Yes / Merkel cell carcinoma (MCC) is an aggressive skin cancer with a high propensity for recurrence and metastasis. Merkel cell polyomavirus (MCPyV) is recognised as the causative factor in the majority of MCC cases. The MCPyV small tumour antigen (ST) is considered to be the main viral transforming factor, however potential mechanisms linking ST expression to the highly metastatic nature of MCC are yet to be fully elucidated. Metastasis is a complex process, with several discrete steps required for the formation of secondary tumour sites. One essential trait that underpins the ability of cancer cells to metastasise is how they interact with adjoining tumour cells and the surrounding extracellular matrix. Here we demonstrate that MCPyV ST expression disrupts the integrity of cell-cell junctions, thereby enhancing cell dissociation and implicate the cellular sheddases, A disintegrin and metalloproteinase (ADAM) 10 and 17 proteins in this process. Inhibition of ADAM 10 and 17 activity reduced MCPyV ST-induced cell dissociation and motility, attributing their function as critical to the MCPyV-induced metastatic processes. Consistent with these data, we confirm that ADAM 10 and 17 are upregulated in MCPyV-positive primary MCC tumours. These novel findings implicate cellular sheddases as key host cell factors contributing to virus-mediated cellular transformation and metastasis. Notably, ADAM protein expression may be a novel biomarker of MCC prognosis and given the current interest in cellular sheddase inhibitors for cancer therapeutics, it highlights ADAM 10 and 17 activity as a novel opportunity for targeted interventions for disseminated MCC. / In parts by the Medical Research Council (95505126) to AW, Royal Society (UF100419) to JM and Biotechnology and Biological Sciences Research Council (BB/R000352/1) to GEB and AW.

No description available.

L’opossum nait dans un état très immature, mais rampe avec ses membres antérieurs (MA) de l’orifice urogénital de la mère à une tétine, où il s’attache pour poursuivre son développement. Des informations sensorielles sont nécessaires pour guider le nouveau-né vers une tétine et déclencher son attachement. Des expériences précédentes ont montré que le système du trijumeau, dont dépend l’innervation somesthésique du museau, influence les mouvements précoces des MA. Le présent projet vise à déterminer si les mécanorécepteurs faciaux sont fonctionnels et exercent une influence sur les MA. On s’intéresse particulièrement aux cellules de Merkel, un mécanorécepteur épidermique innervé par des fibres à adaptation lente de type I (SA I). Ces cellules ont été localisées sur le pourtour du museau de l’opossum nouveau-né en utilisant un traceur cellulaire, l’AM1-43. Nous avons analysé les réponses musculaires des MA consécutives à l’application de forces calibrées au museau sur des préparations in vitro. Ces réponses sont bilatérales et simultanées, très variables, et leur intensité augmente avec la force de la stimulation. Lors de stimulations répétitives pendant 60 min, les réponses diminuent avec le temps. Le retrait de la peau faciale abolit presque ces réponses. De plus, l’application d’un antagoniste des récepteurs métabotropiques du glutamate, qui affecte l’activité des fibres SA I, ou d’un antagoniste des récepteurs purinergiques les diminue fortement, suggérant une participation des cellules de Merkel. Ces résultats soutiennent que le sens du toucher facial relayé par le système du trijumeau est fonctionnel chez l’opossum nouveau-né et qu’il pourrait influencer les mouvements des MA. / The opossum, Monodelphis domestica, is born very immature but crawls, unaided, with its forelimbs (FL) from the mother's birth canal to a nipple where it attaches to pursue its development. Sensory clues are needed to guide the newborn to the nipple and trigger its attachment to it. We postulated that the trigeminal system, responsible for sensory innervation of the face, is involved. Indeed, light pressure applied on the snout evokes FL movements in vivo, low intensity electrical stimulation of the trigeminal ganglion induces motor responses of the FL in vitro, and trigeminal fibers is distributed in the facial dermis and basal epidermis of the newborn. Also, slowly adapting mechanosensory receptors Merkel cells (AM1-43 positive) are present in the face epidermis. To determine if Merkel cells exert an influence on locomotion of newborn opossums, we analyzed the FL muscles responses following application of calibrated forces on the snout in in vitro preparations. Pressure applied to the face induced bilateral and simultaneous FL motor responses, which intensity is proportional to stimulation force. Following consecutive stimulations during 60 min, the responses tended to decrease. Removing the facial skin nearly abolished the responses. Bath applications of the glutamate metabotropic receptor antagonist YM298198, and of the purinergic receptors (P2) antagonist PPADS, decreased the muscles responses. These results support that touch sensitivity of the snout relayed by the trigeminal system is functional in newborn opossums and may influence FL movement, possibly contributing to guiding the animal to the nipple.

by Chan Eliza. / Thesis (Ph.D.)--Chinese University of Hong Kong, 1994. / Includes bibliographical references (leaves 183-196). / ACKNOWLEDGEMENTS / ABSTRACT --- p.i / Chapter CHAPTER ONE: --- INTRODUCTION --- p.1 / Chapter CHAPTER TWO: --- LITERATURE REVIEW / Chapter Section 1: --- History of Merkel cells --- p.3 / Chapter Section 2: --- Morphology and characteristic response of Merkel cell receptors in the skin --- p.5 / Chapter Section 3: --- Merkel cells and other mechanoreceptors in the mammalian sinus hair --- p.16 / Chapter Section 4: --- Functions of Merkel cells --- p.29 / Chapter Section 5: --- Review of technical approaches in the study of Merkel cell physiology --- p.39 / Chapter Section 6: --- Monitoring intracellular Ca2+ with the microfluorimetric technique --- p.42 / Chapter Section 7: --- Properties of voltage-gated and ligand-operated Ca2+ channels --- p.52 / Chapter CHAPTER THREE: --- METHODS / Chapter Section 1: --- Isolation of the rat vibrissal follicles --- p.60 / Chapter Section 2: --- Procedures for fluorimetric studies --- p.63 / Chapter Section 3: --- Procedures for electrophysiological study --- p.72 / Chapter Section 4: --- Chemicals --- p.82 / Chapter CHAPTER FOUR: --- RESULTS / Chapter Section 1: --- Electrophysiological studies in an isolated sinus hair preparation --- p.89 / Chapter Section 2: --- Electrophysiological studies on slowly adapting type I (SA I) mechanoreceptors in an isolated skin-nervein vitro preparation --- p.109 / Chapter Section 3: --- Microfluorimetric studies of Merkel cells in the isolated sinus hair preparation --- p.117

