Extension of the Color Glass Condensate Approach to Diffractive Reactions

We present an evolution equation for the Bjorken x dependence of diffractive dissociation on hadrons and nuclei at high energies. We extend the formulation of Kovchegov and Levin by relaxing the factorization assumption used there. The formulation is based on a technique used by Weigert to describe interjet energy flow. The method can be naturally extended to other exclusive observables

Generierung von Sphingosin-1-Phosphat durch apoptotische Zellen und dessen Einfluss auf die Polarisierung von Makrophagen während der Tumorentwicklung

The removal of apoptotic cells (AC) can be regarded as an integral component of the program to terminate inflammation. Clearance of AC by professional phagocytes such as macrophages induces an anti-inflammatory phenotype in the latter ones. Anti-inflammatory or M2 polarization is also observed in macrophages infiltrating certain human tumors. These tumor-associated macrophages (TAM) contribute actively to tumor progression by promoting immune evasion, angiogenesis and tumor cell survival. The aim of my Ph.D. thesis was to approach the mechanisms as well as the characteristics of macrophage phenotype alterations induced by AC, and to elucidate a possible connection between tumor cell apoptosis and TAM generation. In the first part of my studies, I investigated the impact of AC on macrophage viability. I could show that macrophage survival against pro-apoptotic agents increased after the interaction with AC. Protection of macrophages against cell death required activation of phosphatidylinositol-3 kinase (PI3K), extracellular signal-regulated kinase 1/2 (ERK1/2) and Ca2+ signaling, and correlated with Bcl-XL and Bcl-2 up-regulation as well as Ser136-Bad phosphorylation. Unexpectedly, neither phagocytosis nor binding of apoptotic debris to the phagocyte was necessary to induce protection. AC released the bioactive lipid sphingosine-1-phosphate (S1P), dependent on sphingosine kinase (SphK) 2, as a survival messenger. These data indicated an active role of AC in preventing cell destruction in their neighborhood. My next aim was to elucidate the mechanism of S1P production by AC. During cell death, SphK 2 was cleaved at its N-terminus by caspase-1. Thereupon, the truncated but enzymatically active fragment of SphK 2 was released from cells. This release was coupled to phosphatidylserine exposure, a hallmark of apoptosis and a crucial signal for the phagocyte/apoptotic cell interaction. Thus, I observed a link between common signaling events during apoptosis and the extracellular production of S1P, which is known to affect immune cell attraction and polarization as well as angiogenesis in cancer. In the next part of my studies, I asked for a correlation between tumor cell apoptosis and TAM polarization. During co-culture of human macrophages with human breast cancer carcinoma cells (MCF-7), the latter ones were killed, while macrophages acquired an alternatively activated phenotype. This was characterized by decreased tumor necrosis factor (TNF)-α; and interleukin (IL)-12-p70 production, but increased formation of IL-8 and IL-10. Alternative macrophage activation required tumor cell death, because a co-culture with apoptosis-resistant colon carcinoma cells (RKO) or Bcl-2-overexpressing MCF-7 cells failed to induce phenotype alterations. These phenotype alterations were also achieved with conditioned media from apoptotic tumor cells, which again argued for a soluble factor being involved. Knock-down of SphK2, but not SphK1, to attenuate S1P formation in MCF-7 cells, repressed the otherwise observed alternative macrophage polarization during co-culture. Furthermore, macrophage polarization achieved by tumor cell apoptosis or substitution of authentic S1P was characterized by suppression of pro-inflammatory nuclear factor (NF)-κB DNA binding. These findings suggested that tumor cell apoptosis-derived S1P contributes to the macrophage polarization present in human tumors. To validate these in vitro data, I used an in vivo tumor model to clarify the relevance of SphK2 and S1P in tumor development. The growth of, as well as blood vessel infiltration into SphK2 knock-down MCF-7 (MCF-7-siSphK2) xenografts in nude mice was markedly decreased in comparison to control MCF-7 xenografts. In contrast, macrophage infiltration was similar or even more pronounced. These data provided a first hint for an in vivo role of SphK2-derived S1P in macrophage polarization associated with tumor promotion. In summary, these data indicate a new mechanism how AC