Hepatitis B Virus Increases SphK1-S1P Synthesis by Promoting the Availability of the Transcription Factor USF1.

Hepatitis B virus (HBV) is the most common chronic viral infection globally, affecting ∼360 million people and causing about 1 million deaths annually due to end-stage liver disease or hepatocellular carcinoma. Current antiviral treatments rarely achieve a functional cure for chronic hepatitis B, highlighting the need for improved monitoring and intervention strategies. This study explores the role of the sphingosine kinase 1 (SphK1)-sphingosine-1-phosphate (S1P) axis in HBV-related liver injury. We investigated the association between serum S1P concentration and HBV DNA levels in chronic hepatitis B patients, finding a significant positive correlation. Additionally, SphK1 was elevated in liver tissues of HBV-positive hepatocellular carcinoma patients, particularly in HBsAg-positive regions. HBV infection models in HepG2-sodium taurocholate cotransporting polypeptide cells confirmed that HBV enhances SphK1 expression and S1P production. Inhibition of HBV replication through antiviral agents and the CRISPR-Cas9 system reduced SphK1 and S1P levels. Further, we identified the transcription factor USF1 as a key regulator of SphK1 expression during HBV infection. USF1 binds to the SphK1 promoter, increasing its transcriptional activity, and is upregulated in response to HBV infection. In vivo studies in mice demonstrated that HBV exposure promotes the expression of USF1 and SphK1-S1P. These findings suggest that the SphK1-S1P axis, regulated by HBV-induced USF1, could serve as a potential biomarker and therapeutic target for HBV-related liver injury.

Entanglement of two quantum memories via fibres over dozens of kilometres.

A quantum internet that connects remote quantum processors1,2 should enable a number of revolutionary applications such as distributed quantum computing. Its realization will rely on entanglement of remote quantum memories over long distances. Despite enormous progress3-12, at present the maximal physical separation achieved between two nodes is 1.3 kilometres10, and challenges for longer distances remain. Here we demonstrate entanglement of two atomic ensembles in one laboratory via photon transmission through city-scale optical fibres. The atomic ensembles function as quantum memories that store quantum states. We use cavity enhancement to efficiently create atom-photon entanglement13-15 and we use quantum frequency conversion16 to shift the atomic wavelength to telecommunications wavelengths. We realize entanglement over 22 kilometres of field-deployed fibres via two-photon interference17,18 and entanglement over 50 kilometres of coiled fibres via single-photon interference19. Our experiment could be extended to nodes physically separated by similar distances, which would thus form a functional segment of the atomic quantum network, paving the way towards establishing atomic entanglement over many nodes and over much longer distances.

Molecular basis of locus-specific H3K9 methylation catalyzed by SUVH6 in plants.

Dimethylated histone H3 Lys9 (H3K9me2) is a conserved heterochromatic mark catalyzed by SUPPRESSOR OF VARIEGATION 3-9 HOMOLOG (SUVH) methyltransferases in plants. However, the mechanism underlying the locus specificity of SUVH enzymes has long been elusive. Here, we show that a conserved N-terminal motif is essential for SUVH6-mediated H3K9me2 deposition in planta. The SUVH6 N-terminal peptide can be recognized by the bromo-adjacent homology (BAH) domain of the RNA- and chromatin-binding protein ANTI-SILENCING 1 (ASI1), which has been shown to function in a complex to confer gene expression regulation. Structural data indicate that a classic aromatic cage of ASI1-BAH domain specifically recognizes an arginine residue of SUVH6 through extensive hydrogen bonding interactions. A classic aromatic cage of ASI1 specifically recognizes an arginine residue of SUVH6 through extensive cation-π interactions, playing a key role in recognition. The SUVH6-ASI1 module confers locus-specific H3K9me2 deposition at most SUVH6 target loci and gives rise to distinct regulation of gene expression depending on the target loci, either conferring transcriptional silencing or posttranscriptional processing of mRNA. More importantly, such mechanism is conserved in multiple plant species, indicating a coordinated evolutionary process between SUVH6 and ASI1. In summary, our findings uncover a conserved mechanism for the locus specificity of H3K9 methylation in planta. These findings provide mechanistic insights into the delicate regulation of H3K9 methylation homeostasis in plants.

High-Entropy Magnet Enabling Distinctive Thermal Expansions in Intermetallic Compounds.