Zugl.: Vechta, Hochsch., Diss., 2010

Foreign policy of Germany has gained due to its special development in the post-war period some unique traits -- strong multilateral and westward orientation and civilian character. German unification became a turning point in this respect. The country was confronted with the necessity to find its new place within the changing international system. This paper focuses on the subsequent changes of foreign policy. Its purpose is to evaluate the change or continuity of these unique traits on one side and to describe Germany's new role in the international relations on the other. The initial step is to picture the function of bodies involved in shaping the foreign policy - government, parliament, individual federal countries and president. Further on the paper outlines the main events of German unification, restoring its full international subjectivity. The core descriptive part is divided in three main segments in terms of the personality leading the government, the chancellor. It first gives an account of foreign policy of the "Kohl era", continues with Schröder government and closes with foreign policy of Angela Merkel. With the view of the complexity of such a task the paper focuses on selected policy areas only -- European integration, transatlantic cooperation and partnership with Russia being among them.

This thesis analyzes the management of refugee crisis in the Federal Republic of Germany in relation to the applicable law of the European Union. In theoretical introduction, the thesis focuses on the definition of key concepts and the related areas of EU law. The second part is devoted to the policy of the Federal Republic of Germany led by Federal Chancellor Angela Merkel and the actions adopted. In the last part, these actions are analyzed in accordance with the main research question of this thesis, namely whether Germany is dealing with the immigrant crisis in accordance with the law of the European Union.

Somatosensory neurons densely innervate skin, our largest sensory organ. Adult skin continually remodels throughout the lifespan to maintain a protective barrier for our bodies. How sensory neurons maintain their peripheral endings in the face of continual turnover of their target tissue is not well understood. To address this gap in knowledge, I analyzed the temporal dynamics and mechanisms of structural plasticity of touch receptors in healthy adult skin. My studies focused on the terminals of Merkel-cell afferents in mouse touch domes. These two-part touch receptors comprise epithelial Merkel cells innervated by branching axons of fast-conducting sensory neurons. I show that Merkel cells and their afferents are structurally plastic over the course of hair growth in adults. These two components simplify during active hair growth, with fewer terminal neurites and fewer Merkel cells per touch dome at this stage compared with other phases of hair growth. Merkel-cell removal was observed with multiple molecular markers. Additionally, mice showed diminished touch-evoked behavior during hair growth compared with follicle quiescence. Next, I showed that Sarm1, a key effector of Wallerian degeneration, is not required for structural plasticity of Merkel cell-neurite complexes in young adulthood. Finally, I developed a technique to perform time-lapse in vivo imaging of identified Merkel cells and afferent terminals over the course of a month. These structures were highly plastic, with afferent terminals undergoing frequent growth and regression, as well as both Merkel cells and terminal branches being added or removed. Together, these studies reveal that peripheral nerve terminals undergo a previously unsuspected amount of structural plasticity in healthy tissue.

Merkel cell carcinoma (MCC) is a rare neuroendocrine malignancy of the skin that is highly aggressive and often metastasizes early. MCC is diagnosed based on histopathological findings and is most commonly treated with surgical resection, which may be accompanied by chemotherapy and/or radiation. This report describes a 55-year-old male with history of recurrent malignant melanoma of the right pinna and subsequent excision. Three years following the excision of melanoma, he presents with a lesion to the right forehead as well as a right-sided neck mass that were found to be metastatic Merkel cell carcinoma. Although there have been reports describing the development of second cancers following the treatment of MCC, the development of MCC after the treatment of other malignancies has not been well-described. Merkel cell carcinoma remains a highly aggressive and frequently metastatic malignancy that should not be overlooked, especially when developed after the diagnosis and treatment of other primary cutaneous malignancies such as melanoma.

Since the war´s end in the 1990s, Bosnia and Herzegovina, a young nation in the center of Europe, has struggled to establish a functional democratic system. In line with the Dayton Agreement, which ended the conflict, the nation was split up into two autonomous regions, one of which would belong to the Serbian population and the other to the Bosnian and Croatian populations. In addition to being a peace treaty, the Dayton Agreement would also serve as the nation´s constitution with the intention to construct a democratic government and society. Bosnia and Herzegovina have struggled to establish a fully democratic state of governance since the peace, because of the Dayton Agreement´s power-sharing model, which in practice has given room for the country´s rulers as well as international actors, to view the country as a surface where two independent parts meets, rather than a unified state. The aim of this study is to examine Bosnia and Herzegovina´s democratic constraints from 2018 to 2022 using Wolfgang Merkel´s theory of embedded and defective democracy. It also seeks to determine to what extent Bosnia and Herzegovina can be considered as a defective democracy, based on the theory´s premises. The outcome of this study, in short, implies that Bosnia and Herzegovina´s democratic constraints can be attributed to national political abuse of power, together with corruption, the absence of functioning state institutions and an undue reliance on international actors.