Role of HNF4α-cMyc Interaction in CDE Diet-Induced Liver Injury and Regeneration.

Hepatocyte nuclear factor 4 alpha (HNF4α) is a nuclear factor essential for liver function that regulates the expression of cMyc and plays an important role during liver regeneration. This study investigated the role of the HNF4α-cMyc interaction in regulating liver injury and regeneration using the choline-deficient and ethionine-supplemented (CDE) diet model. Wild-type (WT), hepatocyte-specific HNF4α-knockout (KO), cMyc-KO, and HNF4α-cMyc double KO (DKO) mice were fed a CDE diet for 1 week to induce subacute liver injury. To study regeneration, normal chow diet was fed for 1 week after CDE diet. WT mice exhibited significant liver injury and decreased HNF4α mRNA and protein expression after CDE diet. HNF4α deletion resulted in significantly higher injury with increased inflammation, fibrosis, proliferation, and hepatic progenitor cell activation compared with WT mice after CDE diet but indicated similar recovery. Deletion of cMyc lowered liver injury with activation of inflammatory genes compared with WT and HNF4α-KO mice after CDE diet. DKO mice had a phenotype comparable to that of the HNF4α-KO mice after CDE diet and a complete recovery. DKO mice exhibited a significant increase in hepatic progenitor cell markers both after injury and recovery phase. Taken together, these data show that HNF4α protects against inflammatory and fibrotic changes after CDE diet-induced injury, which is driven by cMyc.

Role of Hepatocyte Nuclear Factor 4 Alpha in Liver Cancer.

Liver cancer is the sixth most common cancer and the fourth leading cause of cancer-related deaths worldwide. Hepatocellular carcinoma (HCC) is the most prevalent primary liver cancer and the incidence of HCC is on the rise. Liver cancers in general and HCC in particular do not respond to chemotherapy. Radiological ablation, surgical resection, and liver transplantation are the only medical therapies currently available. Hepatocyte nuclear factor 4 α (HNF4α) is an orphan nuclear receptor expressed only in hepatocytes in the liver. HNF4α is considered the master regulator of hepatic differentiation because it regulates a significant number of genes involved in various liver-specific functions. In addition to maintaining hepatic differentiation, HNF4α also acts as a tumor suppressor by inhibiting hepatocyte proliferation by suppressing the expression of promitogenic genes and inhibiting epithelial to mesenchymal transition in hepatocytes. Loss of HNF4α expression and function is associated with rapid progression of chronic liver diseases that ultimately lead to liver cirrhosis and HCC, including metabolism-associated steatohepatitis, alcohol-associated liver disease, and hepatitis virus infection. This review summarizes the role of HNF4α in liver cancer pathogenesis and highlights its potential as a potential therapeutic target for HCC.

Role of HNF4alpha-cMyc interaction in liver regeneration and recovery after acetaminophen-induced acute liver injury.

BACKGROUND AND AIMS: Overdose of acetaminophen (APAP) is the major cause of acute liver failure in the western world. We report a novel signaling interaction between hepatocyte nuclear factor 4 alpha (HNF4α) cMyc and nuclear factor erythroid 2-related factor 2 (Nrf2) during liver injury and regeneration after APAP overdose. APPROACH AND RESULTS: APAP-induced liver injury and regeneration were studied in male C57BL/6J (WT) mice, hepatocyte-specific HNF4α knockout mice (HNF4α-KO), and HNF4α-cMyc double knockout mice (DKO). C57BL/6J mice treated with 300 mg/kg maintained nuclear HNF4α expression and exhibited liver regeneration, resulting in recovery. However, treatment with 600-mg/kg APAP, where liver regeneration was inhibited and recovery was delayed, showed a rapid decline in HNF4α expression. HNF4α-KO mice developed significantly higher liver injury due to delayed glutathione recovery after APAP overdose. HNF4α-KO mice also exhibited significant induction of cMyc, and the deletion of cMyc in HNF4α-KO mice (DKO mice) reduced the APAP-induced liver injury. The DKO mice had significantly faster glutathione replenishment due to rapid induction in Gclc and Gclm genes. Coimmunoprecipitation and ChIP analyses revealed that HNF4α interacts with Nrf2 and affects its DNA binding. Furthermore, DKO mice showed significantly faster initiation of cell proliferation resulting in rapid liver regeneration and recovery. CONCLUSIONS: These data show that HNF4α interacts with Nrf2 and promotes glutathione replenishment aiding in recovery from APAP-induced liver injury, a process inhibited by cMyc. These studies indicate that maintaining the HNF4α function is critical for regeneration and recovery after APAP overdose.

