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“The Apocalypse of Peter in Context” offers scholarly inquiries into this complex and frequently overlooked early Christian text from different angles. By extending the boundaries of traditional analyses, this collection of essays elucidates the eschatological beliefs prevalent in nascent Christian communities and the formative influences that gave rise to perceptions of heaven and hell. Through new approaches to authorship, transmission, and materiality, it explores this early apocryphal text’s complex relationship with Jewish literature of the Second Temple period and its reception in (Late) Antiquity and the Middle Ages in various branches of Christianity. It also presents the first comprehensive English translation of the entire Ethiopic transmission context and further possible Ethiopic witnesses never critically edited and translated before. The result of a multidisciplinary conference, this collection provokes new insights and stimulates further research on this captivating witness to a distinct branch of apocalyptic thought within early Christianity

“The Apocalypse of Peter in Context” offers scholarly inquiries into this complex and frequently overlooked early Christian text from different angles. By extending the boundaries of traditional analyses, this collection of essays elucidates the eschatological beliefs prevalent in nascent Christian communities and the formative influences that gave rise to perceptions of heaven and hell. Through new approaches to authorship, transmission, and materiality, it explores this early apocryphal text’s complex relationship with Jewish literature of the Second Temple period and its reception in (Late) Antiquity and the Middle Ages in various branches of Christianity. It also presents the first comprehensive English translation of the entire Ethiopic transmission context and further possible Ethiopic witnesses never critically edited and translated before. The result of a multidisciplinary conference, this collection provokes new insights and stimulates further research on this captivating witness to a distinct branch of apocalyptic thought within early Christianity

Abraham fascinates. As a primeval desert sheikh with dazzling character traits, as the father of many nations and three religions, as a migrant with long wanderings, with trials and tribulations, as a convert and a sacrificer, as a believer and a doubter. Judaism, Christianity and Islam all refer to him, to aspects of his figure, to the memory of him. Daniel Maier explores this fascination with the various facets of the figure of Abraham. Using sources from ancient Judaism, early Christianity and the Koran, he examines Abraham's significance as a figure of identification, his role in the binding of his son, his faith, his obedience and his happiness. Thereby, Maier does not proceed chronologically, but brings the views of the patriarch into conversation in entertaining and manageable chapters. The look at the origins provides new perspectives on the opportunities and challenges of the interreligious trialogue in the 21st century. Abraham fascinates with his impact through the ages - right up to the present day.

Climate change puts at risk what people value in their everyday lives, with evidence of harm and suffering already taking place across all regions of the world. As societies slowly come to grips with the possibility of not being able to save everything that is valued, there is an urgent need to identify what is most important for individuals and groups, to prioritise action and prevent or minimise intolerable losses. Yet, people's priorities vary greatly; individual choices are contingent on what people hold dear in the places they inhabit, which in turn is shaped by their positioning in society and everyday experiences with harm and loss. In this article, we draw on recent epistemological and ontological engagements with climate adaptation and loss from the social sciences to examine how individuals consider their options to protect what they value most in the face of climatic impacts. Drawing on 80+ interviews with residents along an urban–rural transect in Western Australia, we first demonstrate the complex and dynamic nature of individual decision-making ‘worlds’. We do this by using an innovative methodology that allows participants to visualise their value trade-offs, in the present and the future. We then examine similarities and differences between these worlds to show where priorities converge and diverge. We argue that attention to intersecting, conflicting, and potentially uncomfortable processes of prioritisation, and the losses and omissions they (re)produce, provide crucial entry points to negotiate adaptation and navigate risks within and across communities in ways that are inclusive, fair, and sustainable.

Einleitung. Patienten mit malignen hämatologischen Erkrankungen (AML, ALL,NHL) leiden während der Hochdosis-Chemotherapie typischerweise unter einer Verschlechterung der körperlichen Fitness und Lebensqualität. In dieser Studie sollen die Auswirkungen einer angeleiteten, aeroben Sportintervention (über 4-5 Wochen, 2-3 mal pro Woche) während der Induktionschemotherapie (IC) untersucht werden, um gegebenenfalls eine Empfehlung für die Integration der Sportintervention in das Therapieschema geben zu können. Methoden & Materialien. 70 Probanden (24 Versuchs-, 23 Placebo-Kontroll-, 23 Kontrollgruppe) beider Geschlechter (34 weiblich, 36 männlich), 18-78 Jahre alt (Durchschnittsalter 48,64 Jahre), neu diagnostiziert mit AML, ALL oder NHL, wurden innerhalb von 7 Tagen nach Beginn der IC rekrutiert. Die körperliche Fitness wurde im Rahmen einer maximalen Ausbelastung in ansteigender Intensität auf dem Fahrradergometer (in Watt/kg) und die Lebensqualität mithilfe des EORTC QLQ-C30 Fragebogens erhoben. Die Gruppenunterschiede zwischen den beiden Testzeitpunkten, t0 zu Beginn und t1 zum Ende der IC wurden mithilfe von ANOVA, Kruskal-Wallis-Test und Mann-Whitney-U-Test untersucht. Ergebnisse. Es konnten keine signifikanten Gruppenunterschiede für die kardiorespiratorische Fitness (Sig.=0,900) und für die globale Lebensqualität (Sig.=0,656) zwischen der Versuchsgruppe, der Placebo-Kontrollgruppe und der Kontrollgruppe detektiert werden. Fazit. In dieser Studie konnten keine Beweise für die Vorteilhaftigkeit einer Integration einer aeroben Sportintervention in das Therapieschema dokumentiert werden. Es bedarf weiterer Studien mit größeren Stichproben, einer höheren Adhärenz und wegweisender Ergebnisse, um eine eindeutige Empfehlung abgeben zu können.

Climate change puts at risk what people value in their everyday lives, with evidence of harm and suffering already taking place across all regions of the world. As societies slowly come to grips with the possibility of not being able to save everything that is valued, there is an urgent need to identify what is most important for individuals and groups, to prioritise action and prevent or minimise intolerable losses. Yet, people's priorities vary greatly; individual choices are contingent on what people hold dear in the places they inhabit, which in turn is shaped by their positioning in society and everyday experiences with harm and loss. In this article, we draw on recent epistemological and ontological engagements with climate adaptation and loss from the social sciences to examine how individuals consider their options to protect what they value most in the face of climatic impacts. Drawing on 80+ interviews with residents along an urban–rural transect in Western Australia, we first demonstrate the complex and dynamic nature of individual decision-making ‘worlds’. We do this by using an innovative methodology that allows participants to visualise their value trade-offs, in the present and the future. We then examine similarities and differences between these worlds to show where priorities converge and diverge. We argue that attention to intersecting, conflicting, and potentially uncomfortable processes of prioritisation, and the losses and omissions they (re)produce, provide crucial entry points to negotiate adaptation and navigate risks within and across communities in ways that are inclusive, fair, and sustainable.

1.1. Einleitung Die periprothetische Infektion (PPI) gilt als eine der schwersten Komplikationen nach endoprothetischem Gelenkersatz, deren Behandlung einen hohen finanziellen, personellen und zeitlichen Aufwand erfordert. Das Krankheitsbild ist seit Beginn der Endoprothetik bekannt und das Wissen um die Pathophysiologie wurde seitdem vertieft. Die Therapie wurde um stadienadaptierte Konzepte, wirksame Antibiotika und verbesserte Implantate beachtlich erweitert. Dennoch liegt die Inzidenz der PPI beim Kniegelenk unverändert zwischen einem und zwei Prozent, bei Risikopatienten auch deutlich darüber (1). Falle einer PPI sind die primären Ziele aus Patientensicht die Wiederherstellung der Gehfähigkeit und Schmerzfreiheit bei Implantation einer beweglichen Revisionsprothese. Es zeigt sich allerdings, dass nach mehrmaligem Prothesenwechsel die Gelenkfunktion, die Patientenzufriedenheit und das Outcome abnehmen. Nach multiplen Operationen am betroffenen Gelenk leidet der Streckapparat und ein Verlust von Knochen ist unumgänglich. In diesen Extremsituationen müssen neben der Ultima Ratio einer Amputation auch Salvage-Prozeduren, wie das Anlegen einer stabilen Arthrodese, erwogen werden. Das klinische Outcome und die Lebensqualität hiervon sind bisher weitgehend unbekannt. Daher vergleicht die vorliegende Arbeit das klinische und funktionelle Behandlungsergebnis in Kombination mit der resultierenden Lebensqualität von Patienten, bei denen das Anlegen einer stabilen Arthrodese klinisch erforderlich war, mit dem von Patienten nach Implantation einer Revisionsprothese als Resultat eines mehrzeitigen septischen Endoprothesen-Wechsels. 1.2. Material und Methoden Die Studie umfasste 104 Patienten (2010-2017), von denen alle eine periprothetische Infektion einer Knie-Totalendoprothese (KTEP) aufwiesen. In einem mehrzeitigen Verfahren wurde das Implantat gewechselt. Nach Infektberuhigung erfolgte die Implantation eines Revisionsimplantates. Im Falle von ausgedehnten Knochendefekten