themselves shape macrophage polarization, which results in the termination of inflammatory responses and macrophage survival. Furthermore, my studies present evidence that human tumors may utilize this mechanism to foster growth via increased angiogenesis.Die Phagozytose apoptotischer Zellen (AZ) kann als ein integraler Bestandteil des Mechanismus zur Beendigung von Entzündungsreaktionen angesehen werden. Die Beseitigung von AZ induziert einen anti-inflammatorischen Phänotyp in Makrophagen. Ein ähnlicher Phänotyp (M2) ist auch für Makrophagen beschrieben, die in humane Tumore infiltrieren. Diese Tumor- assoziierten Makrophagen (TAM) tragen aktiv zur Tumorprogression bei, indem sie die Gefäßbildung und das Überleben von Tumorzellen fördern, aber auch das körpereigene Immunsystem ausschalten. Das Ziel meiner Doktorarbeit war es, die Mechanismen und Charakteristika der Makrophagenpolarisierung durch AZ besser zu verstehen, und eine mögliche Verbindung von Tumorzell-Apoptose und der Ausprägung des TAM-Phänotyps aufzuzeigen. Im ersten Teil meiner Studien untersuchte ich den Einfluss von AZ auf die Überlebensfähigkeit von Makrophagen. Diese war nach der Interaktion mit AZ erhöht. Der Schutz vor Zelltod benötigte die Aktivierung der Phosphatidylinositol-3 Kinase (PI3K), der Mitogen-aktivierten Proteinkinasen ERK1/2, sowie Calcium-Signale, und korrelierte mit vermehrter Expression von Bcl-2 und Bcl-XL, sowie mit Phosphorylierung von Bad an Ser136. Interessanterweise war der Schutzeffekt unabhängig von Phagozytose oder direkter Interaktion zwischen Makrophagen und AZ, sondern vielmehr von der Freisetzung des bioaktiven Lipids Sphingosin-1-Phosphat (S1P) aus AZ, generiert durch die Sphingosinkinase (SphK) 2. Mein nächstes Ziel war es den dafür verantwortlichen Mechanismus aufzuzeigen. Während des Zelltods fand eine Spaltung der SphK2 durch die Caspase-1 an deren N-Terminus statt, woraufhin ein enzymatisch aktives Fragment aus den AZ freigesetzt wurde. Diese Freisetzung war eng an die Exposition von Phosphatidylserin gekoppelt, welche ein Kennzeichen von Apoptose, und ein wichtiges Signal bei der Interaktion von Makrophagen und AZ ist. Somit konnte ich eine Verknüpfung zwischen allgemeinen Signalwegen der Apoptose und der extrazellulären Produktion von S1P nachweisen. Von letzterem ist bekannt, dass es sowohl die Polarisierung und das Anlocken von Immunzellen, als auch die Gefäßbildung im Tumor beeinflussen kann. Im nachfolgenden Teil meiner Studien untersuchte ich eine mögliche Verbindung zwischen Tumorzell-Apoptose und der TAM- Polarisierung. In einer Ko-Kultur von menschlichen Makrophagen mit MCF-7 Brustkrebszellen wurden letztere getötet, woraufhin die Makrophagen einen alternativ aktivierten Phänotyp annahmen. Dieser war durch verminderte Produktion des Tumor-Nekrose-Faktors (TNF)-α; und des Interleukins (IL)-12p70 sowie durch erhöhte Freisetzung der Interleukine 8 und 10 charakterisiert. Die alternative Aktivierung der Makrophagen in den Ko-Kulturen war Tumorzelltod-abhängig, da Apoptose-resistente Darmkrebszellen (RKO) oder Bcl-2 überexprimierende MCF-7 Zellen diese nicht auslösten. Dies war jedoch mit Zellkulturüberständen von apoptotischen Tumorzellen der Fall, was wiederum auf einen löslichen Faktor hindeutete. Das Ausschalten der SphK2, nicht jedoch der SphK1, was die S1P- Freisetzung von MCF-7 Zellen unterband, verhinderte die alternative Aktivierung von Makrophagen in den Ko-Kulturen. Ein weiteres Charakteristikum der Makrophagenpolarisierung durch apoptotische Tumorzellen und S1P war die Hemmung der DNA-Bindung des entzündungsfördernden Transkriptionsfaktors NF-κB. Um die Relevanz der SphK2 und von S1P in der Tumorentwicklung genauer zu untersuchen, führte ich ein in vivo Tumormodell durch. Tumorzell-Implantate von SphK2-defizienten MCF-7 Zellen in Nacktmäusen wiesen sowohl deutlich reduziertes Wachstum, als auch Blutgefäßbildung, im Vergleich zu Kontrollimplantaten (MCF-7) auf. Die Einwanderung von Makrophagen war jedoch nicht vermindert, sondern eher erhöht. Diese Daten lieferten einen ersten Hinweis auf eine Rolle von SphK2-abhängig freigesetztem S1P in der Makrophagenpolarisierung, in Verbindung mit einer Förderung der Tumorentwicklung. Zusammengefasst deuten meine Daten auf einen neuen Mechanismus hin, wie AZ die Makrophagenpolarisierung gestalten. Dieser Prozess resultiert letztlich in der Beendigung von Entzündungsreaktionen und erhöhter Überlebensfähigkeit von Makrophagen. Weiterhin weisen meine Studien darauf hin, dass Tumore eventuell diesen Mechanismus nutzen, um ihr Wachstum durch vermehrte Gefäßbildung zu sichern

