The CYP2D6 Animal Model: How to Induce Autoimmune Hepatitis in Mice

Autoimmune hepatitis is a rare but life threatening autoimmune disease of the liver of unknown etiology1,2. In the past many attempts have been made to generate an animal model that reflects the characteristics of the human disease 3-5. However, in various models the induction of disease was rather complex and often hepatitis was only transient3-5. Therefore, we have developed a straightforward mouse model that uses the major human autoantigen in type 2 autoimmune hepatitis (AIH-2), namely hCYP2D6, as a trigger6. Type 1 liver-kidney microsomal antibodies (LKM-1) antibodies recognizing hCYP2D6 are the hallmark of AIH-27,8. Delivery of hCYP2D6 into wildtype FVB or C57BL/6 mice was by an Adenovirus construct (Ad-2D6) that ensures a direct delivery of the triggering antigen to the liver. Thus, the ensuing local inflammation generates a fertile field9 for the subsequent development of autoimmunity. A combination of intravenous and intraperitoneal injection of Ad-2D6 is the most effective route to induce a long-lasting autoimmune damage to the liver (section 1). Here we provide a detailed protocol on how autoimmune liver disease is induced in the CYP2D6 model and how the different aspects of liver damage can be assessed. First, the serum levels of markers indicating hepatocyte destruction, such as aminotransferases, as well as the titers of hCYP2D6 antibodies are determined by sampling blood retroorbitaly (section 2). Second, the hCYP2D6-specific T cell response is characterized by collecting lymphocytes from the spleen and the liver. In order to obtain pure liver lymphocytes, the livers are perfused by PBS via the portal vein (section 3), digested in collagen and purified over a Percoll gradient (section 4). The frequency of hCYP2D6-specific T cells is analyzed by stimulation with hCYP2D6 peptides and identification of IFNγ-producing cells by flow cytometry (section 5). Third, cellular infiltration and fibrosis is determined by immunohistochemistry of liver sections (section 6). Such analysis regimen has to be conducted at several times after initiation of the disease in order to prove the chronic nature of the model. The magnitude of the immune response characterized by the frequency and activity of hCYP2D6-specific T and/or B cells and the degree of the liver damage and fibrosis have to be assessed for a subsequent evaluation of possible treatments to prevent, delay or abrogate the autodestructive process of the liver

Morgawr: an experimental Bronze Age-type sewn-plank craft based on the Ferriby boats

Photographs and a link to a video showing the construction and launch of "Morgawr" can also be found in ORE: http://hdl.handle.net/10871/14703This paper reports on the construction of a full-scale Bronze Age-type sewn-plank boat based on the Ferriby boats. The boat, which was named Morgawr, was constructed in the National Maritime Museum Cornwall in Falmouth, England, during 2012 and the first months of 2013, as part of a larger exhibition in the museum. This paper provides the background and context of the project, describes the process of building the craft, and reflects in particular on differences between Morgawr and the ‘hypothetical reconstruction of a complete sewn-plank boat’ published in 1990 by Ted Wright and John Coates which formed the basis for this project.Arts and Humanities Research Council (AHRC

Antigenic Mimicry in Paraneoplastic Immune Thrombocytopenia

International audienceThe association of immune thrombocytopenia (ITP) with cancer has been reported, but the causality of tumor cells in paraneoplastic ITP pathogenesis and maintenance has never been established. We analyzed the unusual case of refractory ITP and coincident urothelial tumor of the kidney with circulating high titer anti-GPIIBIIIA autoantibodies. Intriguingly, after nephrectomy, the patient recovered fully and her anti-GPIIBIIIA autoantibodies disappeared. Proteomic and immunohistochemistry analyses revealed erratic GPIIB expression by the tumor cells, suggesting possible antigenic mimicry chronically stimulating the immune system and leading to this patient's refractory ITP. Such previously unreported findings provide proof-of-concept that requires further confirmation with the prospective study of a larger number of patients

Der Einfluss von mentalem Durchspielen zukünftiger Bedrohungen auf Aspekte der Zukunftsbewältigung

Die Grundidee der Studie basiert auf einer Pandemiesimulation, die Teilnehmende vor der Corona-Pandemie durchführten und in Anschluss daran rückmeldeten, sie würden sich mental vorbereiteter fühlen. Das mentale Durchspielen von bedrohlichen Zukunftssituationen scheinen einen positiven Effekt auf die Zukunftsbewältigung zu haben, dies zeigen auch Studien zum mentalen Kontrastieren. Es zeigt sich auch, dass Ziele eher erreicht werden, wenn sich die Personen nicht nur mit der damit verbundene Wunschzukunft, sondern auch mit den damit verbundenen Hindernissen auseinandersetzen. Das Antizipieren einer negativen Zukunft kann einen positiven Effekt auf die Emotionsregulation haben. Auf Basis dieser Erkenntnisse wird untersucht, ob das mentale Durchspielen einer zukünftigen Bedrohungssituation anhand der WOOP-Methode zu einer Verbesserung der Zukunftsfähigkeit führt. Die Zukunftsfähigkeit wird in dieser Studie mithilfe der Variablen Hoffnung, Kontrollüberzeugung und Challenge- vs. Threat-Wahrnehmung operationalisiert