Background: Large part of patients of stage IB non-small cell lung cancer (IB NSCLC) may suffer recurrence after surgery. This study is to determine risk factors and establish a nomogram for postoperative recurrence and to provide a reference for adjuvant chemotherapy selection in patients with stage IB NSCLC. Methods: A total of 394 patients with postoperative stage IB NSCLC who visited Fujian Medical University Union Hospital between January 2010 and June 2016 were selected. Patients were divided into training and validation cohorts based on the time of diagnosis. Independent risk factors were identified using a Cox proportional hazards regression model. A nomogram was created to predict recurrence-free survival (RFS) and was validated with an independent cohort. The predictive ability of the nomogram was evaluated using the concordance index (C-index) and calibration curve. RFS between the high- and low-risk groups was determined using Kaplan-Meier curves, and subgroup analysis of chemotherapy was performed. Results: Visceral pleura invasion, micropapillary structures, tumor size, preoperative serum carcinoembryonic antigen (CEA) level, preoperative serum cytokeratin-19 fragments (Cyfra21-1) level, and postoperative histology were identified as independent risk factors for stage IB NSCLC recurrence. Discrimination of the nomogram showed good prognostic accuracy and clinical applicability, with a C-index of 0.827 and 0.866 in the training and validation cohorts, respectively. The difference in RFS between the high- and low-risk groups in both cohorts was significant (P<0.05). Finally, a significant difference was observed on whether high-risk group should accept postoperative chemotherapy (P<0.05). Conclusions: This nomogram can predict postoperative recurrence probability in patients with stage IB NSCLC, and can select patients with risk factors who need adjuvant chemotherapy., SCOPUS: ar.j, info:eu-repo/semantics/published

Bandara merupakan salah satu pusat kegiatan peralihan transportasi udara.Dimana di suatu bandara pasti memiliki banyak tenaga kerja.Indonesia memilikiUndang - undang yang mampu menjaga kepentingan tenagakerja, sekaligus mampu menjembatani kepentingan tenagakerja dengan para pengguna tenagakerja.Undang-undang No. 13 tahun 2003 tentang Ketenagakerjaan Bab 1 Pasal 1 angka 2 sendiri menyebutkan tenaga kerja adalah setiap orang yang mampu melakukan pekerjaan untuk memenuhi kebutuhan sendiri ataupun masyarakat, Rumusan Masalah: 1)Bagaimana Kebijakan Penerapan Hukum Ketenagakerjaan dalam Pemenuhan Hak Pekerja Pada PT.Angkasa Pura II Padang? 2). Kendala apa saja yang ditemukan dalam Penerapan Hukum Ketenagakerjaan Pada PT.Angkasa Pura II Padang?3). Upaya apa yang dilakukan dalam mengatasi kendala pada Penerapan Hukum Ketenagakerjaan Pada PT.Angkasa Pura II Padang?. Metode penelitian yang penulis gunakan dalam skripsi ini adalah penelitian hukum sosiologis yaitu penelitian yang dilakukan langsung ke lapangan dengan cara studi dokumen,observasi,dan wawancara untuk mendapatkan data primer. Hasil dari penelitian adalah: 1)Kebijakan Penerapan Hukum Ketenagakerjaan Pada PT.Angkasa Pura II Padang telah terlaksana 2) Kendala yang ditemukan dalam penerapan Hukum Ketenagakerjaan Pada PT. Angkasa Pura II Padang adalah masalah keterlambatan gaji masuk 3) Upaya yang dilakukan dalam menghadapi kendala tersebut adalah dengan bekerjasa sama dengan berbagai pihak dan menginput data karyawan tepat waktu . Kata Kunci :Implementasi,Pekerja, PT.Angkasa Pura II

Bandara merupakan salah satu pusat kegiatan peralihan transportasi udara.Dimana di suatu bandara pasti memiliki banyak tenaga kerja.Indonesia memilikiUndang - undang yang mampu menjaga kepentingan tenagakerja, sekaligus mampu menjembatani kepentingan tenagakerja dengan para pengguna tenagakerja.Undang-undang No. 13 tahun 2003 tentang Ketenagakerjaan Bab 1 Pasal 1 angka 2 sendiri menyebutkan tenaga kerja adalah setiap orang yang mampu melakukan pekerjaan untuk memenuhi kebutuhan sendiri ataupun masyarakat, Rumusan Masalah: 1)Bagaimana Kebijakan Penerapan Hukum Ketenagakerjaan dalam Pemenuhan Hak Pekerja Pada PT.Angkasa Pura II Padang? 2). Kendala apa saja yang ditemukan dalam Penerapan Hukum Ketenagakerjaan Pada PT.Angkasa Pura II Padang?3). Upaya apa yang dilakukan dalam mengatasi kendala pada Penerapan Hukum Ketenagakerjaan Pada PT.Angkasa Pura II Padang?. Metode penelitian yang penulis gunakan dalam skripsi ini adalah penelitian hukum sosiologis yaitu penelitian yang dilakukan langsung ke lapangan dengan cara studi dokumen,observasi,dan wawancara untuk mendapatkan data primer. Hasil dari penelitian adalah: 1)Kebijakan Penerapan Hukum Ketenagakerjaan Pada PT.Angkasa Pura II Padang telah terlaksana 2) Kendala yang ditemukan dalam penerapan Hukum Ketenagakerjaan Pada PT. Angkasa Pura II Padang adalah masalah keterlambatan gaji masuk 3) Upaya yang dilakukan dalam menghadapi kendala tersebut adalah dengan bekerjasa sama dengan berbagai pihak dan menginput data karyawan tepat waktu . Kata Kunci :Implementasi,Pekerja, PT.Angkasa Pura II

Bandara merupakan salah satu pusat kegiatan peralihan transportasi udara.Dimana di suatu bandara pasti memiliki banyak tenaga kerja.Indonesia memilikiUndang - undang yang mampu menjaga kepentingan tenagakerja, sekaligus mampu menjembatani kepentingan tenagakerja dengan para pengguna tenagakerja.Undang-undang No. 13 tahun 2003 tentang Ketenagakerjaan Bab 1 Pasal 1 angka 2 sendiri menyebutkan tenaga kerja adalah setiap orang yang mampu melakukan pekerjaan untuk memenuhi kebutuhan sendiri ataupun masyarakat, Rumusan Masalah: 1)Bagaimana Kebijakan Penerapan Hukum Ketenagakerjaan dalam Pemenuhan Hak Pekerja Pada PT.Angkasa Pura II Padang? 2). Kendala apa saja yang ditemukan dalam Penerapan Hukum Ketenagakerjaan Pada PT.Angkasa Pura II Padang?3). Upaya apa yang dilakukan dalam mengatasi kendala pada Penerapan Hukum Ketenagakerjaan Pada PT.Angkasa Pura II Padang?. Metode penelitian yang penulis gunakan dalam skripsi ini adalah penelitian hukum sosiologis yaitu penelitian yang dilakukan langsung ke lapangan dengan cara studi dokumen,observasi,dan wawancara untuk mendapatkan data primer. Hasil dari penelitian adalah: 1)Kebijakan Penerapan Hukum Ketenagakerjaan Pada PT.Angkasa Pura II Padang telah terlaksana 2) Kendala yang ditemukan dalam penerapan Hukum Ketenagakerjaan Pada PT. Angkasa Pura II Padang adalah masalah keterlambatan gaji masuk 3) Upaya yang dilakukan dalam menghadapi kendala tersebut adalah dengan bekerjasa sama dengan berbagai pihak dan menginput data karyawan tepat waktu . Kata Kunci :Implementasi,Pekerja, PT.Angkasa Pura II

