. Ex vivo pretreatment of LICs with sEVs derived from PLEKHM1-deficient MSCs led to a strong trend toward acceleration of murine and human BCR-ABL1+ B-ALL. In turn, inflammatory mediators such as recombinant or B-ALL cell–derived tumor necrosis factor α or interleukin-1β condition murine and human MSCs in vitro, decreasing PLEKHM1, while increasing syntenin and syndecan-1 in MSCs, thereby perpetuating the sEV-associated circuit. Consistently, human trephine biopsies of patients with B-ALL showed a reduced percentage of PLEKHM1+ MSCs. In summary, our data reveal an important role of BMM-derived sEVs for driving specifically BCR-ABL1+ B-ALL, possibly contributing to its worse prognosis compared with BCR-ABL1− B-ALL, and suggest that secretion of inflammatory cytokines by cancer cells in general may similarly modulate the tumor microenvironment.
In this study, we introduce a novel entity matching (EM) framework. It com-bines state-of-the-art EM approaches based on Artificial Neural Networks (ANN) with a new similarity encoding derived from matching techniques that are preva-lent in finance and economics. Our framework is on-par or outperforms alternative end-to-end frameworks in standard benchmark cases. Because similarity encod-ing is constructed using (edit) distances instead of semantic similarities, it avoids out-of-vocabulary problems when matching dirty data. We highlight this property by applying an EM application to dirty financial firm-level data extracted from historical archives.
Why does the schooling gap close while the wage gap persists across country income comparisons?
(2023)
The schooling gap diminishes because the services sector becomes more pronounced for high-income countries, and the paid hours gap closes. Although gender wage inequality persists across country income groups, differences in schooling years between females and males diminish. We assemble a novel dataset, calibrate a general equilibrium, multi-sector, -gender, and -production technology model, and show that gender-specific sectoral comparative advantages explain the paid hours and schooling gap decline from low- to high-income economies even when the wage gap persists. Additionally, our counterfactual analyses indicate that consumption subsistence and production share heterogeneity across both income groups and genders are essential to explain the co-decline of the schooling and paid hours gaps. Our results highlight effective mechanisms for policies aiming to reduce gender inequality in schooling and suggest that the schooling gap decline and the de-invisibilization of female paid work observed in high-income countries are linked by structural sector movements instead of wage inequality reductions.
Although overexpression and hyperactivity of protein kinases are causative for a wide range of human cancers, protein kinase inhibitors currently approved as cancer drugs address only a limited number of these enzymes. To identify new chemotypes addressing alternative protein kinases, the basic structure of a known PLK1/VEGF-R2 inhibitor class was formally dissected and reassembled. The resulting 7-(2-anilinopyrimidin-4-yl)-1-benzazepin-2-ones were synthesized and proved to be dual inhibitors of Aurora A kinase and VEGF receptor kinases. Crystal structures of two representatives of the new chemotype in complex with Aurora A showed the ligand orientation in the ATP binding pocket and provided the basis for rational structural modifications. Congeners with attached sulfamide substituents retained Aurora A inhibitory activity. In vitro screening of two members of the new kinase inhibitor family against the cancer cell line panel of the National Cancer Institute (NCI) showed antiproliferative activity in the single-digit micromolar concentration range in the majority of the cell lines.
Die Plasmamembran eukaryotischer Zellen dient als Barriere zwischen dem Inneren einer Zelle und ihrer Umgebung. Eine wichtige Aufgabe von Proteinen, die sich in der Plasmamembran befinden, besteht in der Erkennung der Umgebung, der Übermittlung dieser Informationen über die Plasmamembran in das Innere einer Zelle und der Einleitung einer zellulären Antwort. Membranrezeptoren binden Liganden, was zu ihrer Aktivierung und der Rekrutierung von intrazellulären Proteinen führt. Funktionelle Signalkomplexe werden gebildet und leiten einen Informationstransfer durch die Zellmembran ein, so dass die Expression bestimmter Gene stimuliert oder unterdrückt wird. Eine Störung der Signalinitiierung und -übertragung tritt bei vielen Krankheiten auf, so dass Membranproteine ein wichtiges Ziel in der Medikamentenentwicklung sind.