Der Einfluss von mentalem Durchspielen zukünftiger Bedrohungen auf Aspekte der Zukunftsbewältigung

Die Grundidee der Studie basiert auf einer Pandemiesimulation, die Teilnehmende vor der Corona-Pandemie durchführten und in Anschluss daran rückmeldeten, sie würden sich mental vorbereiteter fühlen. Das mentale Durchspielen von bedrohlichen Zukunftssituationen scheinen einen positiven Effekt auf die Zukunftsbewältigung zu haben, dies zeigen auch Studien zum mentalen Kontrastieren. Es zeigt sich auch, dass Ziele eher erreicht werden, wenn sich die Personen nicht nur mit der damit verbundene Wunschzukunft, sondern auch mit den damit verbundenen Hindernissen auseinandersetzen. Das Antizipieren einer negativen Zukunft kann einen positiven Effekt auf die Emotionsregulation haben. Auf Basis dieser Erkenntnisse wird untersucht, ob das mentale Durchspielen einer zukünftigen Bedrohungssituation anhand der WOOP-Methode zu einer Verbesserung der Zukunftsfähigkeit führt. Die Zukunftsfähigkeit wird in dieser Studie mithilfe der Variablen Hoffnung, Kontrollüberzeugung und Challenge- vs. Threat-Wahrnehmung operationalisiert

From anxiety to approach in the context of climate change

This empirical study tests the general process model of threat and defense in the context of climate change. The model posits that a common affective-motivational mechanism underlies solution strategies related to threats and palliative responses to both solvable and existential threats. Specifically, we systematically investigate the temporal dynamics of anxiety induction in response to climate change threats and the subsequent activation of approach motivation following the implementation of defense strategies. Methodology: Participants are randomly assigned to one of three experimental conditions: collective direct resolution, collective palliation, and a control group. In the collective direct resolution condition, participants are tasked with affirming a pro-environmental group that aligns with their values. Conversely, in the collective palliation condition, participants affirm a group not inherently pro-environmental but still in alignment with their values. The control group is instructed to describe daily routines. Hypotheses: We expect that participants across both the direct resolution and palliation groups will experience an immediate surge in anxiety following exposure to climate change threat. Activation of Approach Motivation Distally Following Defense Implementation: We anticipate that after the threat, participants in both the direct resolution and palliation groups will exhibit heightened approach-related affect indicative of an activated approach motivation, following the implementation of their respective defense strategies

Der Einfluss von mentalem Durchspielen zukünftiger Bedrohungen auf Aspekte der Zukunftsbewältigung

Die Grundidee der Studie basiert auf einer Pandemiesimulation, die Teilnehmende vor der Corona-Pandemie durchführten und in Anschluss daran rückmeldeten, sie würden sich mental vorbereiteter fühlen. Das mentale Durchspielen von bedrohlichen Zukunftssituationen scheinen einen positiven Effekt auf die Zukunftsbewältigung zu haben, dies zeigen auch Studien zum mentalen Kontrastieren. Es zeigt sich auch, dass Ziele eher erreicht werden, wenn sich die Personen nicht nur mit der damit verbundene Wunschzukunft, sondern auch mit den damit verbundenen Hindernissen auseinandersetzen. Das Antizipieren einer negativen Zukunft kann einen positiven Effekt auf die Emotionsregulation haben. Auf Basis dieser Erkenntnisse wird untersucht, ob das mentale Durchspielen einer zukünftigen Bedrohungssituation anhand der WOOP-Methode zu einer Verbesserung der Zukunftsfähigkeit führt. Die Zukunftsfähigkeit wird in dieser Studie mithilfe der Variablen Hoffnung, Kontrollüberzeugung und Challenge- vs. Threat-Wahrnehmung operationalisiert

From anxiety to approach in the context of climate change

This empirical study tests the general process model of threat and defense in the context of climate change. The model posits that a common affective-motivational mechanism underlies solution strategies related to threats and palliative responses to both solvable and existential threats. Specifically, we systematically investigate the temporal dynamics of anxiety induction in response to climate change threats and the subsequent activation of approach motivation following the implementation of defense strategies. Methodology: Participants are randomly assigned to one of three experimental conditions: collective direct resolution, collective palliation, and a control group. In the collective direct resolution condition, participants are tasked with affirming a pro-environmental group that aligns with their values. Conversely, in the collective palliation condition, participants affirm a group not inherently pro-environmental but still in alignment with their values. The control group is instructed to describe daily routines. Hypotheses: We expect that participants across both the direct resolution and palliation groups will experience an immediate surge in anxiety following exposure to climate change threat. Activation of Approach Motivation Distally Following Defense Implementation: We anticipate that after the threat, participants in both the direct resolution and palliation groups will exhibit heightened approach-related affect indicative of an activated approach motivation, following the implementation of their respective defense strategies