Bandara merupakan salah satu pusat kegiatan peralihan transportasi udara.Dimana di suatu bandara pasti memiliki banyak tenaga kerja.Indonesia memilikiUndang - undang yang mampu menjaga kepentingan tenagakerja, sekaligus mampu menjembatani kepentingan tenagakerja dengan para pengguna tenagakerja.Undang-undang No. 13 tahun 2003 tentang Ketenagakerjaan Bab 1 Pasal 1 angka 2 sendiri menyebutkan tenaga kerja adalah setiap orang yang mampu melakukan pekerjaan untuk memenuhi kebutuhan sendiri ataupun masyarakat, Rumusan Masalah: 1)Bagaimana Kebijakan Penerapan Hukum Ketenagakerjaan dalam Pemenuhan Hak Pekerja Pada PT.Angkasa Pura II Padang? 2). Kendala apa saja yang ditemukan dalam Penerapan Hukum Ketenagakerjaan Pada PT.Angkasa Pura II Padang?3). Upaya apa yang dilakukan dalam mengatasi kendala pada Penerapan Hukum Ketenagakerjaan Pada PT.Angkasa Pura II Padang?. Metode penelitian yang penulis gunakan dalam skripsi ini adalah penelitian hukum sosiologis yaitu penelitian yang dilakukan langsung ke lapangan dengan cara studi dokumen,observasi,dan wawancara untuk mendapatkan data primer. Hasil dari penelitian adalah: 1)Kebijakan Penerapan Hukum Ketenagakerjaan Pada PT.Angkasa Pura II Padang telah terlaksana 2) Kendala yang ditemukan dalam penerapan Hukum Ketenagakerjaan Pada PT. Angkasa Pura II Padang adalah masalah keterlambatan gaji masuk 3) Upaya yang dilakukan dalam menghadapi kendala tersebut adalah dengan bekerjasa sama dengan berbagai pihak dan menginput data karyawan tepat waktu . Kata Kunci :Implementasi,Pekerja, PT.Angkasa Pura II

Bandara merupakan salah satu pusat kegiatan peralihan transportasi udara.Dimana di suatu bandara pasti memiliki banyak tenaga kerja.Indonesia memilikiUndang - undang yang mampu menjaga kepentingan tenagakerja, sekaligus mampu menjembatani kepentingan tenagakerja dengan para pengguna tenagakerja.Undang-undang No. 13 tahun 2003 tentang Ketenagakerjaan Bab 1 Pasal 1 angka 2 sendiri menyebutkan tenaga kerja adalah setiap orang yang mampu melakukan pekerjaan untuk memenuhi kebutuhan sendiri ataupun masyarakat, Rumusan Masalah: 1)Bagaimana Kebijakan Penerapan Hukum Ketenagakerjaan dalam Pemenuhan Hak Pekerja Pada PT.Angkasa Pura II Padang? 2). Kendala apa saja yang ditemukan dalam Penerapan Hukum Ketenagakerjaan Pada PT.Angkasa Pura II Padang?3). Upaya apa yang dilakukan dalam mengatasi kendala pada Penerapan Hukum Ketenagakerjaan Pada PT.Angkasa Pura II Padang?. Metode penelitian yang penulis gunakan dalam skripsi ini adalah penelitian hukum sosiologis yaitu penelitian yang dilakukan langsung ke lapangan dengan cara studi dokumen,observasi,dan wawancara untuk mendapatkan data primer. Hasil dari penelitian adalah: 1)Kebijakan Penerapan Hukum Ketenagakerjaan Pada PT.Angkasa Pura II Padang telah terlaksana 2) Kendala yang ditemukan dalam penerapan Hukum Ketenagakerjaan Pada PT. Angkasa Pura II Padang adalah masalah keterlambatan gaji masuk 3) Upaya yang dilakukan dalam menghadapi kendala tersebut adalah dengan bekerjasa sama dengan berbagai pihak dan menginput data karyawan tepat waktu . Kata Kunci :Implementasi,Pekerja, PT.Angkasa Pura II

We study combinatorial problems with real world applications such as machine scheduling, routing, and assignment. We propose a method that combines Reinforcement Learning (RL) and planning. This method can equally be applied to both the offline, as well as online, variants of the combinatorial problem, in which the problem components (e.g., jobs in scheduling problems) are not known in advance, but rather arrive during the decision-making process. Our solution is quite generic, scalable, and leverages distributional knowledge of the problem parameters. We frame the solution process as an MDP, and take a Deep Q-Learning approach wherein states are represented as graphs, thereby allowing our trained policies to deal with arbitrary changes in a principled manner. Though learned policies work well in expectation, small deviations can have substantial negative effects in combinatorial settings. We mitigate these drawbacks by employing our graph-convolutional policies as non-optimal heuristics in a compatible search algorithm, Monte Carlo Tree Search, to significantly improve overall performance. We demonstrate our method on two problems: Machine Scheduling and Capacitated Vehicle Routing. We show that our method outperforms custom-tailored mathematical solvers, state of the art learning-based algorithms, and common heuristics, both in computation time and performance.

Mit Hilfe der Laserkühlung können in Speicherringen Ionenstrahlen mit sehr schmaler Geschwindigkeitsverteilung erzeugt werden. Durch den notwendigen atomaren Übergang ist die Laserkühlung Lithium ähnlicher Ionen an bestehenden Anlagen wie dem Schwer- ionenspeicherring ESR in Darmstadt auf relativ leichte Ionen beschränkt. An der neuen Teilchenbeschleunigeranlage FAIR mit dem Ionensynchrotron SIS100 und dem Speicherring HESR wird dagegen die Laserkühlung wesentlich schwererer Ionen möglich sein. Am ESR wurde erfolgreich mit einem durchstimmbaren ultravioletten cw-Lasersystem ein Strahl relativistischer Lithium ähnlicher C^3+-Ionen erzeugt, der eine Breite der relativen Impulsverteilung von weniger als 10^−6 erreichte. Die Höhe der Laserintensität, die zur Kühlung schwererer Lithium ähnlicher Ionen am SIS100 und HESR benötigt wird, wächst schnell mit der Kernladungszahl Z. Daher ist die Übertragung dieser Messergebnisse auf schwerere Ionen nur möglich, wenn ein leistungsstarker UV-Laser zur Verfügung steht. Da bei mittleren ultravioletten Wellenlängen keine schmalbandigen und leistungsstarken Laser existieren, werden in der Regel nichtlineare Konversionsprozesse genutzt, um solche Laserstrahlung zu erzeugen. Die Frequenzverdopplung mittels β-Bariumborat-Kristallen ist dabei die am häufigsten zum Einsatz kommende Methode. Diese Kristalle degradieren allerdings oft unter dem Eindruck der UV-Erzeugung und werden je nach Qualität schnell unbrauchbar. In dieser Arbeit wird eine Methode präsentiert, die trotz einer schlechten Kristallqualität eine hohe und stabile Ausgangsleistung kontinuierlicher schmalbandiger Laserstrahlung bei einer Wellenlänge von 257 nm erlaubt. Es wird eine UV-Leistung von mehr als 600 mW über eine Messdauer von 12 Stunden gezeigt. Als alternatives Kühlschema - zu dem bereits bei relativistischen Strahlen gezeigten mit einem gescannten cw-Laser - bietet sich die Kühlung mittels spektral breitem Laserlicht an. Bei nicht relativistischen Ionengeschwind

