Background and Aims
Hepatocytes undergo profound metabolic rewiring when primed to proliferate during compensatory regeneration and in hepatocellular carcinoma (HCC). However, the metabolic control ...of these processes is not fully understood. In order to capture the metabolic signature of proliferating hepatocytes, we applied state‐of‐the‐art systems biology approaches to models of liver regeneration, pharmacologically and genetically activated cell proliferation, and HCC.
Approach and Results
Integrating metabolomics, lipidomics, and transcriptomics, we link changes in the lipidome of proliferating hepatocytes to altered metabolic pathways including lipogenesis, fatty acid desaturation, and generation of phosphatidylcholine (PC). We confirm this altered lipid signature in human HCC and show a positive correlation of monounsaturated PC with hallmarks of cell proliferation and hepatic carcinogenesis.
Conclusions
Overall, we demonstrate that specific lipid metabolic pathways are coherently altered when hepatocytes switch to proliferation. These represent a source of targets for the development of therapeutic strategies and prognostic biomarkers of HCC.
Considerable promise and excitement exist in the application of environmental DNA (eDNA) methods to environmental monitoring and species inventories as eDNA can provide cost‐effective and accurate ...biodiversity information. However, considerable variation in data quality, rigor, and reliability has eroded confidence in eDNA application and is limiting regulatory and policy uptake. Substantial effort has gone into promoting transparency in reporting and deriving standardized frameworks and methods for eDNA field workflow components, but surprisingly little scrutiny has been given to the design and performance elements of targeted eDNA detection assays which, by far, have been most used in the scientific literature. There are several methods used for eDNA detection. The most accessible, cost‐effective, and conducive to standards development is targeted real‐time or quantitative real‐time polymerase chain reaction (abbreviated as qPCR) eDNA analysis. The present perspective is meant to assist in the development and evaluation of qPCR‐based eDNA assays. It evaluates six steps in the qPCR‐based eDNA assay development and validation workflow identifying and addressing concerns pertaining to poor qPCR assay design and implementation; identifies the need for more fulsome mitochondrial genome sequence information for a broader range of species; and brings solutions toward best practices in forthcoming large‐scale and worldwide eDNA applications, such as at‐risk or invasive species assessments and site remediation monitoring.
The present perspective is meant to assist in the development and evaluation of targeted real‐time or quantitative real‐time polymerase chain reaction (qPCR)‐based eDNA assays. It evaluates six steps in the qPCR‐based eDNA assay development and validation workflow identifying and addressing concerns pertaining to poor qPCR assay design and implementation; identifies the need for more fulsome mitochondrial genome sequence information for a broader range of species; and brings solutions toward best practices in forthcoming large‐scale and worldwide eDNA applications, such as at‐risk or invasive species assessments and site remediation monitoring.
Infection with the novel 2019 coronavirus (SARS-CoV-2) is associated with the development of a viral pneumonia with severe hypoxemia and respiratory failure. In many cases these patients will require ...mechanical ventilation; but in others the severity of disease is significantly less and may not need invasive support. High flow nasal cannula (HFNC) is a widely used modality of delivering high concentrations of oxygen and airflow to patients with hypoxemic respiratory failure, but its use in patients with SARS-CoV-2 is poorly described. Concerns with use of HFNC have arisen including aerosolization of viral particles to healthcare workers (HCW) to delaying intubation and potentially worsening of outcomes. However, use of HFNC in other coronavirus pandemics and previous experimental evidence suggest HFNC is low risk and may be effective in select patients infected with SARS-CoV-2. With the significant increase in resource utilization in care of patients with SARS-CoV-2, identification of those that may benefit from HFNC allowing allocation of ventilators to those more critically ill is of significant importance. In this manuscript, we review pertinent literature regarding the use of HFNC in the current SARS-CoV-2 pandemic and address many concerns regarding its use.
