Finite-time erasing of information stored in fermionic bits

We address the issue of minimizing the heat generated when erasing the information stored in an array of quantum dots in finite time. We identify the fundamental limitations and trade-offs involved in this process and analyze how a feedback operation can help improve it

IGF2 mRNA Binding Protein 2 Transgenic Mice Are More Prone to Develop a Ductular Reaction and to Progress Toward Cirrhosis

The insulin-like growth factor 2 (IGF2) mRNA binding proteins (IMPs/IGF2BPs) IMP1 and 3 are regarded as oncofetal proteins, whereas the hepatic IMP2 expression in adults is controversially discussed. The splice variant IMP2-2/p62 promotes steatohepatitis and hepatocellular carcinoma. Aim of this study was to clarify whether IMP2 is expressed in the adult liver and influences progression toward cirrhosis. IMP2 was expressed at higher levels in embryonic compared to adult tissues as quantified in embryonic, newborn, and adult C57BL/6J mouse livers and suggested by analysis of publicly available human data. In an IMP2-2 transgenic mouse model microarray and qPCR analyses revealed increased expression of liver progenitor cell (LPC) markers Bex1, Prom1, Spp1, and Cdh1 indicating a de-differentiated liver cell phenotype. Induction of these LPC markers was confirmed in human cirrhotic tissue datasets. The LPC marker SPP1 has been described to play a major role in fibrogenesis. Thus, DNA methylation was investigated in order to decipher the regulatory mechanism of Spp1 induction. In IMP2-2 transgenic mouse livers single CpG sites were differentially methylated, as quantified by amplicon sequencing, whereas human HCC samples of a human publicly available dataset showed promoter hypomethylation. In order to study the impact of IMP2 on fibrogenesis in the context of steatohepatitis wild-type or IMP2-2 transgenic mice were fed either a methionine-choline deficient (MCD) or a control diet for 2-12 weeks. MCD-fed IMP2-2 transgenic mice showed a higher incidence of ductular reaction (DR), accompanied by hepatic stellate cell activation, extracellular matrix (ECM) deposition, and induction of the LPC markers Spp1, Cdh1, and Afp suggesting the occurrence of de-differentiated cells in transgenic livers. In human cirrhotic samples IMP2 overexpression correlated with LPC marker and ECM component expression. Progression of liver disease was induced by combined MCD and diethylnitrosamine (DEN) treatment. Combined MCD-DEN treatment resulted in shorter survival of IMP2-2 transgenic compared to wild-type mice. Only IMP2-2 transgenic livers progressed to cirrhosis, which was accompanied by strong DR. In conclusion, IMP2 is an oncofetal protein in the liver that promotes DR characterized by de-differentiated cells toward steatohepatitis-associated cirrhosis development with poor survival

Macrophage Depletion Attenuates Extracellular Matrix Deposition and Ductular Reaction in a Mouse Model of Chronic Cholangiopathies.

Chronic cholangiopathies, such as primary and secondary sclerosing cholangitis, are progressive disease entities, associated with periportal accumulation of inflammatory cells, encompassing monocytes and macrophages, peribiliary extracellular matrix (ECM) deposition and ductular reaction (DR). This study aimed to elucidate the relevance of macrophages in the progression of chronic cholangiopathies through macrophage depletion in a 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) mouse model. One group of mice received a single i.p. injection of Clodronate encapsulated liposomes (CLOLipo) at day 7 of a 14 day DDC treatment, while control animals were co-treated with PBSLipo instead. Mice were sacrificed after 7 or respectively 14 days of treatment for immunohistochemical assessment of macrophage recruitment (F4/80), ECM deposition (Sirius Red, Laminin) and DR (CK19). Macrophage depletion during a 14 day DDC treatment resulted in a significant inhibition of ECM deposition. Porto-lobular migration patterns of laminin-rich ECM and ductular structures were significantly attenuated and a progression of DR was effectively inhibited by macrophage depletion. CLOLipo co-treatment resulted in a confined DR to portal regions without amorphous cell clusters. This study suggests that therapeutic options selectively directed towards macrophages might represent a feasible treatment for chronic cholestatic liver diseases

Spatial Transcriptomics to define transcriptional patterns of zonation and structural components in the mouse liver

