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Hepatitis B caused by infection with the hepatitis B virus (HBV) still ranks among the most challenging infectious diseases of our time. Despite the availability of an effective prophylactic vaccine, 240 million people worldwide are estimated to be chronically infected with HBV and are at risk of developing life-threatening liver diseases, including cirrhosis and liver cancer. The underlying pathogenic mechanisms of HBV-associated liver diseases are only incompletely understood. It is widely accepted that liver pathology results from long-term immune-mediated liver injury and inflammation as a consequence of inefficient viral elimination. This injury can be naturally compensated by liver regeneration. However, chronic liver damage and permanent inflammation debilitates the regenerative capacity of the liver and fosters fibrosis as well as accumulation of chromosomal aberrations, which both contribute to cirrhosis and liver cancer. Liver regeneration requires the presence of the redox-sensitive transcription factor Nrf2 and intact insulin receptor signaling. A lack of Nrf2 causes increased intracellular levels of reactive oxygen species (ROS) that inactivate insulin receptor signaling and induce insulin resistance. Interestingly, HBV was observed to activate Nrf2 and the expression of Nrf2-regulated genes. This argues against an inhibitory effect of HBV on insulin receptor signaling by increased ROS levels. However, chronic HBV infection is associated with dysregulation of hepatocyte proliferation and retardation of liver regeneration. Hence, the aim of this thesis was to investigate the influence of HBV on the process of liver regeneration with respect to the insulin receptor signaling pathway. After short-term carbon tetrachloride (CCl4)-induced liver damage, HBV transgenic mice present prolonged liver damage and impaired liver regeneration as reflected by reduced hepatocyte proliferation and increased apoptosis. Impaired hepatocyte proliferation in HBV transgenic mice correlates with diminished activation of the insulin receptor. It was further observed in vitro that the activation of Nrf2 by HBV induces increased levels of the insulin receptor mRNA and protein in HBV-expressing cells. Strikingly, stably HBV-expressing cells as well as primary mouse hepatocytes from HBV transgenic mice bind less insulin due to reduced amounts of insulin receptor on the cell surface. This is caused by intracellular retention of the insulin receptor in HBV-expressing cells as a consequence of increased amounts of the cellular trafficking factor α-taxilin. The reduced amounts of insulin receptor on the cell surface impair insulin sensitivity in HBV-expressing cells and inactivate downstream signaling cascades that initiate insulin-dependent gene expression and glucose uptake. As a consequence of impaired hepatocyte proliferation and liver regeneration, HBV transgenic mice exhibit increased development of fibrosis after long-term CCl4-induced liver damage. Taken together, in this thesis, a novel pathomechanism could be uncovered that includes inactivation of insulin receptor signaling by HBV via intracellular retention of the insulin receptor leading to impaired liver regeneration after liver damage and promotion of liver fibrosis. These findings significantly contribute to an enhanced understanding of HBV-associated liver pathogenesis.
The first evaluation of an ultra-high granularity digital electromagnetic calorimeter prototype using 1.0–5.8 GeV/c electrons is presented. The 25 × 106 pixel detector consists of 24 layers of ALPIDE CMOS MAPS sensors, with a pitch of around 30 μm, and has a depth of almost 20 radiation lengths of tungsten absorber. Ultra-thin cables allow for a very compact design. The properties that are critical for physics studies are measured: electromagnetic shower response, energy resolution and linearity. The stochastic energy resolution is comparable with the state-of-the art resolution for a Si-W calorimeter, with data described well by a simulation model using Geant4 and Allpix2. The performance achieved makes this technology a good candidate for use in the ALICE FoCal upgrade, and in general demonstrates the strong potential for future applications in high-energy physics.
A prototype of a new type of calorimeter has been designed and constructed, based on a silicon-tungsten sampling design using pixel sensors with digital readout. It makes use of the Alpide MAPS sensor developed for the ALICE ITS upgrade. A binary readout is possible due to the pixel size of ≈30×30μm2. This prototype has been successfully tested with cosmic muons and with test beams at DESY and the CERN SPS. We report on performance results obtained at DESY, showing good energy resolution and linearity, and compare to detailed MC simulations. Also shown are preliminary results of the high-energy performance as measured at the SPS. The two-shower separation capabilities are discussed.
The first evaluation of an ultra-high granularity digital electromagnetic calorimeter prototype using 1.0-5.8 GeV/c electrons is presented. The 25×106 pixel detector consists of 24 layers of ALPIDE CMOS MAPS sensors, with a pitch of around 30~μm, and has a depth of almost 20 radiation lengths of tungsten absorber. Ultra-thin cables allow for a very compact design. The properties that are critical for physics studies are measured: electromagnetic shower response, energy resolution and linearity. The stochastic energy resolution is comparable with the state-of-the art resolution for a Si-W calorimeter, with data described well by a simulation model using GEANT and Allpix2. The performance achieved makes this technology a good candidate for use in the ALICE FoCal upgrade, and in general demonstrates the strong potential for future applications in high-energy physics.
The first evaluation of an ultra-high granularity digital electromagnetic calorimeter prototype using 1.0-5.8 GeV/c electrons is presented. The 25×106 pixel detector consists of 24 layers of ALPIDE CMOS MAPS sensors, with a pitch of around 30~μm, and has a depth of almost 20 radiation lengths of tungsten absorber. Ultra-thin cables allow for a very compact design. The properties that are critical for physics studies are measured: electromagnetic shower response, energy resolution and linearity. The stochastic energy resolution is comparable with the state-of-the art resolution for a Si-W calorimeter, with data described well by a simulation model using GEANT and Allpix2. The performance achieved makes this technology a good candidate for use in the ALICE FoCal upgrade, and in general demonstrates the strong potential for future applications in high-energy physics.
The first evaluation of an ultra-high granularity digital electromagnetic calorimeter prototype using 1.0-5.8 GeV/c electrons is presented. The 25×106 pixel detector consists of 24 layers of ALPIDE CMOS MAPS sensors, with a pitch of around 30~μm, and has a depth of almost 20 radiation lengths of tungsten absorber. Ultra-thin cables allow for a very compact design. The properties that are critical for physics studies are measured: electromagnetic shower response, energy resolution and linearity. The stochastic energy resolution is comparable with the state-of-the art resolution for a Si-W calorimeter, with data described well by a simulation model using GEANT and Allpix2. The performance achieved makes this technology a good candidate for use in the ALICE FoCal upgrade, and in general demonstrates the strong potential for future applications in high-energy physics.
The first evaluation of an ultra-high granularity digital electromagnetic calorimeter prototype using 1.0-5.8 GeV/c electrons is presented. The 25×106 pixel detector consists of 24 layers of ALPIDE CMOS MAPS sensors, with a pitch of around 30~μm, and has a depth of almost 20 radiation lengths of tungsten absorber. Ultra-thin cables allow for a very compact design. The properties that are critical for physics studies are measured: electromagnetic shower response, energy resolution and linearity. The stochastic energy resolution is comparable with the state-of-the art resolution for a Si-W calorimeter, with data described well by a simulation model using GEANT and Allpix2. The performance achieved makes this technology a good candidate for use in the ALICE FoCal upgrade, and in general demonstrates the strong potential for future applications in high-energy physics.