Nonalcoholic fatty liver disease (NAFLD) can progress from simple steatosis (i.e., nonalcoholic fatty liver NAFL) to nonalcoholic steatohepatitis (NASH), cirrhosis, and cancer. Currently, the driver ...for this progression is not fully understood; in particular, it is not known how NAFLD and its early progression affects the distribution of lipids in the liver, producing lipotoxicity and inflammation. In this study, we used dietary and genetic mouse models of NAFL and NASH and translated the results to humans by correlating the spatial distribution of lipids in liver tissue with disease progression using advanced mass spectrometry imaging technology. We identified several lipids with distinct zonal distributions in control and NAFL samples and observed partial to complete loss of lipid zonation in NASH. In addition, we found increased hepatic expression of genes associated with remodeling the phospholipid membrane, release of arachidonic acid (AA) from the membrane, and production of eicosanoid species that promote inflammation and cell injury. The results of our immunohistochemistry analyses suggest that the zonal location of remodeling enzyme LPCAT2 plays a role in the change in spatial distribution for AA‐containing lipids. This results in a cycle of AA‐enrichment in pericentral hepatocytes, membrane release of AA, and generation of proinflammatory eicosanoids and may account for increased oxidative damage in pericentral regions in NASH. Conclusion: NAFLD is associated not only with lipid enrichment, but also with zonal changes of specific lipids and their associated metabolic pathways. This may play a role in the heterogeneous development of NAFLD. (Hepatology 2017;65:1165‐1180)
Bile chemistry during normothermic ex situ liver perfusion (NESLiP) has been suggested to be an indicator of cholangiopathy. The normal range of biochemical variables in bile of livers undergoing ...NESLiP has not been defined, nor have published biliary viability criteria been assessed against instances of posttransplant nonanastomotic bile strictures (NASs).
The bile and perfusate chemistry of 200 livers undergoing NESLiP between February 1, 2018, and October 30, 2023, was compared. In addition, 11 livers that underwent NESLiP and later developed NAS were selected and their bile chemistry was also examined.
In livers that did not develop cholangiopathy, concentrations of sodium, potassium, and chloride were slightly higher in bile than in perfusate, whereas the concentration of calcium was slightly lower. Bile was alkali and had a lower glucose concentration than perfusate. Cholangiocyte glucose reabsorption was shown to saturate at high perfusate concentrations and was more impaired in livers donated after circulatory death than in livers donated after brain death. Published criteria failed to identify all livers that went on to develop NASs.
A significant false-negative rate exists with current biliary viability criteria, probably reflecting the patchy and incomplete nature of the development of NASs in the biliary tree. The data presented here provide a benchmark for future assessment of bile duct chemistry during NESLiP.
Non-alcoholic fatty liver disease (NAFLD) is a silent pandemic associated with obesity and the metabolic syndrome, and also increases cardiovascular- and cirrhosis-related morbidity and mortality. A ...complete understanding of adaptive compensatory metabolic programmes that modulate non-alcoholic steatohepatitis (NASH) progression is lacking.
Transcriptomic analysis of liver biopsies in patients with NASH revealed that NASH progression is associated with rewiring of metabolic pathways, including upregulation of de novo lipid/cholesterol synthesis and fatty acid remodelling. The modulation of these metabolic programmes was achieved by activating sterol regulatory element-binding protein (SREBP) transcriptional networks; however, it is still debated whether, in the context of NASH, activation of SREBPs acts as a pathogenic driver of lipotoxicity, or rather promotes the biosynthesis of protective lipids that buffer excessive lipid accumulation, preventing inflammation and fibrosis. To elucidate the pathophysiological role of SCAP/SREBP in NASH and wound-healing response, we used an Insig1 deficient (with hyper-efficient SREBPs) murine model challenged with a NASH-inducing diet. Despite enhanced lipid and cholesterol biosynthesis, Insig1 KO mice had similar systemic metabolism and insulin sensitivity to Het/WT littermates. Moreover, activating SREBPs resulted in remodelling the lipidome, decreased hepatocellular damage, and improved wound-healing responses.
Our study provides actionable knowledge about the pathways and mechanisms involved in NAFLD pathogenesis, which may prove useful for developing new therapeutic strategies. Our results also suggest that the SCAP/SREBP/INSIG1 trio governs transcriptional programmes aimed at protecting the liver from lipotoxic insults in NASH.