Identifying novel mechanisms of per- and polyfluoroalkyl substance-induced hepatotoxicity using FRG humanized mice.

Per- and polyfluoroalkyl substances (PFAS) such as perfluorooctanoic acid (PFOA) and perfluorooctane sulfonic acid (PFOS) and perfluoro-2-methyl-3-oxahexanoic acid (GenX), the new replacement PFAS, are major environmental contaminants. In rodents, these PFAS induce several adverse effects on the liver, including increased proliferation, hepatomegaly, steatosis, hypercholesterolemia, nonalcoholic fatty liver disease and liver cancers. Activation of peroxisome proliferator receptor alpha by PFAS is considered the primary mechanism of action in rodent hepatocyte-induced proliferation. However, the human relevance of this mechanism is uncertain. We investigated human-relevant mechanisms of PFAS-induced adverse hepatic effects using FRG liver-chimeric humanized mice with livers repopulated with functional human hepatocytes. Male FRG humanized mice were treated with 0.067 mg/L of PFOA, 0.145 mg/L of PFOS, or 1 mg/L of GenX in drinking water for 28 days. PFOS caused a significant decrease in total serum cholesterol and LDL/VLDL, whereas GenX caused a significant elevation in LDL/VLDL with no change in total cholesterol and HDL. All three PFAS induced significant hepatocyte proliferation. RNA-sequencing with alignment to the human genome showed a total of 240, 162, and 619 differentially expressed genes after PFOA, PFOS, and GenX exposure, respectively. Upstream regulator analysis revealed that all three PFAS induced activation of p53 and inhibition of androgen receptor and NR1D1, a transcriptional repressor important in circadian rhythm. Further biochemical studies confirmed NR1D1 inhibition and in silico modeling indicated potential interaction of all three PFAS with the DNA-binding domain of NR1D1. In conclusion, our studies using FRG humanized mice have revealed new human-relevant molecular mechanisms of PFAS including their previously unknown effect on circadian rhythm.

Scale-Fractal Detrended Fluctuation Analysis for Fault Diagnosis of a Centrifugal Pump and a Reciprocating Compressor.

Reciprocating compressors and centrifugal pumps are rotating machines used in industry, where fault detection is crucial for avoiding unnecessary and costly downtime. A novel method for fault classification in reciprocating compressors and multi-stage centrifugal pumps is proposed. In the feature extraction stage, raw vibration signals are processed using multi-fractal detrended fluctuation analysis (MFDFA) to extract features indicative of different types of faults. Such MFDFA features enable the training of machine learning models for classifying faults. Several classical machine learning models and a deep learning model corresponding to the convolutional neural network (CNN) are compared with respect to their classification accuracy. The cross-validation results show that all models are highly accurate for classifying the 13 types of faults in the centrifugal pump, the 17 valve faults, and the 13 multi-faults in the reciprocating compressor. The random forest subspace discriminant (RFSD) and the CNN model achieved the best results using MFDFA features calculated with quadratic approximations. The proposed method is a promising approach for fault classification in reciprocating compressors and multi-stage centrifugal pumps.

Evaluation of Hand-Crafted Feature Extraction for Fault Diagnosis in Rotating Machinery: A Survey.

This article presents a comprehensive collection of formulas and calculations for hand-crafted feature extraction of condition monitoring signals. The documented features include 123 for the time domain and 46 for the frequency domain. Furthermore, a machine learning-based methodology is presented to evaluate the performance of features in fault classification tasks using seven data sets of different rotating machines. The evaluation methodology involves using seven ranking methods to select the best ten hand-crafted features per method for each database, to be subsequently evaluated by three types of classifiers. This process is applied exhaustively by evaluation groups, combining our databases with an external benchmark. A summary table of the performance results of the classifiers is also presented, including the percentage of classification and the number of features required to achieve that value. Through graphic resources, it has been possible to show the prevalence of certain features over others, how they are associated with the database, and the order of importance assigned by the ranking methods. In the same way, finding which features have the highest appearance percentages for each database in all experiments has been possible. The results suggest that hand-crafted feature extraction is an effective technique with low computational cost and high interpretability for fault identification and diagnosis.