Mit Hilfe der Laserkühlung können in Speicherringen Ionenstrahlen mit sehr schmaler Geschwindigkeitsverteilung erzeugt werden. Durch den notwendigen atomaren Übergang ist die Laserkühlung Lithium ähnlicher Ionen an bestehenden Anlagen wie dem Schwer- ionenspeicherring ESR in Darmstadt auf relativ leichte Ionen beschränkt. An der neuen Teilchenbeschleunigeranlage FAIR mit dem Ionensynchrotron SIS100 und dem Speicherring HESR wird dagegen die Laserkühlung wesentlich schwererer Ionen möglich sein. Am ESR wurde erfolgreich mit einem durchstimmbaren ultravioletten cw-Lasersystem ein Strahl relativistischer Lithium ähnlicher C^3+-Ionen erzeugt, der eine Breite der relativen Impulsverteilung von weniger als 10^−6 erreichte. Die Höhe der Laserintensität, die zur Kühlung schwererer Lithium ähnlicher Ionen am SIS100 und HESR benötigt wird, wächst schnell mit der Kernladungszahl Z. Daher ist die Übertragung dieser Messergebnisse auf schwerere Ionen nur möglich, wenn ein leistungsstarker UV-Laser zur Verfügung steht. Da bei mittleren ultravioletten Wellenlängen keine schmalbandigen und leistungsstarken Laser existieren, werden in der Regel nichtlineare Konversionsprozesse genutzt, um solche Laserstrahlung zu erzeugen. Die Frequenzverdopplung mittels β-Bariumborat-Kristallen ist dabei die am häufigsten zum Einsatz kommende Methode. Diese Kristalle degradieren allerdings oft unter dem Eindruck der UV-Erzeugung und werden je nach Qualität schnell unbrauchbar. In dieser Arbeit wird eine Methode präsentiert, die trotz einer schlechten Kristallqualität eine hohe und stabile Ausgangsleistung kontinuierlicher schmalbandiger Laserstrahlung bei einer Wellenlänge von 257 nm erlaubt. Es wird eine UV-Leistung von mehr als 600 mW über eine Messdauer von 12 Stunden gezeigt. Als alternatives Kühlschema - zu dem bereits bei relativistischen Strahlen gezeigten mit einem gescannten cw-Laser - bietet sich die Kühlung mittels spektral breitem Laserlicht an. Bei nicht relativistischen Ionengeschwind

Mit Hilfe der Laserkühlung können in Speicherringen Ionenstrahlen mit sehr schmaler Geschwindigkeitsverteilung erzeugt werden. Durch den notwendigen atomaren Übergang ist die Laserkühlung Lithium ähnlicher Ionen an bestehenden Anlagen wie dem Schwer- ionenspeicherring ESR in Darmstadt auf relativ leichte Ionen beschränkt. An der neuen Teilchenbeschleunigeranlage FAIR mit dem Ionensynchrotron SIS100 und dem Speicherring HESR wird dagegen die Laserkühlung wesentlich schwererer Ionen möglich sein. Am ESR wurde erfolgreich mit einem durchstimmbaren ultravioletten cw-Lasersystem ein Strahl relativistischer Lithium ähnlicher C^3+-Ionen erzeugt, der eine Breite der relativen Impulsverteilung von weniger als 10^−6 erreichte. Die Höhe der Laserintensität, die zur Kühlung schwererer Lithium ähnlicher Ionen am SIS100 und HESR benötigt wird, wächst schnell mit der Kernladungszahl Z. Daher ist die Übertragung dieser Messergebnisse auf schwerere Ionen nur möglich, wenn ein leistungsstarker UV-Laser zur Verfügung steht. Da bei mittleren ultravioletten Wellenlängen keine schmalbandigen und leistungsstarken Laser existieren, werden in der Regel nichtlineare Konversionsprozesse genutzt, um solche Laserstrahlung zu erzeugen. Die Frequenzverdopplung mittels β-Bariumborat-Kristallen ist dabei die am häufigsten zum Einsatz kommende Methode. Diese Kristalle degradieren allerdings oft unter dem Eindruck der UV-Erzeugung und werden je nach Qualität schnell unbrauchbar. In dieser Arbeit wird eine Methode präsentiert, die trotz einer schlechten Kristallqualität eine hohe und stabile Ausgangsleistung kontinuierlicher schmalbandiger Laserstrahlung bei einer Wellenlänge von 257 nm erlaubt. Es wird eine UV-Leistung von mehr als 600 mW über eine Messdauer von 12 Stunden gezeigt. Als alternatives Kühlschema - zu dem bereits bei relativistischen Strahlen gezeigten mit einem gescannten cw-Laser - bietet sich die Kühlung mittels spektral breitem Laserlicht an. Bei nicht relativistischen Ionengeschwind

Mit Hilfe der Laserkühlung können in Speicherringen Ionenstrahlen mit sehr schmaler Geschwindigkeitsverteilung erzeugt werden. Durch den notwendigen atomaren Übergang ist die Laserkühlung Lithium ähnlicher Ionen an bestehenden Anlagen wie dem Schwer- ionenspeicherring ESR in Darmstadt auf relativ leichte Ionen beschränkt. An der neuen Teilchenbeschleunigeranlage FAIR mit dem Ionensynchrotron SIS100 und dem Speicherring HESR wird dagegen die Laserkühlung wesentlich schwererer Ionen möglich sein. Am ESR wurde erfolgreich mit einem durchstimmbaren ultravioletten cw-Lasersystem ein Strahl relativistischer Lithium ähnlicher C^3+-Ionen erzeugt, der eine Breite der relativen Impulsverteilung von weniger als 10^−6 erreichte. Die Höhe der Laserintensität, die zur Kühlung schwererer Lithium ähnlicher Ionen am SIS100 und HESR benötigt wird, wächst schnell mit der Kernladungszahl Z. Daher ist die Übertragung dieser Messergebnisse auf schwerere Ionen nur möglich, wenn ein leistungsstarker UV-Laser zur Verfügung steht. Da bei mittleren ultravioletten Wellenlängen keine schmalbandigen und leistungsstarken Laser existieren, werden in der Regel nichtlineare Konversionsprozesse genutzt, um solche Laserstrahlung zu erzeugen. Die Frequenzverdopplung mittels β-Bariumborat-Kristallen ist dabei die am häufigsten zum Einsatz kommende Methode. Diese Kristalle degradieren allerdings oft unter dem Eindruck der UV-Erzeugung und werden je nach Qualität schnell unbrauchbar. In dieser Arbeit wird eine Methode präsentiert, die trotz einer schlechten Kristallqualität eine hohe und stabile Ausgangsleistung kontinuierlicher schmalbandiger Laserstrahlung bei einer Wellenlänge von 257 nm erlaubt. Es wird eine UV-Leistung von mehr als 600 mW über eine Messdauer von 12 Stunden gezeigt. Als alternatives Kühlschema - zu dem bereits bei relativistischen Strahlen gezeigten mit einem gescannten cw-Laser - bietet sich die Kühlung mittels spektral breitem Laserlicht an. Bei nicht relativistischen Ionengeschwind

Mit Hilfe der Laserkühlung können in Speicherringen Ionenstrahlen mit sehr schmaler Geschwindigkeitsverteilung erzeugt werden. Durch den notwendigen atomaren Übergang ist die Laserkühlung Lithium ähnlicher Ionen an bestehenden Anlagen wie dem Schwer- ionenspeicherring ESR in Darmstadt auf relativ leichte Ionen beschränkt. An der neuen Teilchenbeschleunigeranlage FAIR mit dem Ionensynchrotron SIS100 und dem Speicherring HESR wird dagegen die Laserkühlung wesentlich schwererer Ionen möglich sein. Am ESR wurde erfolgreich mit einem durchstimmbaren ultravioletten cw-Lasersystem ein Strahl relativistischer Lithium ähnlicher C^3+-Ionen erzeugt, der eine Breite der relativen Impulsverteilung von weniger als 10^−6 erreichte. Die Höhe der Laserintensität, die zur Kühlung schwererer Lithium ähnlicher Ionen am SIS100 und HESR benötigt wird, wächst schnell mit der Kernladungszahl Z. Daher ist die Übertragung dieser Messergebnisse auf schwerere Ionen nur möglich, wenn ein leistungsstarker UV-Laser zur Verfügung steht. Da bei mittleren ultravioletten Wellenlängen keine schmalbandigen und leistungsstarken Laser existieren, werden in der Regel nichtlineare Konversionsprozesse genutzt, um solche Laserstrahlung zu erzeugen. Die Frequenzverdopplung mittels β-Bariumborat-Kristallen ist dabei die am häufigsten zum Einsatz kommende Methode. Diese Kristalle degradieren allerdings oft unter dem Eindruck der UV-Erzeugung und werden je nach Qualität schnell unbrauchbar. In dieser Arbeit wird eine Methode präsentiert, die trotz einer schlechten Kristallqualität eine hohe und stabile Ausgangsleistung kontinuierlicher schmalbandiger Laserstrahlung bei einer Wellenlänge von 257 nm erlaubt. Es wird eine UV-Leistung von mehr als 600 mW über eine Messdauer von 12 Stunden gezeigt. Als alternatives Kühlschema - zu dem bereits bei relativistischen Strahlen gezeigten mit einem gescannten cw-Laser - bietet sich die Kühlung mittels spektral breitem Laserlicht an. Bei nicht relativistischen Ionengeschwind

