Nierenzellkarzinome (NZKs) gelten als stark immunogene Tumore. Dies ist insbesondere auf die Infiltration durch verschiedene Immunzellpopulationen, wie T-Lymphozyten und Natürliche Killer (NK)-Zellen, sowie das klinische Ansprechen auf immuntherapeutische Strategien zurückzuführen. Bisher existieren jedoch nur sehr wenige Studien zur Rolle von humanen nativen dendritischen Zellen (DCs) in NZK-Geweben und über die Tumor-vermittelte Modulation dieser DCs. DCs nehmen als professionelle Antigen-präsentierende Zellen eine zentrale Schlüsselrolle bei der Induktion und Aufrechterhaltung der angeborenen sowie adaptiven Immunantwort ein. Daher wurde im Rahmen dieser Arbeit erstmals der Effekt von klarzelligen NZKs auf den Phänotyp sowie die immunmodulatorischen Fähigkeiten von 6-sulfo LacNAc+ (slan)DCs evaluiert. SlanDCs, welche eine große Subpopulation humaner Blut-DCs darstellen, sind neben der Sekretion großer Mengen proinflammatorischer Zytokine dazu befähigt, Tumorzellen direkt zu lysieren. Des Weiteren sind slanDCs in der Lage, die antitumoralen Effekte von NK-Zellen zu fördern und CD4+ T-Helfer-Zellen sowie Tumor-reaktive CD8+ T-Lymphozyten effizient zu stimulieren. Angesichts dieser proinflammatorischen Eigenschaften können slanDCs wesentlich an einer Tumor-gerichteten Immunantwort beteiligt sein. Auf dieser Grundlage erfolgte im Rahmen der vorliegenden Arbeit der immunhistochemische Nachweis von slanDCs in klarzelligen NZK-Geweben. Im Vergleich zu Tumor-freiem Nierengewebe trat in den primären Tumorgeweben eine erhöhte Zahl infiltrierender slanDCs auf. Zudem wurde die Präsenz von slanDCs in Lymphknoten- sowie Fernmetastasen von NZK-Patienten beobachtet. Weiterführende Untersuchungen an frischen klarzelligen NZK-Geweben demonstrierten, dass NZK-infiltrierende slanDCs einen unreifen Phänotyp ausprägen und Interleukin-10 produzieren. Ausgehend von diesen Erkenntnissen erfolgten funktionelle Analysen, bei denen der Einfluss der kommerziell erhältlichen klarzelligen NZK-Linien ACHN und Caki-1 sowie der primären klarzelligen NZK-Linien MZ1257RC und MZ2877RC auf bedeutende immunmodulatorische Fähigkeiten von slanDCs untersucht wurde. In diesem Zusammenhang zeigte sich, dass NZK-Zellen effektiv in der Lage sind, sowohl die slanDC-vermittelte Proliferation von CD4+ und CD8+ T-Lymphozyten, als auch die slanDC-induzierte Differenzierung naïver CD4+ T-Lymphozyten in proinflammatorische T-Helfer 1-Zellen zu inhibieren. Darüber hinaus wurde demonstriert, dass NZK-Zellen das Potenzial von slanDCs zur Aktivierung von NK-Zellen hemmen. Untersuchungen der zugrunde liegenden Mechanismen zeigten, dass die funktionelle Inhibition von slanDCs durch klarzellige NZK-Zellen über membranständige Moleküle vermittelt wird. Die im Rahmen dieser Dissertation gewonnenen Erkenntnisse weisen darauf hin, dass NZKs die Ausreifung sowie wesentliche funktionelle Eigenschaften von DCs inhibieren. Dies deutet auf einen neuen Immunescape-Mechanismus klarzelliger NZKs hin, welcher auf einer Tumorzell-vermittelten Generierung von tolerogenen slanDCs basiert und eine unzureichende Aktivierung der angeborenen sowie adaptiven Tumor-gerichteten Immunantwort zur Folge hat. Diese neuen Erkenntnisse können einen Beitrag zu einem besseren Verständnis der Interaktion von NZKs mit nativen humanen DCs leisten und die Konzeption neuer therapeutischer Strategien ermöglichen, welche auf einer Verstärkung der antitumoralen Eigenschaften von DCs beruhen.