HIV and COVID-19 in Latin America and the Caribbean.

PURPOSE OF REVIEW: Latin America and the Caribbean (LAC) has been hit hard by COVID-19 due to political instability, flawed health systems, and structural inequalities. The repercussion of the pandemic on vulnerable populations, like people living with HIV (PLWH), is complex. This review aims to explore the interactions between the HIV and COVID-19 pandemics in this region. RECENT FINDINGS: Data regarding the interactions of HIV and COVID-19 in LAC is scarce. Only case reports or small case series have been published regarding the clinical course of COVID-19 in PLWH and regarding the clinical course of COVID-19 in PLWH, which appears to be similar to the general population. The pandemic has disrupted prevention and treatment of PLWH. However, there have been country efforts to counteract those effects. There are some lessons from the HIV response which have been effectively applied in the region to address COVID-19. COVID-19 has had an unprecedented impact on the cascade-of-care among PLWH in LAC. There is a need for longitudinal studies that assess clinic implication of these pandemic interactions in LAC.

Aging with HIV in Latin America and the Caribbean: a Systematic Review.

PURPOSE OF REVIEW: With the establishment of antiretroviral treatment (ART) programs in low- and middle-income countries, people with HIV (PWH) in Latin America and the Caribbean (LAC) are living longer, subsequently developing chronic non-communicable diseases (NCDs). Few studies focus on the impact of aging among older LAC PWH. This systematic review aims to fill this information gap and understand the burden of aging with HIV in LAC. We identified peer-reviewed literature published in English, Spanish, or Portuguese from several databases to assess currently available evidence on the burden of aging with HIV in LAC and selected six common NCDs found in older PWH (cardiovascular disease [CVD], bone and musculoskeletal [MSK] disorders, cancer, renal disease, neurocognitive impairment [NCI], and depression). RECENT FINDINGS: Of the 5942 publications reviewed, only 53 articles were found with populations 40 years and older or age-related findings (27 CVD, 13 NCI or depression, 6 MSK disorders, 4 renal disease, 3 cancer). Most (79%) publications were from Brazil with few longitudinal studies on aging with HIV. Prevalence of illnesses such as CVD, NCI, depression, or osteoporosis varied widely depending on the screening instrument utilized and geographic population surveyed. Age was a significant predictor of comorbidity in nearly all studies. Our results demonstrate the need for longitudinal studies and validated screening instruments appropriate for use among PWH in LAC. Understanding the mechanisms behind aging in HIV and the roles of sociocultural factors and genetic diversity specific to LAC is needed to appropriately manage chronic comorbidities as PWH age.

Generative Transfer Learning for Intelligent Fault Diagnosis of the Wind Turbine Gearbox.

Intelligent fault diagnosis algorithms based on machine learning and deep learning techniques have been widely used in industrial applications and have obtained much attention as well as achievements. In real industrial applications, working loads of machines are always changing. Hence, directly applying the traditional algorithms will cause significant degradation of performance with changing conditions. In this paper, a novel domain adaptation method, named generative transfer learning (GTL), is proposed to tackle this problem. First, raw datasets were transformed to time-frequency domain based on short-time Fourier transformation. A domain discriminator was then built to distinguish whether the data came from the source or the target domain. A target domain classification model was finally acquired by the feature extractor and the classifier. Experiments were carried out for the fault diagnosis of a wind turbine gearbox. The t-distributed stochastic neighbor embedding technique was used to visualize the output features for checking the effectiveness of the proposed algorithm in feature extraction. The results showed that the proposed GTL could improve classification rates under various working loads. Compared with other domain adaptation algorithms, the proposed method exhibited not only higher accuracy but faster convergence speed as well.

Chemistry, Biological Activities and In Silico Bioprospection of Sterols and Triterpenes from Mexican Columnar Cactaceae.

The Cactaceae family is an important source of triterpenes and sterols. The wide uses of those plants include food, gathering, medicinal, and live fences. Several studies have led to the isolation and characterization of many bioactive compounds. This review is focused on the chemistry and biological properties of sterols and triterpenes isolated mainly from some species with columnar and arborescent growth forms of Mexican Cactaceae. Regarding the biological properties of those compounds, apart from a few cases, their molecular mechanisms displayed are not still fully understand. To contribute to the above, computational chemistry tools have given a boost to traditional methods used in natural products research, allowing a more comprehensive exploration of chemistry and biological activities of isolated compounds and extracts. From this information an in silico bioprospection was carried out. The results suggest that sterols and triterpenoids present in Cactaceae have interesting substitution patterns that allow them to interact with some bio targets related to inflammation, metabolic diseases, and neurodegenerative processes. Thus, they should be considered as attractive leads for the development of drugs for the management of chronic degenerative diseases.