In dieser Arbeit wird die Fragestellung bearbeitet, wie der Tumornekrosefaktor-Rezeptor 1 (TNFR1) in funktionelle Komplexe in der Plasmamembran einer intakten Zelle organisiert ist. TNFR1 besitzt vier cysteinreiche Domänen (CRDs) in seiner extrazellulären Region. Die erste und von der Plasmamembran am weitesten entfernte CRD ist die Pre-Ligand Assembly Domain (PLAD). Kristallstrukturen zeigten, dass sich in einem TNFR1-Dimer zwei PLAD in unmittelbarer Nähe befinden. Crosslinking-Experimente berichteten über mehrere oligomere Zustände von TNFR1; die Ergebnisse unterschieden sich nach Art und Konzentration des Crosslinkers. In der nativen Umgebung einer intakten Zelle wurde der oligomere Zustand von TNFR1 bisher nicht bestimmt. Der kanonische Ligand für TNFR1 ist der Tumornekrosefaktor alpha (TNF), ein Homotrimer, welches in löslicher oder membrangebundener Form vorliegt. Nach der Bindung von TNF an TNFR1 bilden sich Rezeptortrimere. Diese Proteinkomplexe rekrutieren intrazellulär Proteine und bilden einen funktionellen Membrankomplex, der intrazelluläre Signalkaskaden aktiviert. Die kanonische Signalweiterleitung erfolgt durch den nuclear factor kappa-light-chain-enhancer of activated B-cells (NF-B), welcher Zellteilung oder Entzündung induziert. TNFR1 kann auch andere Signalwege wie beispielsweise Apoptose durch einen zytosolischen Komplex und die Procaspase-8, oder Nekroptose durch das Nekrosom und die mixed lineage kinase domain-like (MLKL)-Domäne einleiten. Die Dysregulation von TNFR1 ist bei einer Vielzahl von Krankheiten zu finden. Erhöhte TNFR1-Expressiosraten treten bei acquired immune deficiency syndrome (AIDS), multipler Sklerose und verschiedenen Krebsarten auf.
In einem zweiten Projekt wurde in Zusammenarbeit mit Prof. Dr. Michael Lanzer (Heidelberg, Germany) der Expressionsgrad des Proteins VAR2CSA in membranassoziierten knobs bestimmt, welche in Erythrozyten vorkommen, die mit dem Parasiten Plasmodium falciparum infizierten wurden. VAR2CSA gehört zur Proteinfamilie des Plasmodium falciparum erythrocyte membrane protein 1 (pfEMP1). Nach einer Infektion wird VAR2CSA zur Wirtszellmembran transportiert und in knobs eingelagert. Patienten, die Sichelzellenanämie-Erythrozyten (HbAS) aufweisen, sind im Gegensatz zu Patienten mit gesunden Erythrozyten (HbAA) immun gegen Malaria. Während die beiden Erythrozytentypen eine unterschiedliche Morphologie der knobs aufweisen, blieb ihre Zusammensetzung in Bezug auf VAR2CSA bisher ungeklärt.
Das Verständnis der Proteinfunktion erfordert eine Beschreibung der molekularen Organisation funktioneller Einheiten in der zellulären Umgebung. Hierfür ist die Fluoreszenzmikroskopie eine geeignete Methode, da sie eine gezielte Markierung von Zielproteinen ermöglicht. Die hohe Sensitivität ermöglicht die Visualisierung einzelner Proteine. Eine Einschränkung in der konventionellen Fluoreszenzmikroskopie ist die Auflösungsgrenze. Strukturelle Elemente, die kleiner als etwa die halbe Anregungswellenlänge sind (für die meisten Anwendungen 200 bis 300 nm) können nicht aufgelöst werden. Die Entwicklung der hochauflösenden Fluoreszenzmikroskopie ermöglichte es, diese Auflösungsgrenze zu umgehen und eine räumliche Auflösung von wenigen Nanometern zu erreichen, was die Visualisierung und Charakterisierung einzelner Proteinkomplexe ermöglichte. Eine Art der hochauflösenden Fluoreszenzmikroskopie ist die single-molecule localization microscopy (SMLM), die auf der Detektion einzelner Fluorophore, einer genauen Bestimmung ihrer Position (Lokalisation) und der Erzeugung eines rekonstruierten Bildes unterhalb der optischen Auflösungsgrenze basiert. Da die meisten Proben in der Fluoreszenzmikroskopie eine zu hohe räumliche Dichte an Fluorophoren aufweisen, um den Nachweis von einzelnen Fluorophoren zu ermöglichen, werden Verfahren zur Kontrolle der Emission von Fluorophoren eingesetzt. Eine Möglichkeit ist der Einsatz von Fluorophoren, die optisch zwischen einem nicht-fluoreszierenden und einem fluoreszierenden Zustand geschaltet werden können, z.B. photoschaltbare fluoreszierende Proteine in photoactivated localization microscopy (PALM) oder organische Farbstoffe in (direct) stochastic optical reconstruction microscopy ((d)STORM). SMLM erreicht eine räumliche Auflösung von 20 nm, was in den meisten Fällen ausreicht, um einzelne Proteinkomplexe in einer Zelle aufzulösen. Diese räumliche Auflösung ist jedoch nicht ausreichend, um Untereinheiten innerhalb eines Proteinkomplexes zu visualisieren. Zu diesem Zweck wurde SMLM erweitert und die verfügbare kinetische Information genutzt, die bei der Detektion einzelner Fluorophore ausgelesen wird. Viele Fluorophore weisen metastabile Dunkelzustände auf, die eine Lebensdauer von bis zu Sekunden aufweisen. Diese Übergänge erscheinen als "Blinken" der Fluoreszenzemission. In Kombination mit kinetischen Modellen kann aus der Anzahl an Blink-Ereignissen die Anzahl der Fluorophore ermittelt werden. Angewendet auf hochaufgelöste Proteinkomplexe kann die Auflösungsgrenze von hochauflösender Mikroskopie umgangen werden, und die Anzahl der Protein-Untereinheiten in einem hochaufgelösten Proteincluster ermittelt werden. Hierzu wird beispielsweise das photoschaltbare fluoreszierende Protein mEos2 an ein Zielprotein funsioniert (quantitative PALM (qPALM)).