Likelihood-free (a.k.a. simulation-based) inference problems are inverse problems with expensive, or intractable, forward models. ODE inverse problems are commonly treated as likelihood-free, as their forward map has to be numerically approximated by an ODE solver. This, however, is not a fundamental constraint but just a lack of functionality in classic ODE solvers, which do not return a likelihood but a point estimate. To address this shortcoming, we employ Gaussian ODE filtering (a probabilistic numerical method for ODEs) to construct a local Gaussian approximation to the likelihood. This approximation yields tractable estimators for the gradient and Hessian of the (log-)likelihood. Insertion of these estimators into existing gradient-based optimization and sampling methods engenders new solvers for ODE inverse problems. We demonstrate that these methods outperform standard likelihood-free approaches on three benchmark-systems., Comment: 11 pages (+ 5 pages appendix), 6 figures

We consider the problem of robust optimization within the well-established Bayesian optimization (BO) framework. While BO is intrinsically robust to noisy evaluations of the objective function, standard approaches do not consider the case of uncertainty about the input parameters. In this paper, we propose Noisy-Input Entropy Search (NES), a novel information-theoretic acquisition function that is designed to find robust optima for problems with both input and measurement noise. NES is based on the key insight that the robust objective in many cases can be modeled as a Gaussian process, however, it cannot be observed directly. We evaluate NES on several benchmark problems from the optimization literature and from engineering. The results show that NES reliably finds robust optima, outperforming existing methods from the literature on all benchmarks.

Bayesian Optimization (BO) is an effective method for optimizing expensive-to-evaluate black-box functions with a wide range of applications for example in robotics, system design and parameter optimization. However, scaling BO to problems with large input dimensions (>10) remains an open challenge. In this paper, we propose to leverage results from optimal control to scale BO to higher dimensional control tasks and to reduce the need for manually selecting the optimization domain. The contributions of this paper are twofold: 1) We show how we can make use of a learned dynamics model in combination with a model-based controller to simplify the BO problem by focusing onto the most relevant regions of the optimization domain. 2) Based on (1) we present a method to find an embedding in parameter space that reduces the effective dimensionality of the optimization problem. To evaluate the effectiveness of the proposed approach, we present an experimental evaluation on real hardware, as well as simulated tasks including a 48-dimensional policy for a quadcopter.

Ultra-short pulse laser processing of hard materials, such as cemented tungsten carbide, requires an accurate and agile experimental and analytical investigation to obtain adequate information and setting parameters to maximize ablation rate. Therefore, this study presents a systematic approach which, first, experimentally searches for the variables with the most significant influence on the objective using a design of experiments method; and second, analyzes by means of existing ablation theory the interaction of the material and laser taking into account the Beer-Lambert law and incubation effect. Therefore, this places a basis for future analytical-experimental validation of the examined material. © 2013 The Authors.

Policy gradient methods are powerful reinforcement learning algorithms and have been demonstrated to solve many complex tasks. However, these methods are also data-inefficient, afflicted with high variance gradient estimates, and frequently get stuck in local optima. This work addresses these weaknesses by combining recent improvements in the reuse of off-policy data and exploration in parameter space with deterministic behavioral policies. The resulting objective is amenable to standard neural network optimization strategies like stochastic gradient descent or stochastic gradient Hamiltonian Monte Carlo. Incorporation of previous rollouts via importance sampling greatly improves data-efficiency, whilst stochastic optimization schemes facilitate the escape from local optima. We evaluate the proposed approach on a series of continuous control benchmark tasks. The results show that the proposed algorithm is able to successfully and reliably learn solutions using fewer system interactions than standard policy gradient methods., Comment: Includes appendix. Accepted for ICML 2019

Transferring knowledge across tasks to improve data-efficiency is one of the open key challenges in the field of global black-box optimization. Readily available algorithms are typically designed to be universal optimizers and, therefore, often suboptimal for specific tasks. We propose a novel transfer learning method to obtain customized optimizers within the well-established framework of Bayesian optimization, allowing our algorithm to utilize the proven generalization capabilities of Gaussian processes. Using reinforcement learning to meta-train an acquisition function (AF) on a set of related tasks, the proposed method learns to extract implicit structural information and to exploit it for improved data-efficiency. We present experiments on a simulation-to-real transfer task as well as on several synthetic functions and on two hyperparameter search problems. The results show that our algorithm (1) automatically identifies structural properties of objective functions from available source tasks or simulations, (2) performs favourably in settings with both scarse and abundant source data, and (3) falls back to the performance level of general AFs if no particular structure is present.

Parkinson's Disease (PD) is characterized by disorders in motor function such as freezing of gait, rest tremor, rigidity, and slowed and hyposcaled movements. Medication with dopaminergic medication may alleviate those motor symptoms, however, side-effects may include uncontrolled movements, known as dyskinesia. In this paper, an automatic PD motor-state assessment in free-living conditions is proposed using an accelerometer in a wrist-worn wearable sensor. In particular, an ensemble of convolutional neural networks (CNNs) is applied to capture the large variability of daily-living activities and overcome the dissimilarity between training and test patients due to the inter-patient variability. In addition, class activation map (CAM), a visualization technique for CNNs, is applied for providing an interpretation of the results., Comment: This is a pre-print of an article published in Annals of Biomedical Engineering (ABME)

Innovative chip breakers for cutting tools made of very hard materials require laser ablation and demand a high quality regarding the manufactured surface. When processing materials such as polycrystalline cubic boron-nitride or tungsten carbide the surface roughness by laser ablation reaches Sa= 1,0-2,9 μm compared to Sa= 0,42 μm achieved by grinding. Therefore in the presented research the influence of the hatching exposure strategy on surface roughness during picosecond laser ablation of tungsten carbide is examined. The areal, layerwise ablation process is separated into its elements which are represented by intersection zones between single and multiple laser vectors. Thus two mechanisms of roughness formation are identified and described by model functions. Further the mechanisms are transferred to areal ablation in which surface roughness decreases due to improved hatching angles compared to a commonly used one of φ= 0°/90°. With this approach the roughness is reduced by approximately factor 2,0-3,5 to Sa= 0,82 μm. In conclusion guidelines are derived which present favorable settings for high quality laser ablation processes.

Banyak manula dan orang difabel yang tidak mampu berjalan dengan kakinya sendiri. Alat yang biasa ditemui untuk menolong mereka adalah kursi roda. Saat pihak keluarga ingin membantu mendorong kursi roda tersebut, beberapa dari mereka akan kesulitan, karena bobot yang tidak ringan. Beberapa manula juga memiliki kelemahan tubuh yang lain, yaitu penurunan daya ingat, bahkan ada juga yang lupa jalan pulang. Kursi roda akan lebih ringan bila dikendalikan secara elektrik. Pengendali elektrik harus bisa digunakan oleh pengguna kursi roda elektrik dan pihak keluarga. Alat pengendali yang ditambahkan berupa PS2 wireless controller, Arduino, dan EMS 30A H-Bridge. Alat pemantauan posisi juga akan ditambahkan pada kursi roda elektrik, agar bisa memantau manula yang tidak ingat jalan pulang. Alat pemantauan ini berupa sebuah Arduino, GPRS/GSM/GPS module V3.0, dan android. Kursi roda elektrik yang dimodifikasi dengan tambahan alat pengendali dan pemantauan dapat membantu pengguna kursi roda elektrik dan pihak keluarga, tetapi masih ada kelemahan pada alat pemantauan. Posisi yang ditampilkan oleh alat pemantauan masih bergeser sekitar 12 meter dari posisi sebenarnya.

Background: Malignant pleural mesothelioma (MPM) is a highly aggressive tumour first-line treated with a combination of cisplatin and pemetrexed. MDM2 and P14/ARF (CDKN2A) are upstream regulators of TP53 and may contribute to its inactivation. In the present study, we now aimed to define the impact of miRNA expression on this mechanism. Material and Methods: 24 formalin-fixed paraffin-embedded (FFPE) tumour specimens were used for miRNA expression analysis of the 800 most important miRNAs using the nCounter technique (NanoString). Significantly deregulated miRNAs were identified before a KEGG-pathway analysis was performed. Results: 17 miRNAs regulating TP53, 18 miRNAs regulating MDM2, and 11 miRNAs directly regulating CDKN2A are significantly downregulated in MDM2-expressing mesotheliomas. TP53 is downregulated in MDM2-negative tumours through miRNAs with a miSVR prediction score of 11.67, RB1 with a prediction score of 8.02, MDM2 with a prediction score of 4.50 and CDKN2A with a prediction score of 1.27. Conclusion: MDM2 expression seems to impact miRNA expression levels in MPM. Especially, miRNAs involved in TP53-signaling are strongly decreased in MDM2-positive mesotheliomas. A better understanding of its tumour biology may open the chance for new therapeutic approaches and thereby augment patients' outcome.