This study examined the alleged prevalence of Satanism in Zambia, with a particular reference to the Kabwe District during the period 2010-2013. The overall objective was to ascertain the claims and speculations on the alleged prevalence of Satanism in the district of Kabwe. The claims about the alleged prevalence of Satanism and the satanic scare were found by this study to be a reality in Kabwe, with eighty-eight per cent (88%) of the respondents acknowledging the alleged prevalence of the phenomenon. People’s knowledge of Satanism was mainly through rumours, messages from Churches and the electronic media. Studies on rumours (by Stephen Ellis, Gerrie Ter Haar and Jeffrey Victor) have shown that rumours can be investigated in the search for facts, especially rumours that offer plausible explanations for people’s shared anxieties. The above mentioned scholars argue that with efforts at corroboration, such as by interviewing key informants, the researcher can seek credibility on prevailing rumours by verifying or dismissing mere rumours from true stories. The assertions from scholars above justified the use of rumours as a methodological tool in this study. From sources of information the study relied on, claims about the alleged prevalence of Satanism in the district were investigated. The study refuted the satanic claims in a number of cases that were analysed, because they were mostly based on ‘pious legends’ hence lacked objective evidence. From the few incidents that suggested the prevalence of Satanism, there were still two basic problems faced in assessing their credibility: the first being the difficulty in determining the reliability of the confessions from informants who in this case either claimed they were ex-Satanists or served on behalf of Satanists. The second problem consisted in what seemed to be the inconsistency in the explanations of motives behind human killings found in the ritual murders. Some explanations did not suggest satanic motives. One example of refuted claims concerned the two locations within Kabwe district which were highly rumoured to be sites for Satanists, which were found by this study to be Freemasonry Lodges, contrary to what was rumoured.From the findings of this study, it was believed that people joined Satanism either because of the greedy for riches or to avoid poverty. It was also believed that other peoples joined Satanism unconsciously through luring methods used by Satanists. The study also found the satanic scare to have effects on the lives of people in the district. For example, it caused some people to become more committed Christians in their defence against the alleged satanic forces. Because people had associated riches to Satanism, certain individuals avoided getting rich for fear of being labelled ‘Satanists’. / Religious Studies and Arabic / D. Litt. et Phil. (Religious Studies)

Comment comprendre qu’un bébé naissant doté de vitalité et de potentialités à l’humanité, devienne un jour tueur en série ? Cette thèse propose une étude de la psychogenèse de la violence du tueur en série, à travers les cinq périodes qui structurent le développement humain : archaïque, infantile, latence, adolescence, adulte. Elle s’appuie sur un cas clinique et sur du matériel expertal. Ma réflexion s’ouvre par un parallèle avec la clinique du génocide, qui conduit à définir la criminalité des tueurs en série comme un crime contre l’Humain, invitant dès lors à reconstruire les différentes étapes de la déstructuration de leur processus d’humanisation. Le contexte d’émergence de cette criminalité est situé dans la rencontre avec un environnement parental impitoyable qui a désorganisé doublement, chez le bébé, l’appropriation de l’identité humaine héritée génétiquement mais aussi la construction de l’identité subjective construite au fil de l’enfance. La criminalité du tueur en série est envisagée comme une « organisation défensive » dirigée contre une « agonie primitive » spécifique (ou « angoisse impensable ») qui