Tumour stroma-derived lipocalin-2 promotes breast cancer metastasis

Tumour cell-secreted factors skew infiltrating immune cells towards a tumour-supporting phenotype, expressing pro-tumourigenic mediators. However, the influence of lipocalin-2 (Lcn2) on the metastatic cascade in the tumour micro-environment is still not clearly defined. Here, we explored the role of stroma-derived, especially macrophage-released, Lcn2 in breast cancer progression. Knockdown studies and neutralizing antibody approaches showed that Lcn2 contributes to the early events of metastasis in vitro. The release of Lcn2 from macrophages induced an epithelial–mesenchymal transition programme in MCF-7 breast cancer cells and enhanced local migration as well as invasion into the extracellular matrix, using a three-dimensioanl (3D) spheroid model. Moreover, a global Lcn2 deficiency attenuated breast cancer metastasis in both the MMTV–PyMT breast cancer model and a xenograft model inoculating MCF-7 cells pretreated with supernatants from wild-type and Lcn2-knockdown macrophages. To dissect the role of stroma-derived Lcn2, we employed an orthotopic mammary tumour mouse model. Implantation of wild-type PyMT tumour cells into Lcn2-deficient mice left primary mammary tumour formation unaltered, but specifically reduced tumour cell dissemination into the lung. We conclude that stroma-secreted Lcn2 promotes metastasis in vitro and in vivo, thereby contributing to tumour progression. Our study highlights the tumourigenic potential of stroma-released Lcn2 and suggests Lcn2 as a putative therapeutic target

Value creation from analytics with limited data : a case study on the retailing of durable consumer goods

Companies are pinning high hopes on competitive advantages through data analytics. So far, value gains through analytics have been demonstrated for IT-heavy and data-rich business areas. Yet, research has paid little attention to value creation through data analytics in the plethora of companies with limited data (i.e., having transactions in the hundreds and attributes in the tens). Building on the literature of big data value creation and the resource-based view, we carried out an in-depth analytics case study with a retailer of renewable energy systems. Firms in this business area operate with expensive but few sales, so their available data are notoriously limited. Our findings demonstrate that data analytics capabilities and value creation mechanisms (democratize, contextualize, experiment with data, and execute data insights) are also effective in situations with limited data. Practice and research should therefore put not only emphasis on the volume and the variety of data but also on contextual factors related to managers (e.g., clear strategy, vision, leadership) and all employees (e.g., openness for agile working mode, data awareness)

A Cognitive Computing Solution to Foster Retailing of Renewable Energy Systems

Renewable energy systems (RES) in the residential sector, like photovoltaic systems, heat pumps and battery storage, are corner¬stones of a sustainable energy supply. Nevertheless–and despite major fiscal stimuli–private investment in such technologies has not yet reached a satisfactory level, also because sale of such products is time-consuming and requires a high level of expertise from suppliers. In practice, small and medium-sized installation firms are often responsible for addressing customers, advising, designing and implementing the appropriate systems, but they struggle with offering the complex technology and are exposed to fierce competition in their market. In a joint research initiative with a RES supplier and a software development company, we drive the development of information systems that support installation companies in their tasks. To this end, we are using action design to develop a cognitive computing solution based on Machine Learning (ML) to promote the sale of sustainable energy products. Based on 4,909 real customer requests for RES and survey data from 666 homeowners (which we use as ground truth data for ML), a predictive model can reliably identify promising RES installations out of a list of customer requests and thereby supports an important business task. Despite these promising results, we face a number of challenges in developing our cognitive computing solution. To address these challenges, design principles for similar systems are developed, contributing to the current debate on how information systems research can support sustainable development and how artificial intelligence can be used profitably in enterprises

Management of chronic immune thrombocytopenic purpura: targeting insufficient megakaryopoiesis as a novel therapeutic principle