Synthesis and antioxidant activity of new lipophilic dihydropyridines.

Dihydropyridines (DHPs) obtained from Hantzsch multicomponent reactions are an important pharmaceutical class of compounds marketed as antihypertensive (e.g., nifedipine, nitrendipine, and amlodipine) drugs. This study synthesized new symmetrical and unsymmetrical long-chain fatty DHPs using multicomponent reactions under metal-free conditions with sulfamic acid as a catalyst. The DHPs were tested for antioxidant activity using three different methods. The insertion of a long chain into the DHP core contributed to antioxidant potential, and compounds derived from nitro aldehydes have better antioxidant potential than the antihypertensive drug nifedipine. In addition, fatty analogs to nifedipine derived from palmitic and oleic chains showed similar antioxidant activity to the common standards butylated hydroxytoluene and vitamin E. These results showed that our new synthesized products may find novel applications as antioxidant additives or for tools for use in drug discovery.

UCT943, a Next-Generation Plasmodium falciparum PI4K Inhibitor Preclinical Candidate for the Treatment of Malaria.

The 2-aminopyridine MMV048 was the first drug candidate inhibiting Plasmodium phosphatidylinositol 4-kinase (PI4K), a novel drug target for malaria, to enter clinical development. In an effort to identify the next generation of PI4K inhibitors, the series was optimized to improve properties such as solubility and antiplasmodial potency across the parasite life cycle, leading to the 2-aminopyrazine UCT943. The compound displayed higher asexual blood stage, transmission-blocking, and liver stage activities than MMV048 and was more potent against resistant Plasmodium falciparum and Plasmodium vivax clinical isolates. Excellent in vitro antiplasmodial activity translated into high efficacy in Plasmodium berghei and humanized P. falciparum NOD-scid IL-2Rγ null mouse models. The high passive permeability and high aqueous solubility of UCT943, combined with low to moderate in vivo intrinsic clearance, resulted in sustained exposure and high bioavailability in preclinical species. In addition, the predicted human dose for a curative single administration using monkey and dog pharmacokinetics was low, ranging from 50 to 80 mg. As a next-generation Plasmodium PI4K inhibitor, UCT943, based on the combined preclinical data, has the potential to form part of a single-exposure radical cure and prophylaxis (SERCaP) to treat, prevent, and block the transmission of malaria.

Potent Plasmodium falciparum gametocytocidal compounds identified by exploring the kinase inhibitor chemical space for dual active antimalarials.

Objectives: Novel chemical tools to eliminate malaria should ideally target both the asexual parasites and transmissible gametocytes. Several imidazopyridazines (IMPs) and 2-aminopyridines (2-APs) have been described as potent antimalarial candidates targeting lipid kinases. However, these have not been extensively explored for stage-specific inhibition of gametocytes in Plasmodium falciparum parasites. Here we provide an in-depth evaluation of the gametocytocidal activity of compounds from these chemotypes and identify novel starting points for dual-acting antimalarials. Methods: We evaluated compounds against P. falciparum gametocytes using several assay platforms for cross-validation and stringently identified hits that were further profiled for stage specificity, speed of action and ex vivo efficacy. Physicochemical feature extraction and chemogenomic fingerprinting were applied to explore the kinase inhibition susceptibility profile. Results: We identified 34 compounds with submicromolar activity against late stage gametocytes, validated across several assay platforms. Of these, 12 were potent at <100 nM (8 were IMPs and 4 were 2-APs) and were also active against early stage gametocytes and asexual parasites, with >1000-fold selectivity towards the parasite over mammalian cells. Front-runner compounds targeted mature gametocytes within 48 h and blocked transmission to mosquitoes. The resultant chemogenomic fingerprint of parasites treated with the lead compounds revealed the importance of targeting kinases in asexual parasites and gametocytes. Conclusions: This study encompasses an in-depth evaluation of the kinase inhibitor space for gametocytocidal activity. Potent lead compounds have enticing dual activities and highlight the importance of targeting the kinase superfamily in malaria elimination strategies.