Robots are on the verge of becoming ubiquitous. In the form of affordable humanoid toy robots, autonomous cars, vacuum robots or quadrocopters, robots are becoming part of our everyday life. As of today, most of these robots still follow largely hard coded behavior routines. Constraining a robot’s behavior to pre-programmed routines, however, limits its potential in several important ways. For example, programming even simple behavior patterns is a challenging task and programming behavior with human like performance by hand seems impossible. The goal of this thesis, thus, is to develop methods which allow robots to learn solutions to tasks through trial and error instead of relying on manual programming. These learned solutions should fulfill a range of desired properties. Foremost, the solutions should be learned on real world robots and not be constrained to simplified simulation environments. Furthermore, we would like the robot to learn versatile solutions which are able to cope with different variations of a task. Finally, we would like to be able to also solve more complicated tasks which require sequencing of multiple skills. In the first part of this thesis, we propose an algorithm to learn such versatile solutions. The proposed algorithm aims to find a hierarchical policy, consisting of a gating policy and a set of sub-policies. The gating policy selects a sub-policy and the sub-policy decides which action to take. Each of the learned sub-policies may be able to solve the task or a part of the overall task. To learn multiple sub-policies from one sample set, we employ an expectation-maximization based learning algorithm, where the sub-policies are updated according to their responsibilities for individual samples. These responsibilities indicate how likely it is that a certain sub-policy generated a given state-action pair. By constraining our learning algorithm to solutions which increase the entropy of the responsibilities, the robot will learn a set of

Robots are on the verge of becoming ubiquitous. In the form of affordable humanoid toy robots, autonomous cars, vacuum robots or quadrocopters, robots are becoming part of our everyday life. As of today, most of these robots still follow largely hard coded behavior routines. Constraining a robot’s behavior to pre-programmed routines, however, limits its potential in several important ways. For example, programming even simple behavior patterns is a challenging task and programming behavior with human like performance by hand seems impossible. The goal of this thesis, thus, is to develop methods which allow robots to learn solutions to tasks through trial and error instead of relying on manual programming. These learned solutions should fulfill a range of desired properties. Foremost, the solutions should be learned on real world robots and not be constrained to simplified simulation environments. Furthermore, we would like the robot to learn versatile solutions which are able to cope with different variations of a task. Finally, we would like to be able to also solve more complicated tasks which require sequencing of multiple skills. In the first part of this thesis, we propose an algorithm to learn such versatile solutions. The proposed algorithm aims to find a hierarchical policy, consisting of a gating policy and a set of sub-policies. The gating policy selects a sub-policy and the sub-policy decides which action to take. Each of the learned sub-policies may be able to solve the task or a part of the overall task. To learn multiple sub-policies from one sample set, we employ an expectation-maximization based learning algorithm, where the sub-policies are updated according to their responsibilities for individual samples. These responsibilities indicate how likely it is that a certain sub-policy generated a given state-action pair. By constraining our learning algorithm to solutions which increase the entropy of the responsibilities, the robot will learn a set of

Background: Malignant pleural mesothelioma (MPM) is a highly aggressive tumour first-line treated with a combination of cisplatin and pemetrexed. MDM2 and P14/ARF (CDKN2A) are upstream regulators of TP53 and may contribute to its inactivation. In the present study, we now aimed to define the impact of miRNA expression on this mechanism. Material and Methods: 24 formalin-fixed paraffin-embedded (FFPE) tumour specimens were used for miRNA expression analysis of the 800 most important miRNAs using the nCounter technique (NanoString). Significantly deregulated miRNAs were identified before a KEGG-pathway analysis was performed. Results: 17 miRNAs regulating TP53, 18 miRNAs regulating MDM2, and 11 miRNAs directly regulating CDKN2A are significantly downregulated in MDM2-expressing mesotheliomas. TP53 is downregulated in MDM2-negative tumours through miRNAs with a miSVR prediction score of 11.67, RB1 with a prediction score of 8.02, MDM2 with a prediction score of 4.50 and CDKN2A with a prediction score of 1.27. Conclusion: MDM2 expression seems to impact miRNA expression levels in MPM. Especially, miRNAs involved in TP53-signaling are strongly decreased in MDM2-positive mesotheliomas. A better understanding of its tumour biology may open the chance for new therapeutic approaches and thereby augment patients' outcome.

Robots are on the verge of becoming ubiquitous. In the form of affordable humanoid toy robots, autonomous cars, vacuum robots or quadrocopters, robots are becoming part of our everyday life. As of today, most of these robots still follow largely hard coded behavior routines. Constraining a robot’s behavior to pre-programmed routines, however, limits its potential in several important ways. For example, programming even simple behavior patterns is a challenging task and programming behavior with human like performance by hand seems impossible. The goal of this thesis, thus, is to develop methods which allow robots to learn solutions to tasks through trial and error instead of relying on manual programming. These learned solutions should fulfill a range of desired properties. Foremost, the solutions should be learned on real world robots and not be constrained to simplified simulation environments. Furthermore, we would like the robot to learn versatile solutions which are able to cope with different variations of a task. Finally, we would like to be able to also solve more complicated tasks which require sequencing of multiple skills. In the first part of this thesis, we propose an algorithm to learn such versatile solutions. The proposed algorithm aims to find a hierarchical policy, consisting of a gating policy and a set of sub-policies. The gating policy selects a sub-policy and the sub-policy decides which action to take. Each of the learned sub-policies may be able to solve the task or a part of the overall task. To learn multiple sub-policies from one sample set, we employ an expectation-maximization based learning algorithm, where the sub-policies are updated according to their responsibilities for individual samples. These responsibilities indicate how likely it is that a certain sub-policy generated a given state-action pair. By constraining our learning algorithm to solutions which increase the entropy of the responsibilities, the robot will learn a set of

As our knowledge of the eukaryotic genome structure and organization has evolved, a new family of small non-coding regulatory RNAs, called microRNAs (miRNAs), has emerged. 20 years after their first discovery, our comprehension of these molecules and their interactions is still limited yet. Bound to an Argonaute (AGO) containing ribonucleoprotein complex (miRNP), miRNAs were suggested to form a requisite post-transcriptional regulation layer controlling many cellular processes. Recent CLIP-Seq technologies allowed for the first time, the determination of miRNP target sites of a whole transcriptome with high specificity. This doctoral thesis aimed to quantitatively elucidate basic miRNP:target interaction paradigms, to examine how these are impacted by genetic variance, and finally, to develop a novel computational approach to qualitatively model global miRNA-mediated regulation by means of novel information extracted from available AGO-bound CLIP-Seq libraries., Über die letzten Jahrzehnte expandierte unser Wissen über die Topologie des eukaryotischen Genoms in einem beachtlichen Ausmaß. Hierbei sind viele neue Elemente beschrieben worden - unter anderem auch eine Familie kleiner nicht-kodierender RNAs, den sogenannten microRNAs (miRNAs). Noch heute, 20 Jahre nach ihrer ersten Entdeckung, sind unsere Erkenntnisse über diese Moleküle und deren Interaktionen limitiert. Integriert in einem Ribonukleoproteinkomplex (miRNP) bilden miRNAs eine essentielle post-transkriptionelle Regulationsebene, welche eine Vielzahl zellulärer Prozesse kontrolliert. Neue CLIP-Seq Technologien ermöglichen zum ersten Mal, eine hoch-spezfische, transkriptomweite Identifikation von miRNP Bindestellen. Diese Doktorarbeit hatte das Ziel, anhand der quantitativen Exploration von verfügbaren AGO CLIP-Seq Bibliotheken, grundlegende miRNP:Zielgen Interaktionsparadigmen aufzuklären, zu erörtern wie diese durch genetische Variation beeinflusst werden und letztlich einen Ansatz zu entwickeln, um globale qualitative Modelle zellulärer miRNA-mediierter Regulation berechnen zu können.

