Molecular Regulation of Maternal Hepatic Adaptations to Pregnancy

Indiana University-Purdue University Indianapolis (IUPUI)The maternal liver exhibits robust adaptations to pregnancy to accommodate the metabolic needs of developing and growing placenta and fetus by largely unknown mechanisms. We found that achaete-scute homolog 1 (Ascl1), a basic helix-loop-helix transcription factor essential for neuronal development, is highly activated in maternal hepatocytes during the second half of gestation in mice. Our aim is to investigate whether and how Ascl1 plays a pregnancy-dependent role. We deleted the Ascl1 gene in the maternal liver using three independent mouse models from mid-gestation until term and identified multiple Ascl1-dependent phenotypes. When Ascl1 was deficient in maternal hepatocytes, maternal livers exhibited aberrant hepatocyte histology, fat accumulation, increased hepatocyte cell cycle, and enlarged size, accompanied by reduced albumin production and elevated levels of free fatty acids, ALT, and AST in the maternal blood, indicating maternal liver dysfunction. In the same situation, maternal spleen and pancreas displayed marked enlargement without an overt structural change; the placenta exhibited striking overgrowth with increased ALP production; and the cecal microbiome showed alterations in the relative abundance of several bacterial subpopulations. Moreover, litters born from maternal hepatic Ascl1 null mutated dam experienced abnormal postnatal growth after weaning. RNA-seq analysis revealed Ascl1-regulated genes in the maternal liver associated with Ascl1-dependent phenotypes. Of particular interest, we found that, in maternal hepatocytes, Ascl1 loss-of-function caused the activation of paternally imprinted gene insulin-like growth factor 2 (Igf2) encoding a major placental and fetal growth factor. IGF2 is also a known mitogen for hepatocytes and several hematopoietic lineages. Thus, IGF2 is a potential inducer of Ascl1-dependent phenotypes including placental overgrowth and maternal organ enlargement. Our studies revealed Ascl1 as a novel regulator of maternal liver physiology during pregnancy. Ascl1 activation in maternal hepatocytes is essential for normal placental growth and appropriate maternal organ adaptations, ensuring the health of both the mother and the fetus

Limits to Continuity of Unsaturated, Compacted Soils

Geotechnical engineers are interested in flow phenomena of unsaturated soils, as they play an important role in interpreting the stability and deformation of slopes, retaining walls, and pavements under unsaturated conditions. Fundamental material characteristics of flow phenomena such as soil-water retention curve (SWRC), which is required to define the driving potential for the flow process, and hydraulic conductivity function (HCF), which is required to define the resistance to the flow process, are still primary concerns for characterizing the flow phenomena in unsaturated soils. Characterizing the SWRC and the HCF in flow phenomena of unsaturated soils is a challenge for many researchers even though the several measurement techniques have been proposed.A flow pump system (FPS) was developed in early 1990 at the University of Colorado in order to characterize unsaturated soils. FPS has been improved over the past 20 years for characterizing the flow phenomena of unsaturated soils, and the new FPS technique is developed for measuring the suction response and SWRC induced by the flow pump during drying and wetting cycles. And, HCF is evaluated by using an inverse problem solution approach.Three materials such as a uniform sand and well graded soils are used in this study for investigating flow phenomena in unsaturated soils. The following conclusions are drawn from the research result. The prediction models commonly used for HCF cannot properly represent the actual hydraulic conductivity of unsaturated soils. The results also show that the liquid-phase flow of pore water stops at relatively high degree of saturation and low suction. The threshold saturation and corresponding hydraulic conductivity values are difficult to determine for each material, and this confirms the hypothesis that hydraulic conductivity for unsaturated soils must be determined through careful experimentation and that no prediction model is valid for all soils. This research developed an adequate methodology to conduct such experiments straightforward, and paved a rational way to predict suction changes in soils due to environmental conditions

Coal fired power plant water chemistry issues: Amine selection at supercritical conditions and sodium leaching from ion exchange mixed beds