Reconstruction of heterogeneity through single cell transcriptional profiling has greatly advanced our understanding of the spatial liver transcriptome in recent years. However, global transcriptional differences across lobular units remain elusive in physical space. Here, we apply Spatial Transcriptomics to perform transcriptomic analysis across sectioned liver tissue. We confirm that the heterogeneity in this complex tissue is predominantly determined by lobular zonation. By introducing novel computational approaches, we enable transcriptional gradient measurements between tissue structures, including several lobules in a variety of orientations. Further, our data suggests the presence of previously transcriptionally uncharacterized structures within liver tissue, contributing to the overall spatial heterogeneity of the organ. This study demonstrates how comprehensive spatial transcriptomic technologies can be used to delineate extensive spatial gene expression patterns in the liver, indicating its future impact for studies of liver function, development and regeneration as well as its potential in pre-clinical and clinical pathology. Global transcriptional differences across lobular units in the liver remain unknown. Here the authors perform spatial transcriptomics of liver tissue to delineate transcriptional differences in physical space, confirm lobular zonation along transcriptional gradients and suggest the presence of previously uncharacterized structures within liver tissue

DUCT reveals architectural mechanisms contributing to bile duct recovery in a mouse model for Alagille syndrome

Organ function depends on tissues adopting the correct architecture. However, insights into organ architecture are currently hampered by an absence of standardized quantitative 3D analysis. We aimed to develop a robust technology to visualize, digitalize, and segment the architecture of two tubular systems in 3D: double resin casting micro computed tomography (DUCT). As proof of principle, we applied DUCT to a mouse model for Alagille syndrome (Jag1Ndr/Ndr mice), characterized by intrahepatic bile duct paucity, that can spontaneously generate a biliary system in adulthood. DUCT identified increased central biliary branching and peripheral bile duct tortuosity as two compensatory processes occurring in distinct regions of Jag1Ndr/Ndr liver, leading to full reconstitution of wild-type biliary volume and phenotypic recovery. DUCT is thus a powerful new technology for 3D analysis, which can reveal novel phenotypes and provide a standardized method of defining liver architecture in mouse models

DDC diet induces biliary damage in mice.

<p>(A) Bilirubin and ALT serum levels were measured from control animals and after 7 and 14 days of DDC-diet with a clinical chemistry module. (B, C) Liver sections of control animals and mice subjected to DDC-Diet for 7 and 14 days were stained with HE, anti-F4/80 Ab, anti-CK19 Ab, Sirius Red and anti- Laminin Ab as described in material and methods. All images were taken in 40x original magnification. The percentage of F4/80-, CK19-, PicroSirius- and Laminin -positive area per field was assessed as described in detail in materials and methods section. All data are presented as mean ± SEM for n = 5/group, *p<0.05 and ***p<0.001.</p

Macrophage depletion attenuates activation of myofibroblast like cells and preserves a type I ductular reaction in DDC fed mice.

<p>(A) Bilirubin and ALT serum levels were measured from control animals and mice subjected to a 14 day DDC diet in co-treatment with either CLO^Lipo or PBS^Lipo at experimental day 7. (B) Liver sections were stained with HE, anti-F4/80 Ab, anti-CK19 Ab, Sirius Red, anti-Laminin Ab and anti-alpha-Sma Ab as described in material and methods. All single stained images were taken in 20x, original magnification. Orange arrow indicate irregular CK19⁺ cell clusters migrating from the portal tract into parenchyma or porto-portal (Type II DR). The percentage of F4/80-, CK19-, Sirius red-, Laminin- and αSma- positive area per field was assessed as described in materials and methods. All data are presented as mean ± SEM for n = 5/group. *p<0.05, **p<0.01, ***p<0.001.</p

Overall amount of laminin matrix deposition and maximum migration distance of CK19 positive cell clusters is positively correlated.

<p>(A) Liver sections of control animals and mice subjected to a 14 day DDC-Diet in co-treatment with either CLO^Lipo or PBS^Lipo at experimental day 7, were co-stained with CK19/Laminin to assess the correlation between CK19⁺ cell clusters and ECM. (B) Positive correlation between overall amount of laminin matrix deposition. (C) Maximum migration distance of CK19⁺ cell clusters from the portal vicinity into the lobule. All stainings and quantifications were performed as described in materials and methods. All data are presented as mean ± SEM for n = 5/group, *p<0.05 and ***p<0.001.</p

Under macrophage depletion proliferation of CK19 positive ductules in the portal region is inhibited.

<p>(A) Liver sections of the same mouse collective were co-stained with CK19/Ki67 to visualize the proliferation index. All images were taken in 40x original magnification. PV = Portal vein. White arrow indicating porphyrin deposition. (B) To quantify the proliferation index, the quantity of Ki 67-positive cells/field was determined. (C) To obtain the extent of apoptosis, TUNEL stainings were carried out (<b><a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0162286#pone.0162286.s008" target="_blank">S8 Fig</a>)</b> and the amount of TUNEL pos. cells per field was quantified. All stainings and quantifications were performed as described in materials and methods. All data are presented as mean ± SEM for n = 5/group, ***p<0.001.</p