Background: Neuroendocrine tumors of the lung (NELC) account for 25% of all lung cancer cases and transcription factors may drive dedifferentiation of these tumors. This study was conducted to identify supportive diagnostic and prognostic biomarkers. Materials & methods: A total of 16 TC, 13 AC, 16 large cell neuroendocrine carcinomas and 15 small cell lung cancer were investigated for the mRNA expression of 11 transcription factors and related genes (MYB, MYBBP1A, OCT4, PAX6, PCDHB, RBP1, SDCBP, SOX2, SOX4, SOX11, TEAD2). Results:SOX4 (p = 0.0002), SOX11 (p < 0.0001) and PAX6 (p = 0.0002) were significant for tumor type. Elevated PAX6 and SOX11 expression correlated with poor outcome in large cell neuroendocrine carcinomas and small cell lung cancer (p < 0.0001 and p = 0.0232, respectively) based on survival data of 34 patients (57%). Conclusion: Aggressiveness of NELC correlated with increasing expression of transcription factors. SOX11 seems to be a highly valuable diagnostic and prognostic marker for aggressive NELC.

Background: Lung cancer is the leading cause of cancer-related deaths worldwide. The typical and atypical carcinoid (TC and AC), the large-cell neuroendocrine carcinoma (LCNEC) and the small-cell lung cancers (SCLC) are subgroups of pulmonary tumours that show neuroendocrine differentiations. With the rising impact of molecular pathology in routine diagnostics the interest for reliable biomarkers, which can help to differentiate these subgroups and may enable a more personalised treatment of patients, grows. Methods: A collective of 70 formalin-fixed, paraffin-embedded (FFPE) pulmonary neuroendocrine tumours (17 TCs, 17 ACs, 19 LCNECs and 17 SCLCs) was used to identify biomarkers by high-throughput sequencing. Using the Illumina TruSeq Amplicon-Cancer Panel on the MiSeq instrument, the samples were screened for alterations in 221 mutation hot spots of 48 tumour-relevant genes. Results: After filtering >26 000 detected variants by applying strict algorithms, a total of 130 mutations were found in 29 genes and 49 patients. Mutations in JAK3, NRAS, RB1 and VHL1 were exclusively found in SCLCs, whereas the FGFR2 mutation was detected in LCNEC only. KIT, PTEN, HNF1A and SMO were altered in ACs. The SMAD4 mutation corresponded to the TC subtype. We prove that the frequency of mutations increased with the malignancy of tumour type. Interestingly, four out of five ATM-mutated patients showed an additional alteration in TP53, which was by far the most frequently altered gene (28 out of 130; 22%). We found correlations between tumour type and IASLC grade for ATM-(P = 0.022; P = 0.008) and TP53-mutated patients (P<0.001). Both mutated genes were also associated with lymph node invasion and distant metastasis (P <= 0.005). Furthermore, PIK3CA-mutated patients with high-grade tumours showed a reduced overall survival (P = 0.040) and the mutation frequency of APC and ATM in high-grade neuroendocrine lung cancer patients was associated with progression-free survival (PFS) (P = 0.0

Background: Neuroendocrine tumors of the lung (NELC) account for 25% of all lung cancer cases and transcription factors may drive dedifferentiation of these tumors. This study was conducted to identify supportive diagnostic and prognostic biomarkers. Materials & methods: A total of 16 TC, 13 AC, 16 large cell neuroendocrine carcinomas and 15 small cell lung cancer were investigated for the mRNA expression of 11 transcription factors and related genes (MYB, MYBBP1A, OCT4, PAX6, PCDHB, RBP1, SDCBP, SOX2, SOX4, SOX11, TEAD2). Results:SOX4 (p = 0.0002), SOX11 (p < 0.0001) and PAX6 (p = 0.0002) were significant for tumor type. Elevated PAX6 and SOX11 expression correlated with poor outcome in large cell neuroendocrine carcinomas and small cell lung cancer (p < 0.0001 and p = 0.0232, respectively) based on survival data of 34 patients (57%). Conclusion: Aggressiveness of NELC correlated with increasing expression of transcription factors. SOX11 seems to be a highly valuable diagnostic and prognostic marker for aggressive NELC.

Background: Neuroendocrine tumors of the lung comprise typical (TC) and atypical carcinoids (AC), large-cell neuroendocrine cancer (LCNEC) and small-cell lung cancer (SCLC). Cell cycle and apoptosis are key pathways of multicellular homeostasis and deregulation of these pathways is associated with cancerogenesis. Materials and Methods: Sixty representative FFPE-specimens (16 TC, 13 AC, 16 LCNEC and 15 SCLC) were used for mRNA expression analysis using the NanoString technique. Eight genes related to apoptosis and ten genes regulating key points of cell cycle were investigated. Results: ASCL1, BCL2, CASP8, CCNE1, CDK1, CDK2, CDKN1A and CDKN2A showed lower expression in carcinoids compared to carcinomas. In contrast, CCNE1 and CDK6 showed elevated expression in carcinoids compared to carcinomas. The calculated BCL2/BAX ratio showed increasing values from TC to SCLC. Between SCLC and LCNEC CDK2, CDKN1B, CDKN2A and PNN expression was significantly different with higher expression in SCLC. Conclusion: Carcinoids have increased CDK4/6 and CCND1 expression controlling RB1 phosphorylation via this signaling cascade. CDK2 and CCNE1 were increased in carcinomas showing that these use the opposite way to control RB1. BAX and BCL2 are antagonists in regulating apoptosis. BCL2 expression increased over BAX expression with increasing malignancy of the tumor from TC to SCLC.

Background: Lung cancer is the leading cause of cancer-related deaths worldwide. The typical and atypical carcinoid (TC and AC), the large-cell neuroendocrine carcinoma (LCNEC) and the small-cell lung cancers (SCLC) are subgroups of pulmonary tumours that show neuroendocrine differentiations. With the rising impact of molecular pathology in routine diagnostics the interest for reliable biomarkers, which can help to differentiate these subgroups and may enable a more personalised treatment of patients, grows. Methods: A collective of 70 formalin-fixed, paraffin-embedded (FFPE) pulmonary neuroendocrine tumours (17 TCs, 17 ACs, 19 LCNECs and 17 SCLCs) was used to identify biomarkers by high-throughput sequencing. Using the Illumina TruSeq Amplicon-Cancer Panel on the MiSeq instrument, the samples were screened for alterations in 221 mutation hot spots of 48 tumour-relevant genes. Results: After filtering >26 000 detected variants by applying strict algorithms, a total of 130 mutations were found in 29 genes and 49 patients. Mutations in JAK3, NRAS, RB1 and VHL1 were exclusively found in SCLCs, whereas the FGFR2 mutation was detected in LCNEC only. KIT, PTEN, HNF1A and SMO were altered in ACs. The SMAD4 mutation corresponded to the TC subtype. We prove that the frequency of mutations increased with the malignancy of tumour type. Interestingly, four out of five ATM-mutated patients showed an additional alteration in TP53, which was by far the most frequently altered gene (28 out of 130; 22%). We found correlations between tumour type and IASLC grade for ATM-(P = 0.022; P = 0.008) and TP53-mutated patients (P<0.001). Both mutated genes were also associated with lymph node invasion and distant metastasis (P <= 0.005). Furthermore, PIK3CA-mutated patients with high-grade tumours showed a reduced overall survival (P = 0.040) and the mutation frequency of APC and ATM in high-grade neuroendocrine lung cancer patients was associated with progression-free survival (PFS) (P = 0.0

As our knowledge of the eukaryotic genome structure and organization has evolved, a new family of small non-coding regulatory RNAs, called microRNAs (miRNAs), has emerged. 20 years after their first discovery, our comprehension of these molecules and their interactions is still limited yet. Bound to an Argonaute (AGO) containing ribonucleoprotein complex (miRNP), miRNAs were suggested to form a requisite post-transcriptional regulation layer controlling many cellular processes. Recent CLIP-Seq technologies allowed for the first time, the determination of miRNP target sites of a whole transcriptome with high specificity. This doctoral thesis aimed to quantitatively elucidate basic miRNP:target interaction paradigms, to examine how these are impacted by genetic variance, and finally, to develop a novel computational approach to qualitatively model global miRNA-mediated regulation by means of novel information extracted from available AGO-bound CLIP-Seq libraries., Über die letzten Jahrzehnte expandierte unser Wissen über die Topologie des eukaryotischen Genoms in einem beachtlichen Ausmaß. Hierbei sind viele neue Elemente beschrieben worden - unter anderem auch eine Familie kleiner nicht-kodierender RNAs, den sogenannten microRNAs (miRNAs). Noch heute, 20 Jahre nach ihrer ersten Entdeckung, sind unsere Erkenntnisse über diese Moleküle und deren Interaktionen limitiert. Integriert in einem Ribonukleoproteinkomplex (miRNP) bilden miRNAs eine essentielle post-transkriptionelle Regulationsebene, welche eine Vielzahl zellulärer Prozesse kontrolliert. Neue CLIP-Seq Technologien ermöglichen zum ersten Mal, eine hoch-spezfische, transkriptomweite Identifikation von miRNP Bindestellen. Diese Doktorarbeit hatte das Ziel, anhand der quantitativen Exploration von verfügbaren AGO CLIP-Seq Bibliotheken, grundlegende miRNP:Zielgen Interaktionsparadigmen aufzuklären, zu erörtern wie diese durch genetische Variation beeinflusst werden und letztlich einen Ansatz zu entwickeln, um globale qualitative Modelle zellulärer miRNA-mediierter Regulation berechnen zu können.