Scope and Method of Study: This study evaluated thermal degradation kinetics of neutralizing amines in steam cycle coal fired power plants operating supercritical conditions as functions of temperature and pressure. The loading amounts of amines into the reaction tube were evaluated by vapor liquid equilibrium (VLE) data from NIST database and the temperature ramp up and down inside tube was applied for evaluation of Arrhenius constants.Findings and Conclusions: Thermal degradation of neutralizing amines over a range of supercritical temperature (300-600ºC) and pressure (1000-5000 psia) in laboratory scale and found no clear preference based on degradation rates since all neutralizing amines are not stable at high temperature. Ammonia, acetic acid and formic acid were the main thermal degradation byproducts of all selected neutralizing amines and unknown nitrogen complexes beside ammonia were expected from the nitrogen balance. Thermal degradation was dominated by temperature significantly; however pressure effect has an even weak influence on the degradation at the higher temperature. 5AP shows the slowest thermal degradation rate however it is still highly reactive. Hence, no neutralizing amine tested is acceptable for use at supercritical operating conditions

Keap1 modulates the redox cycle and hepatocyte cell cycle in regenerating liver

Keap1 negatively controls the activity of transcription factor Nrf2. This Keap1/Nrf2 pathway plays a critical role in combating oxidative stress. We aimed at determining whether and how Keap1 modulates the cell cycle of replicating hepatocytes during liver regeneration. Two-thirds partial hepatectomy (PH) was performed on wild-type mice and Keap1+/- (Keap1 knockdown) mice. We found that, following PH, Keap1 knockdown resulted in a delay in S-phase entry, disruption of S-phase progression, and loss of mitotic rhythm of replicating hepatocytes. These events are associated with dysregulation of c-Met, EGFR, Akt1, p70S6K, Cyclin A2, and Cyclin B1 in regenerating livers. Astonishingly, normal regenerating livers exhibited the redox fluctuation coupled with hepatocyte cell cycle progression, while keeping Nrf2 quiescent. Keap1 knockdown caused severe disruption in both the redox cycle and the cell cycle of replicating hepatocytes. Thus, we demonstrate that Keap1 is a potent regulator of hepatic redox cycle and hepatocyte cell cycle during liver regeneration

Surgical Repair of Giant Right Atrial Aneurysm in a Neonate

Right atrial aneurysm is an extremity rare congenital heart defect. We report a case which was diagnosed during the early fetal stage and operated on in a 2 week old neonate. Following median sternotomy, aneurysmectomy was performed under a cardiopulmonary bypass. Histopathological examination of the resected atiral tissue showed a lipotomatous degeneration and reduction of the muscular elements. There were no postoperative complications

Presence of Foxp3-expressing CD19(+)CD5(+) B Cells in Human Peripheral Blood Mononuclear Cells: Human CD19(+)CD5(+)Foxp3(+) Regulatory B Cell (Breg)

Foxp3 is a transcript factor for regulatory T cell development. Interestingly, Foxp3-expressing cells were identified in B cells, especially in CD19(+)CD5(+) B cells, while those were not examined in CD19(+)CD5(-) B cells. Foxp3-expressing CD5(+) B cells in this study were identified in human PBMCs and were found to consist of 8.5±3.5% of CD19(+)CD5(+) B cells. CD19(+)CD5(+)Foxp3(+) B cells showed spontaneous apoptosis. Rare CD19(+)CD5(+) Foxp3(+) regulatory B cell (Breg) population was unveiled in human peripheral blood mononuclear cells and suggested as possible regulatory B cells (Breg) as regulatory T cells (Treg). The immunologic and the clinical relevant of Breg needs to be further investigated

Nuclear Factor Erythroid 2-Related Factor 2 Deficiency Results in Amplification of the Liver Fat-Lowering Effect of Estrogen

Transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) regulates multiple biologic processes, including hepatic lipid metabolism. Estrogen exerts actions affecting energy homeostasis, including a liver fat-lowering effect. Increasing evidence indicates the crosstalk between these two molecules. The aim of this study was to evaluate whether Nrf2 modulates estrogen signaling in hepatic lipid metabolism. Nonalcoholic fatty liver disease (NAFLD) was induced in wild-type and Nrf2-null mice fed a high-fat diet and the liver fat-lowering effect of exogenous estrogen was subsequently assessed. We found that exogenous estrogen eliminated 49% and 90% of hepatic triglycerides in wild-type and Nrf2-null mice with NAFLD, respectively. This observation demonstrates that Nrf2 signaling is antagonistic to estrogen signaling in hepatic fat metabolism; thus, Nrf2 absence results in striking amplification of the liver fat-lowering effect of estrogen. In addition, we found the association of trefoil factor 3 and fatty acid binding protein 5 with the liver fat-lowering effect of estrogen. In summary, we identified Nrf2 as a novel and potent inhibitor of estrogen signaling in hepatic lipid metabolism. Our finding may provide a potential strategy to treat NAFLD by dually targeting Nrf2 and estrogen signaling

