Absent expansion of AXIN2+ hepatocytes and altered physiology in Axin2CreERT2 mice challenges the role of pericentral hepatocytes in homeostatic liver regeneration

Background & Aims: Mouse models of lineage tracing have helped to describe the important subpopulations of hepatocytes responsible for liver regeneration. However, conflicting results have been obtained from different models. Herein, we aimed to reconcile these conflicting reports by repeating a key lineage-tracing study from pericentral hepatocytes and characterising this Axin2CreERT2 model in detail. Methods: We performed detailed characterisation of the labelled population in the Axin2CreERT2 model. We lineage traced this cell population, quantifying the labelled population over 1 year and performed in-depth phenotypic comparisons, including transcriptomics, metabolomics and analysis of proteins through immunohistochemistry, of Axin2CreERT2 mice to WT counterparts. Results: We found that after careful definition of a baseline population, there are marked differences in labelling between male and female mice. Upon induced lineage tracing there was no expansion of the labelled hepatocyte population in Axin2CreERT2 mice. We found substantial evidence of disrupted homeostasis in Axin2CreERT2 mice. Offspring are born with sub-Mendelian ratios and adult mice have perturbations of hepatic Wnt/β-catenin signalling and related metabolomic disturbance. Conclusions: We find no evidence of predominant expansion of the pericentral hepatocyte population during liver homeostatic regeneration. Our data highlight the importance of detailed preclinical model characterisation and the pitfalls which may occur when comparing across sexes and backgrounds of mice and the effects of genetic insertion into native loci. Impact and implications: Understanding the source of cells which regenerate the liver is crucial to harness their potential to regrow injured livers. Herein, we show that cells which were previously thought to repopulate the liver play only a limited role in physiological regeneration. Our data helps to reconcile differing conclusions drawn from results from a number of prior studies and highlights methodological challenges which are relevant to preclinical models more generally

Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death 2018.

Over the past decade, the Nomenclature Committee on Cell Death (NCCD) has formulated guidelines for the definition and interpretation of cell death from morphological, biochemical, and functional perspectives. Since the field continues to expand and novel mechanisms that orchestrate multiple cell death pathways are unveiled, we propose an updated classification of cell death subroutines focusing on mechanistic and essential (as opposed to correlative and dispensable) aspects of the process. As we provide molecularly oriented definitions of terms including intrinsic apoptosis, extrinsic apoptosis, mitochondrial permeability transition (MPT)-driven necrosis, necroptosis, ferroptosis, pyroptosis, parthanatos, entotic cell death, NETotic cell death, lysosome-dependent cell death, autophagy-dependent cell death, immunogenic cell death, cellular senescence, and mitotic catastrophe, we discuss the utility of neologisms that refer to highly specialized instances of these processes. The mission of the NCCD is to provide a widely accepted nomenclature on cell death in support of the continued development of the field

Effect of litigation risk on management forecasts

Thesis: S.M. in Management Research, Massachusetts Institute of Technology, Sloan School of Management, 2018.Cataloged from PDF version of thesis.Includes bibliographical references (pages 29-32).I examine the link between changes in the disclosure behavior of firms and changes in ex ante litigation risk as proxied by changes in the firms' director and officer insurance premiums. I find evidence that there is a negative link between the voluntary disclosure of bad news and ex ante litigation risk. I find no evidence of a statistically significant link between the voluntary disclosure of good news and ex ante litigation risk.by William A. Powley.S.M. in Management Researc

Examination of pulmonary benzene metabolism

Benzene is an occupational hazard and environmental toxicant. The main concern for humans is acute myelogenous leukemia with limited evidence to suggest lung cancer may result. The toxic effects of benzene are dependent on its metabolism by cytochrome P450. Most physiologically based pharmacokinetic models assume that benzene is metabolized only by CYP2E1 and only in liver. However, the accuracy of these models in predicting metabolism is questionable, especially following inhalation exposure. Two main hypotheses were tested. The first was that cytochrome P450 isozymes other than CYP2E1 are involved in benzene metabolism. The second was that the lung is capable of metabolizing benzene in an in vivo simulation. Studies using specific chemical inhibitors of CYP2E1, CYP2B, and CYP2F in microsomal preparations indicate that CYP2E1 is the P450 isozyme primarily responsible for benzene metabolism to phenol, hydroquinone, and catechol in the livers of mice, rats, and humans. CYP2F plays an important role in pulmonary benzene metabolism in all species examined, while CYP2E1 is of slightly lesser importance. These conclusions were confirmed by the finding of very low metabolic activity in CYP2E1 knockout mice compared to wild-type mice. This study also showed that while CYP2E1 is the most important cytochrome P450 isozyme in the liver, it was only responsible for ∼50% of pulmonary benzene metabolism. In the metabolism of phenol, a benzene metabolite, the use of specific chemical inhibitors showed that CYP2E1 is responsible for ∼50% of hepatic and pulmonary metabolism. The remaining hepatic activity is not due to the action of CYP2F2 or CYP2B. However, CYP2F2 is important in pulmonary metabolism of phenol. The use of CYP2E1 knockout and wild-type mice show that CYP2E1 is not the only cytochrome P450 isozyme involved in phenol metabolism by hepatic or pulmonary microsomes. These results are consistent with the results of the specific chemical inhibitor study. Further evidence of the lung\u27s importance in benzene metabolism was demonstrated in isolated perfused rodent lung experiments. Benzene was metabolized in rats during exposure via the pulmonary vasculature and mice during both exposure via the pulmonary vasculature and inhalation

Calculating the exclusion probability and paternity index for X-chromosomal loci in the presence of substructure

There has been recent interest in the use of X-chromosomal loci for forensic and relatedness testing casework, with many authors developing new X-linked short tandem repeat (STR) loci suitable for forensic use. Here we present formulae for two key quantities in paternity testing, the average probability of exclusion and the paternity index, which are suitable for Xchromosomal loci in the presence of population substructure