...
Collective flow phenomena are a sensitive probe for the properties of extreme QCD matter. However, their interpretation relies on the understanding of the initial conditions e.g. the eccentricity of the nuclear overlap region. HADES [1] provides a large acceptance combined with a high mass-resolution and therefore allows to study di-electron and hadron production in heavy-ion collisions with unprecedented precision. In this contribution, the capability of HADES to study flow harmonics by utilizing multi-particle azimuthal correlation techniques is discussed. Due to the high statistics of seven billion Au+Au collisions at 1.23 AGeV collected in 2012, a systematic study of higher-order flow harmonics, the differentiation between collective and non-flow effects, and as well the multi-differential (pt, rapidity, centrality) analysis is possible.
In this thesis, the flow coefficients vn of the orders n = 1 − 6 are studied for protons and light nuclei in Au+Au collisions at Ebeam = 1.23 AGeV, equivalent to a center-of-mass energy in the nucleon-nucleon system of √sNN = 2.4 GeV. The detailed multi-differential measurement is performed with the HADES experiment at SIS18/GSI. HADES, with its large acceptance, covering almost full azimuth angle, combined with its high mass-resolution and good particle-identification capability, is well equipped to study the azimuthal flow pattern not only for protons, deuterons, and tritons but also for charged pions, kaons, the φ-mesons, electrons/positrons, as well as light nuclei like helions and alphas. The high statistics of more than seven billion Au-Au collisions recorded in April/May 2012 with HADES enables for the first time the measurement of higher order flow coefficients up to the 6th harmonic. Since the Fourier coefficient of 7th and 8th order are beyond the statistical significance only an upper bound is given. The Au+Au collision system is the largest reaction system with the highest particle multiplicities, which was measured so far with HADES. A dedicated correction method for the flow measurement had to be developed to cope with the reconstruction in-efficiencies due to occupancies of the detector system. The systematical bias of the flow measurement is studied and several sources of uncertainties identified, which mainly arise from the quality selection criteria applied to the analyzed tracks, the correction procedure for reconstruction inefficiencies, the procedures for particle identification (PID) and the effects of an azimuthally non-uniform detector acceptance. The systematic point-to-point uncertainties are determined separately for each particle type (proton, deuteron and triton), the order of the flow harmonics vn, and the centrality class. Further, the validity of the results is inspected in the range of their evaluated systematic uncertainties with several consistency checks. In order to enable meaningful comparisons between experimental observations and predictions of theoretical models, the classification of events should be well defined and in sufficiently narrow intervals of impact parameter. Part of this work included the implementation of the procedure to determine the centrality and orientation of the reaction.
In the conclusion the experimental results are discussed, including various scaling properties of the flow harmonics. It is found that the ratio v4/v2 for protons and light nuclei (deuterons and tritons) at midrapidity for all centrality classes approaches values close to 0.5 at high transverse momenta, which was suggested to be indicative for an ideal hydrodynamic behaviour. A remarkable scaling is observed in the pt dependence of v2 (v4) at mid-rapidity of the three hydrogen isotopes, when dividing by their nuclear mass number A (A^2) and pt by A. This is consistent with naive expectations from nucleon coalescence, butraises the question whether this mass ordering can also be explained by a hydrodynamical-inspired approach, like the blast-wave model. The relation of v2 and v4 to the shape of the initial eccentricity of the collision system is studied. It is found that v2 is independent of centrality for all three particle species after dividing it by the averaged second order participant eccentricity v2/⟨ε2⟩. A similar scaling is shown for v4 after division by ⟨ε2⟩^2.
The HADES experiment provides a large acceptance combined with a high mass resolution and therefore makes it possible to study dielectron and hadron production in heavy-ion collisions with unprecedented precision. With the high statistics of seven billion Au+Au collisions at 1.23 AGeV recorded in 2012 the investigation of collective effects and particle correlations is possible with unprecedented accuracy. We present multi-differential data on directed (v1) and elliptic (v2) flow, and the first measurement of triangular flow (v3), of protons and deuterons.
HADES has a large acceptance combined with a good mass-resolution and therefore allows the study of dielectron and hadron production in heavy-ion collisions with unprecedented precision. With the statistics of seven billion Au-Au collisions at 1.23A GeV recorded in 2012, the investigation of higher-order flow harmonics is possible. At the BEVALAC and SIS18 directed and elliptic flow has been measured for pions, charged kaons, protons, neutrons and fragments, but higher-order harmonics have not yet been studied. They provide additional important information on the properties of the dense hadronic medium produced in heavy-ion collisions. We present here a high-statistics, multidifferential measurement of v1 and v2 for protons in Au+Au collisions at 1.23A GeV.