a « offensé » le potentiel à l’humanité du bébé, dans la lignée des théories de D. W. Winnicott. La violence du tueur en série est étudiée grâce à une construction théorico-clinique créée sur mesure, mais elle est aussi resituée dans le cadre plus large de l’inhumanité de l’humain. Surtout, cette thèse a le souci constant de proposer une réflexion accessible au lecteur néophyte en quête de réponses (victimes, familles de victimes, professionnels de terrain peu habitués à la terminologie psychanalytique). / How shall we understand that a new born baby full of life and ready to embrace humanity might become one day a serial killer ? The purpose of this thesis is to study the psychogenesis of the serial killer violence through the analysis of the five key stages which are structuring human devel-opment : archaic stage, childish stage, latency stage, teenage & adult stages. This work is based on a clinical case and experts’ documents.My work is starting with a comparison with the clinical analysis of a genocide, which is de-fining serial killers’ criminality as a crime against humankind, and therefore leading us to rebuilding the different steps of their humanity breakdown process. The context, in which this criminality is emerging, lays in the confluence with a ruthless parental environment which has disorganized both the baby’s ownership of the genetically inherited human identity and the construction of a subjective identity. The serial killer criminality is considered as a “defense organization” aimed at protecting against a specific “primitive agony” (or “unthinkable anxiety”) which has “offended” the baby’s potential to humanity – in line with D.W. Winnicott’s theories.The serial killer’s violence is studied using a custom made theoretical and clinical construction, but it is also considered in the wider scope of human inhumanity. More importantly, this thesis aims at providing analysis and understanding which are accessible to neophyte readers looking for answers (victims and their families, field experts not used to psychoanalytic terminology).

<div>Cancer is responsible for the second highest cause of death in the United States, and lung cancer accounts for 13% of new cancer diagnoses, with the highest rate of cancer death at 24%. Almost 85% of these cases represent non-small cell lung cancer (NSCLC), which includes lung adenocarcinoma, the most common NSCLC subtype. Traditional cancer treatments often only temporarily stop the spread of the disease, but immunotherapies, which are becoming a standard of care, are much more promising. Natural killer (NK) cells are powerful effectors of innate immunity, and genetically engineered NK cells as immunotherapies have had encouraging clinical responses in the treatment of various cancers. However, more progress is needed for solid tumor treatment, especially for lung adenocarcinoma. The activation of cancer-associated ectoenzymes, CD39 and CD73 catalyze the phosphorylation of ATP to AMP to produce extracellular adenosine (ADO), which is a highly immunosuppressive mechanism contributing to the pathogenesis of solid tumors. Understanding adenosine effects on NK cells will help develop more robust immunotherapeutic treatments to improve cytotoxicity against solid tumors. Here, we established that tumor microenvironment ADO results in impaired metabolic and anti-tumor functions of cytokine-primed NK cells. Specifically, peripheral blood-derived NK cells stimulated with IL-2, IL-15, or a combination of IL-12 and IL-15 showed suppressed anti-tumor immunity due to ADO. This was observed by the downregulation of activation receptor expression, cytotoxicity inhibition, impairment of metabolic activity, and alterations in gene expression. To target ADO-producing CD73 on cancer cells, we redirected NK cells by fusing CD73 ScFv with intracellular and transmembrane regions of NK cell specific signaling components derived from FCyRIIIa (CD16). Engineered NK cells were shown to be cytotoxic against lung adenocarcinoma <i>in vitro</i> and impede tumor growth in a lung adenocarcinoma mouse model <i>in vivo</i>. Engineered cells also had higher levels of degranulation and cytokine release, as well as more infiltration into tumors and longer survival time in mice. In summary, the microenvironment of solid tumors is highly immunosupressive, and redirecting NK cell function using a NK-specific anti-CD73 targeting construct will help to promote anti-tumor immunity and</div><div>inhibit cancer growth for a potentially powerful new immunotherapy against solid tumors.</div>