Morpho-physiological characteristics by sweet potato cultivars as function of irrigation depth.

The sweet potato is an alternative energy source, but its sustainability depends on efficient water use. The objective of this study was to evaluate sweet potato morpho-physiological characteristics, and water use efficiency (WUE). Irrigation depths of 50, 75, 100, and 125% of crop evapotranspiration (ETc) were applied. The morpho-physiological indicators, WUE, leaf area index (LAI), leaf water potential, leaf temperature, and leaf chlorophyll index (ICF), were evaluated. The WUE of the sweet potato cultivars increased until the 75% water depth of the ETc. The LAI of these cultivars increased with irrigation depth, with higher values at 100% of the ETc. The leaf water potential of the two sweet potato cultivars was lowest with the lower irrigation depth. Leaf temperature was closer to that of ambient temperatures in treatments with greater irrigation depth. The increase of the WUE with the greater accumulation of dry biomass is due to greater CO2 diffusion by stomata. The reduction in the growth of these plants is due to water stress limiting stomatal conductance, transpiration, leaf growth (LAI) and chlorophyll concentration, proportional to soil moisture conditions. The functional relationship between soil moisture and growth is essential to optimize irrigation management at different growth stages.

Facile Formation of Redox-Active Totally Organic Nanoparticles in Water by In Situ Reduction of Organic Precursors Stabilized through Aromatic-Aromatic Interactions by Aromatic Polyelectrolytes.

The formation of redox-active, totally organic nanoparticles in water is achieved following a strategy similar to that used to form metal nanoparticles. It is based on two fundamental concepts: i) complexation through aromatic-aromatic interactions of a water-soluble precursor aromatic molecule with polyelectrolytes bearing complementary charged aromatic rings, and ii) reduction of the precursor molecule to achieve stabilized nanoparticles. Thus, formazan nanoparticles are synthesized by reduction of a tetrazolium salt with ascorbic acid using polyelectrolytes bearing benzene sulfonate residues of high linear aromatic density, but cannot be formed in the presence of nonaromatic polyelectrolytes. The red colored nanoparticles are efficiently encapsulated in calcium alginate beads, showing macroscopic homogeneity. Bleaching kinetics with chlorine show linear rates on the order of tenths of milli-meters per minute. A linear behavior of the dependence of the rate of bleaching on the chlorine concentration is found, showing the potential of the nanoparticles for chlorine sensing.

Fault Diagnosis for Rotating Machinery Using Vibration Measurement Deep Statistical Feature Learning.

Fault diagnosis is important for the maintenance of rotating machinery. The detection of faults and fault patterns is a challenging part of machinery fault diagnosis. To tackle this problem, a model for deep statistical feature learning from vibration measurements of rotating machinery is presented in this paper. Vibration sensor signals collected from rotating mechanical systems are represented in the time, frequency, and time-frequency domains, each of which is then used to produce a statistical feature set. For learning statistical features, real-value Gaussian-Bernoulli restricted Boltzmann machines (GRBMs) are stacked to develop a Gaussian-Bernoulli deep Boltzmann machine (GDBM). The suggested approach is applied as a deep statistical feature learning tool for both gearbox and bearing systems. The fault classification performances in experiments using this approach are 95.17% for the gearbox, and 91.75% for the bearing system. The proposed approach is compared to such standard methods as a support vector machine, GRBM and a combination model. In experiments, the best fault classification rate was detected using the proposed model. The results show that deep learning with statistical feature extraction has an essential improvement potential for diagnosing rotating machinery faults.

Multi-Stage Feature Selection by Using Genetic Algorithms for Fault Diagnosis in Gearboxes Based on Vibration Signal.

There are growing demands for condition-based monitoring of gearboxes, and techniques to improve the reliability, effectiveness and accuracy for fault diagnosis are considered valuable contributions. Feature selection is still an important aspect in machine learning-based diagnosis in order to reach good performance in the diagnosis system. The main aim of this research is to propose a multi-stage feature selection mechanism for selecting the best set of condition parameters on the time, frequency and time-frequency domains, which are extracted from vibration signals for fault diagnosis purposes in gearboxes. The selection is based on genetic algorithms, proposing in each stage a new subset of the best features regarding the classifier performance in a supervised environment. The selected features are augmented at each stage and used as input for a neural network classifier in the next step, while a new subset of feature candidates is treated by the selection process. As a result, the inherent exploration and exploitation of the genetic algorithms for finding the best solutions of the selection problem are locally focused. The Sensors 2015, 15 23904 approach is tested on a dataset from a real test bed with several fault classes under different running conditions of load and velocity. The model performance for diagnosis is over 98%.