•Human NASH biopsies’ transcriptomics analysis features metabolic pathway rewiring.•SCAP/SREBP/INSIG1 modulation promotes lipid/cholesterol synthesis/remodelling in NASH.•Loss of Insig1 promotes lipid remodelling, preventing hepatic lipotoxicity in NASH.•Loss of Insig1 improves liver damage and wound healing and restrains NASH progression.
An optimal immune response should differentiate between harmful and innocuous antigens. Primitive systems of innate immunity, such as the complement system, may play a role in this distinction. When ...activated, the C3 component of complement attaches to potential antigens on microorganisms. To determine whether this alters acquired immune recognition, mice were immunized with a recombinant model antigen, hen egg lysozyme (HEL), fused to murine C3d. HEL bearing two and three copies of C3d was 1000- and 10,000-fold more immunogenic, respectively, than HEL alone. Thus, C3d is a molecular adjuvant of innate immunity that profoundly influences an acquired immune response.
Following the ends to the civil wars in Nicaragua, El Salvador and Guatemala, the revolutionary coalitions that had led the fight against authoritarian regimes began to fracture. However, none of the ...splinter parties that broke from the Sandinista National Liberation Front, Farabundo Martí National Liberation Front, and Guatemalan National Revolutionary Unit has succeeded on their own as political parties. In this article, I argue that there is no single reason to explain the poor performances of the Democratic Party (PD), the Renovating Movement (MR), and the Democratic Front Party (FDR) in El Salvador, the Sandinista Renovation Movement (Renovate-MRS) and the Movement to Rescue Sandinismo (Rescue-MRS) in Nicaragua, and the New Nation Alliance (ANN) in Guatemala. However, their limited financial resources, alliances with non-revolutionary centrist and centre-right parties, and voter tendency to overlook internal ideological and personal debates within the original political parties, especially the FSLN and FMLN, have not helped. Tras el final de las guerras civiles en Nicaragua, El Salvador y Guatemala, las coaliciones revolucionarias que habían encabezado la lucha en contra de los regímenes autoritarios empezaron a fracturarse. Sin embargo, ninguno de los grupos que rompieron con el Frente Sandinista de Liberación Nacional, el Frente Farabundo Martí para la Liberación Nacional y la Unidad Revolucionaria Nacional Guatemalteca ha tenido éxito como partido político. En este artículo señalo que no hay una sola razón para explicar el pobre desempeño del Partido Democrático (PD), el Movimiento Renovador (MR), y el Frente Democrático Revolucionario (FRD) en El Salvador; del Movimiento de Renovación Sandinista (Renovación-MRS) y el Movimiento para el Rescate del Sandinismo (Rescate-MRS) en Nicaragua; y de la Alianza Nueva Nación (ANN) en Guatemala. Sin embargo, sus limitados recursos financieros, sus alianzas con partidos centristas no revolucionarios y de centro-derecha, y la tendencia de los votantes de no fijarse en los debates ideológicos y personales internos en los partidos políticos originales, especialmente del FSLN y el FMLN, no han ayudado en este proceso. Após o término das guerras civis na Nicarágua, em El Salvador e na Guatemala, as coalizões revolucionárias que haviam liderado as lutas de oposição aos regimes autoritários começam a dividir-se. No entanto, nenhum dos partidos surgidos a partir das rupturas com a Frente Sandinista de Liberación Nacional, Frente Farabundo Martí para la Liberación Nacional, e Unidad Revolucionária Nacional Guatemalteca obteve sucesso isoladamente como novo partido político. Neste artigo, argumento que não há nenhuma razão única que explique o fraco desempenho do Partido Democrático (PD), do Movimiento Renovador (MR), e da Frente Democrático Revolucionario (FDR) em El Salvador; do Movimiento de Renovación Sandinista (MRS) e do Movimiento para el Rescate del Sandinismo (MPRS) na Nicarágua; e da Alianza Nueva Nación (ANN) na Guatemala. No entanto, seus recursos financeiros limitados, as alianças com partidos não-revolucionários de tendências centristas e partidos de centro-direita, e a tendência do eleitorado a não levar em consideração debates ideológicos e pessoais dentro dos partidos políticos originais, particularmente o FSLN e FMLN, não ajudaram.
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