Nierenzellkarzinome (NZKs) gelten als stark immunogene Tumore. Dies ist insbesondere auf die Infiltration durch verschiedene Immunzellpopulationen, wie T-Lymphozyten und Natürliche Killer (NK)-Zellen, sowie das klinische Ansprechen auf immuntherapeutische Strategien zurückzuführen. Bisher existieren jedoch nur sehr wenige Studien zur Rolle von humanen nativen dendritischen Zellen (DCs) in NZK-Geweben und über die Tumor-vermittelte Modulation dieser DCs. DCs nehmen als professionelle Antigen-präsentierende Zellen eine zentrale Schlüsselrolle bei der Induktion und Aufrechterhaltung der angeborenen sowie adaptiven Immunantwort ein. Daher wurde im Rahmen dieser Arbeit erstmals der Effekt von klarzelligen NZKs auf den Phänotyp sowie die immunmodulatorischen Fähigkeiten von 6-sulfo LacNAc+ (slan)DCs evaluiert. SlanDCs, welche eine große Subpopulation humaner Blut-DCs darstellen, sind neben der Sekretion großer Mengen proinflammatorischer Zytokine dazu befähigt, Tumorzellen direkt zu lysieren. Des Weiteren sind slanDCs in der Lage, die antitumoralen Effekte von NK-Zellen zu fördern und CD4+ T-Helfer-Zellen sowie Tumor-reaktive CD8+ T-Lymphozyten effizient zu stimulieren. Angesichts dieser proinflammatorischen Eigenschaften können slanDCs wesentlich an einer Tumor-gerichteten Immunantwort beteiligt sein. Auf dieser Grundlage erfolgte im Rahmen der vorliegenden Arbeit der immunhistochemische Nachweis von slanDCs in klarzelligen NZK-Geweben. Im Vergleich zu Tumor-freiem Nierengewebe trat in den primären Tumorgeweben eine erhöhte Zahl infiltrierender slanDCs auf. Zudem wurde die Präsenz von slanDCs in Lymphknoten- sowie Fernmetastasen von NZK-Patienten beobachtet. Weiterführende Untersuchungen an frischen klarzelligen NZK-Geweben demonstrierten, dass NZK-infiltrierende slanDCs einen unreifen Phänotyp ausprägen und Interleukin-10 produzieren. Ausgehend von diesen Erkenntnissen erfolgten funktionelle Analysen, bei denen der Einfluss der kommerziell erhältlichen klarzelligen NZK-Linien ACHN und Caki-1 sowie der primären klarzelligen NZK-Linien MZ1257RC und MZ2877RC auf bedeutende immunmodulatorische Fähigkeiten von slanDCs untersucht wurde. In diesem Zusammenhang zeigte sich, dass NZK-Zellen effektiv in der Lage sind, sowohl die slanDC-vermittelte Proliferation von CD4+ und CD8+ T-Lymphozyten, als auch die slanDC-induzierte Differenzierung naïver CD4+ T-Lymphozyten in proinflammatorische T-Helfer 1-Zellen zu inhibieren. Darüber hinaus wurde demonstriert, dass NZK-Zellen das Potenzial von slanDCs zur Aktivierung von NK-Zellen hemmen. Untersuchungen der zugrunde liegenden Mechanismen zeigten, dass die funktionelle Inhibition von slanDCs durch klarzellige NZK-Zellen über membranständige Moleküle vermittelt wird. Die im Rahmen dieser Dissertation gewonnenen Erkenntnisse weisen darauf hin, dass NZKs die Ausreifung sowie wesentliche funktionelle Eigenschaften von DCs inhibieren. Dies deutet auf einen neuen Immunescape-Mechanismus klarzelliger NZKs hin, welcher auf einer Tumorzell-vermittelten Generierung von tolerogenen slanDCs basiert und eine unzureichende Aktivierung der angeborenen sowie adaptiven Tumor-gerichteten Immunantwort zur Folge hat. Diese neuen Erkenntnisse können einen Beitrag zu einem besseren Verständnis der Interaktion von NZKs mit nativen humanen DCs leisten und die Konzeption neuer therapeutischer Strategien ermöglichen, welche auf einer Verstärkung der antitumoralen Eigenschaften von DCs beruhen.