Traditionally, anti-platelet autoantibodies accelerating platelet clearance from the peripheral circulation have been recognized as the primary pathopysiological mechanism in chronic immune thrombocytopenia (ITP). Recently, increasing evidence supports the co-existence of insufficient megakaryopoiesis. Inadequate low thrombopoietin (TPO) levels are associated with insufficient proliferation and differentiation of megakaryocytes, decreased proplatelet formation, and subsequent platelet release. Recently two novel activators of TPO receptors have been made available: romiplostim and eltrombopag. In several phase III studies, both agents demonstrated increase of platelet counts in about 80% of chronic ITP patients within 2 to 3 weeks. These agents substantially broaden the therapeutic options for patients with chronic ITP although long-term results are still pending. This review will provide an update on the current conception of underlying mechanisms in ITP and novel, pathophysiologically based treatment options

Identification and classification of heat pump problems in the field and their implication for a user-centric problem recognition

Heat pumps are at the heart of the transition to sustainable heating in buildings. Yet, minor installation and setting errors add to unnoticed performance drops over the system’s lifetime. With the advent of smart meters that constantly measure electricity consumption, data patterns of heat pumps have become available, even for the many not connected to the Internet. These data hold the potential to monitor heat pumps continuously, identify issues, and thus assist energy consultants and heat pump owners in lifting hidden conservation potential. Yet, research and practice lack an overview of specific problems that could help in this task. In a mixed-method approach, this study investigated 228 protocols of on-site heat pump inspections in Switzerland and found 47 problem classes with varying frequencies. Based on this empirical data and expert interviews, a classification scheme for heat pump issues is proposed and validated. It uncovers the cause of problems, how and by whom they can be recognised and solved, and potential benefits. The work demonstrates that (i) several problems are likely to create smart meter patterns and that (ii) heat pump owners could be involved in the problem recognition and solving process if they get guidance (i.e. simple rules and instructions). Finally, this study discusses implications for developing information systems to automate and assist the recognition and solving of problems. Such information systems may raise not only the attention of heat pump owners but also trigger desired actions (i.e. request consultancy, inspect heat pump themselves)

A spin chain model with non-Hermitian interaction: the Ising quantum spin chain in an imaginary field

We investigate a lattice version of the Yang-Lee model which is characterized by a non-Hermitian quantum spin chain Hamiltonian. We propose a new way to implement PT-symmetry on the lattice, which serves to guarantee the reality of the spectrum in certain regions of values of the coupling constants. In that region of unbroken PT-symmetry we construct a Dyson map, a metric operator and find the Hermitian counterpart of the Hamiltonian for small values of the number of sites, both exactly and perturbatively. Besides the standard perturbation theory about the Hermitian part of the Hamiltonian, we also carry out an expansion in the second coupling constant of the model. Our constructions turns out to be unique with the sole assumption that the Dyson map is Hermitian. Finally we compute the magnetization of the chain in the z and x direction

Plasma levels of leptin, omentin, collagenous repeat-containing sequence of 26-kDa protein (CORS-26) and adiponectin before and after oral glucose uptake in slim adults

BACKGROUND: Adipose tissue secreted proteins are collectively named adipocytokines and include leptin, adiponectin, resistin, collagenous repeat-containing sequence of 26-kDa protein (CORS-26) and omentin. Several of these adipocytokines influence insulin sensitivity and glucose metabolism and therefore systemic levels may be affected by oral glucose uptake. Whereas contradictory results have been published for leptin and adiponectin, resistin has not been extensively investigated and no reports on omentin and CORS-26 do exist. METHODS: Therefore the plasma levels of these proteins before and 120 min after an oral glucose load were analyzed in 20 highly-insulin sensitive, young adults by ELISA or immunoblot. RESULTS: Circulating leptin was reduced 2 h after glucose uptake whereas adiponectin and resistin levels are not changed. Distribution of adiponectin and CORS-26 isoforms were similar before and after glucose ingestion. Omentin is highly abundant in plasma and immunoblot analysis revealed no alterations when plasma levels before and 2 h after glucose intake were compared. CONCLUSION: Taken together our data indicate that only leptin is reduced by glucose uptake in insulin-sensitive probands whereas adiponectin and resistin are not altered. CORS-26 was demonstrated for the first time to circulate as high molecular weight form in plasma and like omentin was not influenced by oral glucose load. Omentin was shown to enhance insulin-stimulated glucose uptake but systemic levels are not correlated to postprandial blood glucose