OBJECTIVE: To evaluate cosmesis, body image, pain, and quality of life (QoL) after single-port laparoscopic cholecystectomy (SPLC) versus conventional 4-port laparoscopic cholecystectomy (4PLC). BACKGROUND: The impact of SPLC on improving cosmesis, body image, pain, and QoL has not been evaluated in double-blinded randomized controlled trials (RCT). This approach therefore remains controversial. METHODS: Between October 2011 and February 2014, 110 patients from 2 centers were randomly assigned to SPLC (n = 55) or 4PLC (n = 55). Primary endpoints were a validated cosmesis (3-24 points) and body image (5-20 points) score after 3 and 12 months. Secondary endpoints included operative duration, postoperative pain, complications, QoL, and length of hospital stay. Patients, physicians, and nurses were blinded until the seventh postoperative day. RESULTS: Demographics were equally distributed between both groups (mean age: 46 years, SD: 14, 62 females, 34 males). The SPLC-group showed superior mean cosmesis and body image compared with the 4PLC-group at 12-weeks (21 vs 16, P < 0.001 and 5 vs 6, P = 0.013, respectively) and at 1-year (24 vs 16, P < 0.001 and 5 vs 6, P < 0.017, respectively). Operation duration was longer in the SPLC-group (mean 101 vs 90 minutes, p = 0.031). Although postoperative pain was less in the SPLC-group (mean VAS 1 vs 2, p = 0.005), there were no differences in complications, and length of hospital-stay. CONCLUSIONS: This is the first multicenter double-blinded RCT reporting superior short- and long-term cosmetic and body image, postoperative pain, and QoL in SPLC compared with 4PLC. Although cost-effectiveness is still a subject of ongoing debate, SPLC should be offered to patients undergoing surgery for benign gallbladder disease.

Background: Proteasomal subunit PSMB4 was suggested to be a survival gene in an animal model of hepatocellular carcinoma and in glioblastoma cell lines. In pulmonary adenocarcinoma, a high expression of these genes was found to be associated with poor differentiation and survival. This study investigates the gene expression levels of 26S proteasome subunits in human pulmonary neuroendocrine tumours including typical (TC) and atypical (AC) carcinoid tumours as well as small cell (SCLC) and large cell (LCNEC) neuroendocrine carcinomas. Material and methods: Gene expression levels of proteasomal subunits (PSMA1, PSMA5, PSMB4, PSMB5 and PSMD1) were investigated in 80 neuroendocrine pulmonary tumours (each 20 TC, AC, LCNLC and SCLC) and compared to controls. mRNA levels were determined by using TaqMan assays. Immunohistochemistry on tissue microarrays (TMA) was performed to determine the expression of ki67, cleaved caspase 3 and PSMB4. Results: All proteasomal subunit gene expressions were significantly upregulated in TC, AC, SCLC and LCNEC compared to controls. PSMB4 mRNA is differently expressed between all neuroendocrine tumour subtypes demonstrating the highest expression and greatest range in LCNEC (p=0.043), and is significantly associated with proliferative activity (p=0.039). Conclusion: In line with other 26S proteasomal subunits PSMB4 is significantly increased, but differently expressed between pulmonary neuroendocrine tumours and is associated with the proliferative activity. Unlike in pulmonary adenocarcinomas, no association with biological behaviour was observed, suggesting that increased proteasomal subunit gene expression is a common and probably early event in the tumorigenesis of pulmonary neuroendocrine tumours regardless of their differentiation.

Background: Proteasomal subunit PSMB4 was suggested to be a survival gene in an animal model of hepatocellular carcinoma and in glioblastoma cell lines. In pulmonary adenocarcinoma, a high expression of these genes was found to be associated with poor differentiation and survival. This study investigates the gene expression levels of 26S proteasome subunits in human pulmonary neuroendocrine tumours including typical (TC) and atypical (AC) carcinoid tumours as well as small cell (SCLC) and large cell (LCNEC) neuroendocrine carcinomas. Material and methods: Gene expression levels of proteasomal subunits (PSMA1, PSMA5, PSMB4, PSMB5 and PSMD1) were investigated in 80 neuroendocrine pulmonary tumours (each 20 TC, AC, LCNLC and SCLC) and compared to controls. mRNA levels were determined by using TaqMan assays. Immunohistochemistry on tissue microarrays (TMA) was performed to determine the expression of ki67, cleaved caspase 3 and PSMB4. Results: All proteasomal subunit gene expressions were significantly upregulated in TC, AC, SCLC and LCNEC compared to controls. PSMB4 mRNA is differently expressed between all neuroendocrine tumour subtypes demonstrating the highest expression and greatest range in LCNEC (p=0.043), and is significantly associated with proliferative activity (p=0.039). Conclusion: In line with other 26S proteasomal subunits PSMB4 is significantly increased, but differently expressed between pulmonary neuroendocrine tumours and is associated with the proliferative activity. Unlike in pulmonary adenocarcinomas, no association with biological behaviour was observed, suggesting that increased proteasomal subunit gene expression is a common and probably early event in the tumorigenesis of pulmonary neuroendocrine tumours regardless of their differentiation.

The present work covers two parts: A first part deals with a new method of biomimetic functionalization of silicon surfaces with model membranes supported on polymeric tethers and with the structural characterization of these surfaces. The second part, that required a substantial part of the time, dealt with experimental work on assembling the neutron reflectometer with option for small angle scattering REFSANS at the scientific neutron reactor Heinz Maier-Leibnitz in Garching near Munich, which successfully went operational., Die vorliegende Arbeit umfasst im Wesentlichen zwei Teile: Der erste Teil befasst sich mit einer neuen Methode zur biomimetischen Funktionalisierung von Siliziumoberflächen mittels Modellmembranen auf Polymerstützen und der strukturellen Charakterisierung dieser Oberflächen. Der zweite Teil der Arbeit, der einen erheblichen Teil der Zeit in Anspruch genommen hat, bestand aus experimentellen Aufbauarbeiten am Neutronenreflektometer mit Option zur Kleinwinkelstreuung REFSANS an der Forschungs-Neutronenquelle Heinz Maier-Leibnitz in Garching bei München, das erfolgreich in Betrieb genommen wurde.

The present work covers two parts: A first part deals with a new method of biomimetic functionalization of silicon surfaces with model membranes supported on polymeric tethers and with the structural characterization of these surfaces. The second part, that required a substantial part of the time, dealt with experimental work on assembling the neutron reflectometer with option for small angle scattering REFSANS at the scientific neutron reactor Heinz Maier-Leibnitz in Garching near Munich, which successfully went operational., Die vorliegende Arbeit umfasst im Wesentlichen zwei Teile: Der erste Teil befasst sich mit einer neuen Methode zur biomimetischen Funktionalisierung von Siliziumoberflächen mittels Modellmembranen auf Polymerstützen und der strukturellen Charakterisierung dieser Oberflächen. Der zweite Teil der Arbeit, der einen erheblichen Teil der Zeit in Anspruch genommen hat, bestand aus experimentellen Aufbauarbeiten am Neutronenreflektometer mit Option zur Kleinwinkelstreuung REFSANS an der Forschungs-Neutronenquelle Heinz Maier-Leibnitz in Garching bei München, das erfolgreich in Betrieb genommen wurde.

Massachusetts Institute of Technology. Dept. of Physics. Thesis. 1970. B.S., Bibliography: leaf 20., B.S.