Indiana University-Purdue University Indianapolis (IUPUI) / The immune system initiates tissue repair following injury. In response to sterile tissue injury, neutrophils infiltrate the tissue to remove tissue debris and subsequently undergo apoptosis. Proper clearance of apoptotic neutrophils in the tissue by recruited macrophages, in a process termed efferocytosis, is critical to facilitate the resolution of inflammation and tissue repair. However, the events leading to suppression of sterile inflammation following efferocytosis, and the contribution of other innate cell types are not clearly defined in an in vivo setting. Using a sterile mouse peritonitis model, we identified IL-4 production from efferocytosing macrophages in the peritoneum that activate invariant NKT cells to produce cytokines including IL-4 and IL-13. Importantly, IL-4 from macrophages functions in autocrine and paracrine circuits to promote alternative activation of peritoneal exudate macrophages and augment type-2 cytokine production from NKT cells to suppress inflammation. The increased peritonitis in mice deficient in IL-4, NKT cells, or IL-4Ra expression on myeloid cells suggested that each is a key component for resolution of sterile inflammation. The phagocyte NADPH oxidase, a multi-subunit enzyme complex we demonstrated to require a physical interaction between the Rac GTPase and the oxidase subunit gp91phox for generation of reactive oxygen species (ROS), is required for production of ROS within macrophage phagosomes containing ingested apoptotic cells. In mice with X-linked chronic granulomatous disease (X-CGD) that lack gp91phox, efferocytosing macrophages were unable to produce ROS and were defective in activating iNKT during sterile peritonitis, resulting in enhanced and prolonged inflammation. Thus, efferocytosis-induced IL-4 production and activation of IL-4-producing iNKT cells by macrophages are immunomodulatory events in an innate immune circuit required to resolve sterile inflammation and promote tissue repair.

Artificial intelligence (AI) is one of the fastest developing technologies globally. AI has recently entered warfare and thus taken a place in international law. Today the use of AI in warfare is through machine learning and autonomous weapon systems. Autonomous weapons are expected to play a decisive role in future war- fare and therefore have a major impact on both civilians and combatants. This gives rise to an examination of the role of artificial intelligence, machine learning and autonomous weapon systems in international law, specifically international humanitarian law (IHL).  The purpose and main research question of the thesis is to examine how the use of AI, machine learning and autonomous weapon systems is regulated within international law. Further the thesis examines if the regulations sufficiently can ensure the protection that is guaranteed within IHL or if additional regulation is needed. The research question is answered by examining the relevant rules in IHL, compliance with the protection stated in the principles of distinction, pro- portionality and precautions in attack and lastly by analyzing the consequences for civilians and combatants.  Conclusions that can be made is that the rules of IHL are both applicable and sufficient to, in theory, regulate autonomous weapon systems. However the weapon itself must be capable to follow IHL and in order to guarantee this ad- ditional regulation is needed on the use of autonomous weapons. The use of autonomous weapon systems does not necessarily violate the principles of dis- tinction, proportionality and precaution in attack. On the contrary, the use of autonomous weapons can possibly ensure that the principles are respected even further. This however depends on the actual capabilities of autonomous weapon systems and whether they can make the complex judgments required for each principle. It is although still of importance to ensure that the element of human control is never completely lost. The issue that keeps returning is the potential loss of human control. At all times human control must be guaranteed to ensure that the final decision always remains with a human. If humanity in warfare is lost the consequences and risks for civilians will increase. Not only is there a possibility of increase in use of violence but also an increase of indiscriminate attacks. The rules of IHL aim to protect civilians as well as combatants, and the use of this new weapon will lead to difficulties to navigate armed situations for combatants. This will increase the suffering of civilians, but also risk overriding the protection of combatants that IHL ensures.