Nrf2 is essential for timely M phase entry of replicating hepatocytes during liver regeneration

The transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) regulates various cellular activities, including redox balance, detoxification, metabolism, autophagy, proliferation, and apoptosis. Several studies have demonstrated that Nrf2 regulates hepatocyte proliferation during liver regeneration. The aim of this study was to investigate how Nrf2 modulates the cell cycle of replicating hepatocytes in regenerating livers. Wild-type and Nrf2 null mice were subjected to 2/3 partial hepatectomy (PH) and killed at multiple time points for various analyses. Nrf2 null mice exhibited delayed liver regrowth, although the lost liver mass was eventually restored 7 days after PH. Nrf2 deficiency did not affect the number of hepatocytes entering the cell cycle but did delay hepatocyte mitosis. Mechanistically, the lack of Nrf2 resulted in increased mRNA and protein levels of hepatic cyclin A2 when the remaining hepatocytes were replicating in response to PH. Moreover, Nrf2 deficiency in regenerating livers caused dysregulation of Wee1, Cdc2, and cyclin B1 mRNA and protein expression, leading to decreased Cdc2 activity. Thus, Nrf2 is required for timely M phase entry of replicating hepatocytes by ensuring proper regulation of cyclin A2 and the Wee1/Cdc2/cyclin B1 pathway during liver regeneration

Activation of Proneuronal Transcription Factor Ascl1 in Maternal Liver Ensures a Healthy Pregnancy

Background & aims: Maternal liver shows robust adaptations to pregnancy to accommodate the metabolic needs of the developing and growing placenta and fetus by largely unknown mechanisms. We found that Ascl1, a gene encoding a basic helix-loop-helix transcription factor essential for neuronal development, is highly activated in maternal hepatocytes during the second half of gestation in mice. Methods: To investigate whether and how Ascl1 plays a pregnancy-dependent role, we deleted the Ascl1 gene specifically in maternal hepatocytes from midgestation until term. Results: As a result, we identified multiple Ascl1-dependent phenotypes. Maternal livers lacking Ascl1 showed aberrant hepatocyte structure, increased hepatocyte proliferation, enlarged hepatocyte size, reduced albumin production, and increased release of liver enzymes, indicating maternal liver dysfunction. Simultaneously, maternal pancreas and spleen and the placenta showed marked overgrowth; and the maternal ceca microbiome showed alterations in relative abundance of several bacterial subpopulations. Moreover, litters born from maternal hepatic Ascl1-deficient dams experienced abnormal postnatal growth after weaning, implying an adverse pregnancy outcome. Mechanistically, we found that maternal hepatocytes deficient for Ascl1 showed robust activation of insulin-like growth factor 2 expression, which may contribute to the Ascl1-dependent phenotypes widespread in maternal and uteroplacental compartments. Conclusions: In summary, we show that maternal liver, via activating Ascl1 expression, modulates the adaptations of maternal organs and the growth of the placenta to maintain a healthy pregnancy. Our studies show that Ascl1 is a novel and critical regulator of the physiology of pregnancy

IL-10 is Predominantly Produced by CD19(low)CD5(+) Regulatory B Cell Subpopulation: Characterisation of CD19 (high) and CD19(low) Subpopulations of CD5(+) B cells

IL-10 production by CD19(+)CD5(+) B cells was investigated, by determining the expression levels of CD19, a classical B cell marker. Peripheral mononuclear cells were stained with fluorescence-conjugated anti-CD5, anti-CD19, anti-IL-10, and Annexin V. Interestingly, IL-10-producing B cells were found to be localised within the CD19(low)CD5(+) B cell subset. Apoptotic changes were also observed mainly in CD19(low) cells among B cells. Thus, CD5(+) B cells should be classified as CD19(high) and CD19(low) cells, and the immunological significance of CD19 for the IL-10 production by CD5(+) B cells requires further studies