Structure-activity relationship studies of antiplasmodial aminomethylthiazoles.

Structure-activity relationship (SAR) studies around a previously reported antimalarial aminomethylthiazole pyrazole carboxamide 1 are reported. Several analogues were synthesised and profiled for in vitro antiplasmodial activity against the drug-sensitive Plasmodium falciparum malaria parasite strain, NF54. Although all the reported analogues exhibited inferior in vitro antiplasmodial activity (IC50 = 0.125-173 µM) relative to compound 1 (IC50 = 0.0203 µM), one analogue, compound 5a, retained submicromolar activity (IC50 = 0.125 µM).

Analysis of the Physicochemical Properties of Anti-Schistosomal Compounds to Identify Next-Generation Leads.

To investigate the physicochemical properties of anti-schistosomal compounds reported between 2008 and 2023, a simple but extensive literature scrutiny was conducted. Keywords were searched in Chemical Abstracts Service (CAS) SciFinder and primary medicinal chemistry and pharmacology literature to locate publications with compounds displaying ex vivo and/or in vivo anti-schistosomal activity. A total of 57 repurposed U.S. Food and Drug Administration (FDA)-approved drugs, hits and their derivatives were manually extracted, curated and compared to known anti-schistosomal oral drugs in view of establishing trends of calculated critical molecular properties. From this analysis, it was determined that more than 65% of the compounds display cLogD7.4 > 3 values, whereas oxamniquine, metrifonate and praziquantel (PZQ), previous and currently used oral anti-schistosomal drugs, possess lower cLogD7.4 values (≤2.5). Furthermore, the lipophilicity associated with PZQ corresponds to a highly permeable and sparingly soluble compound, characteristics that favor drug absorption and compound penetration in the parasite. These physicochemical properties together with PZQ's anti-schistosomal activity make PZQ an essential medicine for the treatment of schistosomiasis and demonstrate the importance of finding the right balance among potency (e.g., EC50 < 5 and 0.5 µM), cell permeability (e.g., Papp > 2 × 106 cm/s) and kinetic aqueous solubility (e.g., >10 µM) to provide high-quality hits and/or leads for the discovery of new oral anti-schistosomal therapeutics.

Role of HNF4alpha-cMyc interaction in liver regeneration after partial hepatectomy.

Background: Hepatocyte nuclear factor 4 alpha (HNF4α) is the master regulator of hepatic differentiation. Recent studies have also revealed the role of HNF4α in hepatocyte proliferation via negatively regulating the expression of proto-mitogenic genes, including cMyc. Here, we aimed to study the interaction between HNF4α-cMyc during liver regeneration after partial hepatectomy (PHX). Methods: Wild-type (WT), hepatocyte-specific knockout of HNF4α (HNF4α-KO), cMyc (cMyc-KO), and HNF4α-cMyc double knockout (DKO) mice were subjected to PHX to induce liver regeneration. Blood and liver tissue samples were collected at 0h, 24h, 48h, 7D, and 14D after PHX for further analysis. Results: WT, HNF4α-KO, cMyc-KO and DKO mice regained liver weight by 14 days after PHX. The deletion of cMyc did not affect liver regeneration, which was similar to the WT mice. WT and cMyc-KO mice started regaining liver weight as early as 24 hours after PHX, with a peak proliferation response at 48 hours after PHX. HNF4α- KO and DKO showed a delayed response with liver weight increase by day 7 after PHX. The overall hepatocyte proliferation response by DKO mice following PHX was lower than that of other genotypes. Interestingly, the surviving HNF4α-KO and DKO mice showed re-expression of HNF4α at mRNA and protein levels on day 14 after PHX. This was accompanied by a significant increase in the expression of Krt19 and Epcam, hepatic progenitor cell markers, in the DKO mice on day 14 after PHX. Conclusion: These data indicate that, in the absence of HNF4α, cMyc contributes to hepatocyte-driven proliferation to compensate for the lost tissue mass. Furthermore, in the absence of both HNF4α and cMyc, HPC-driven proliferation occurs to support liver regeneration.