Glycosphingolipids (GSLs), composed of a polar saccharide head and a lipophilic ceramide tail, are ubiquitous components of the plasma membrane of eukaryotic cells. They serve in many regulatory capacities and have antigenic properties towards natural killer T (NKT) cells of the innate immune system. Critical to the recognition of glycosylceramides by NKT cells are antigen presenting cells (APC), such as dendritic cells, which are responsible for binding, processing, and delivery of ligands to these lymphocytes. This event is mediated by CD1d, a major histocompatibility complex-like protein expressed on the surface of APCs, which binds GSL antigens by the ceramide moiety and presents the polar group to the T cell receptors of CD1d-restricted cells. The subsequent immune response involves NKT cell proliferation and emission of numerous cytokines, such as interferon-gamma (IFN-gamma) and interleukin-4 (IL-4), resulting in the stimulation of the innate and adaptive immune systems through maturation of APCs, activation of T cells, and secretion of antibodies by B cells. To understand the structure-activity relationship between GSLs and NKT cell activity and the requirements for intracellular processing of antigens, analogs of the model compound alphaGalCer (KRN-7000) have been synthesized. These include fluorophore-appended 6”-amino-α-galactosylceramides and N-alkenoyl GSLs, such as PBS-57, a potent alphaGalCer surrogate useful in NKT cell stimulation studies. A nonantigenic beta-C-galactosylceramide has also been prepared as an inhibitor of these innate lymphocytes. To probe the potential for using NKT cells to bias the immune system between the proinflammatory TH1 response or the immunomodulatory TH2 mode, versions of alphaGalCer with shortened ceramides have been created. One of these truncated analogs, PBS-25, has successfully been cocrystallized with CD1d and the binary complex structure solved by X-ray crystallography. Synthetic glycosphingolipids derived from Novosphingobium capsulatum and Sphingomonas paucimobilis have also been made. In assays with classical Valpha14i/Valpha24i NKT cell lines, these Gram-negative bacterial antigens were recognized directly and specifically by host immune systems through CD1d-restriction, unlike GSL-deficient microbes (e.g., Salmonella typhimurium). A search for other GSL-bearing alpha-proteobacteria led to the discovery of another natural glycosphingolipid, an N-alkenoylphytosphingoid-alpha-galactoside, isolated from the outer membrane of Ehrlichia muris.

When Mormons arrived in northern Arizona among the Navajo and Hopi Indians in the late 1850s, Mormon-Indian relations were initially friendly. It was not too long, however, before trouble began in conflicts over water use and land rights. Federal agents would soon consider Mormons a threat to the peaceful Hopis because both the Navajo and Mormons were expanding their land claims. Indian agents relentlessly pleaded with Washington to establish a separate Indian reservation. They anticipated this reservation would satisfy all three parties, but its creation in 1882 only created more problems, climaxing in the 1892 death of Lot Smith at the hands of Atsidí, the local Navajo headman. Tensions continued to increase until federal agents intervened in 1900 and placed Tuba City under a Presidential Executive Order. The order withdrew Tuba City from white claims and resulted in the expulsion of the Mormons from Tuba City in 1903. My contribution is to show how the Navajo and Hopi Indians may have considered the coming of the Mormons as an invasion by a group of foreigners which led to the resulting contest between the trios for the limited natural resources of the northern Arizona desert. Tuba City/Moenkopi has a complicated history and its origins remain contested because it was claimed not only by Mormons, but also by the Navajos and Hopi. Previous historians have neglected the wealth of history that come from using Native American oral histories. This thesis will include the Native point of view but will also integrate it with Mormon and non-Mormon narratives. Doing so will provide another perspective on some of the following: the founding of Tuba City, the creation of the 1882 and 1900 Executive Orders for Navajo and Hopi reservation expansions, the death of the Mormon Lot Smith, and Native American-Mormon relations in the late 1800s in northern Arizona.

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