The high-entropy strategy has gained increasing popularity in the design of functional materials due to its four core effects. In this study, we introduce the concept of a "high-entropy magnet (HEM)", which integrates diverse magnetic compounds within a single phase and is anticipated to demonstrate unique magnetism-related properties beyond that of its individual components. This concept is exemplified in AB2-type layered Kagome intermetallic compounds (Ti,Zr,Hf,Nb,Fe)Fe2. It is revealed that the competition among individual magnetic states and the presence of magnetic Fe in originally nonmagnetic high-entropy sites lead to intricate magnetic transitions with temperature. Consequently, unusual transformations in thermal expansion property (from positive to zero, negative, and back to near zero) are observed. Specifically, a near-zero thermal expansion is achieved over a wide temperature range (10-360 K, αv = -0.62 × 10-6 K-1) in the A-site equal-atomic ratio (Ti1/5Zr1/5Hf1/5Nb1/5Fe1/5)Fe2 compound, which is associated with successive deflection of average Fe moments. The HEM strategy holds promise for discovering new functionalities in solid materials.

Single-Shot Readout of a Nuclear Spin in Silicon Carbide.

Solid-state qubits with a photonic interface is very promising for quantum networks. Color centers in silicon carbide have shown excellent optical and spin coherence, even when integrated with membranes and nanostructures. Additionally, nuclear spins coupled with electron spins can serve as long-lived quantum memories. Pioneering work previously has realized the initialization of a single nuclear spin and demonstrated its entanglement with an electron spin. In this Letter, we report the first realization of single-shot readout for a nuclear spin in SiC. We obtain a deterministic nuclear spin initialization and readout fidelity of 94.95% with a measurement duration of 1 ms. With a dual-step readout scheme, we obtain a readout fidelity as high as 99.03% within 0.28 ms by sacrificing the success efficiency. Our Letter complements the experimental toolbox of harnessing both electron and nuclear spins in SiC for future quantum networks.

Twin-Field Quantum Key Distribution with Local Frequency Reference.

Twin-field quantum key distribution (TFQKD) overcomes the linear rate-loss limit, which promises a boost of secure key rate over long distance. However, the complexity of eliminating the frequency differences between the independent laser sources hinders its practical application. We analyzed and determined the frequency stability requirements for implementing TFQKD using frequency-stabilized lasers. Based on this analysis, we proposed and demonstrated a simple and practical approach that utilizes the saturated absorption spectroscopy of acetylene as an absolute reference, eliminating the need for fast frequency locking to achieve TFQKD. Adopting the 4-intensity sending-or-not-sending TFQKD protocol, we experimentally demonstrated the TFQKD over 502, 301, and 201 km ultralow-loss optical fiber, respectively. We expect this high-performance scheme will find widespread usage in future intercity and free-space quantum communication networks.

Experimental Generation of Spin-Photon Entanglement in Silicon Carbide.

A solid-state approach for quantum networks is advantageous, as it allows the integration of nanophotonics to enhance the photon emission and the utilization of weakly coupled nuclear spins for long-lived storage. Silicon carbide, specifically point defects within it, shows great promise in this regard due to the easy of availability and well-established nanofabrication techniques. Despite of remarkable progresses made, achieving spin-photon entanglement remains a crucial aspect to be realized. In this Letter, we experimentally generate entanglement between a silicon vacancy defect in silicon carbide and a scattered single photon in the zero-phonon line. The spin state is measured by detecting photons scattered in the phonon sideband. The photonic qubit is encoded in the time-bin degree of freedom and measured using an unbalanced Mach-Zehnder interferometer. Photonic correlations not only reveal the quality of the entanglement but also verify the deterministic nature of the entanglement creation process. By harnessing two pairs of such spin-photon entanglement, it becomes straightforward to entangle remote quantum nodes at long distance.

Quantum Light Generation Based on GaN Microring toward Fully On-Chip Source.

An integrated quantum light source is increasingly desirable in large-scale quantum information processing. Despite recent remarkable advances, a new material platform is constantly being explored for the fully on-chip integration of quantum light generation, active and passive manipulation, and detection. Here, for the first time, we demonstrate a gallium nitride (GaN) microring based quantum light generation in the telecom C-band, which has potential toward the monolithic integration of quantum light source. In our demonstration, the GaN microring has a free spectral range of 330 GHz and a near-zero anomalous dispersion region of over 100 nm. The generation of energy-time entangled photon pair is demonstrated with a typical raw two-photon interference visibility of 95.5±6.5%, which is further configured to generate a heralded single photon with a typical heralded second-order autocorrelation g_{H}^{(2)}(0) of 0.045±0.001. Our results pave the way for developing a chip-scale quantum photonic circuit.

New strategies to study in depth the metabolic mechanism of astaxanthin biosynthesis in Phaffia rhodozyma.

Astaxanthin, a ketone carotenoid known for its high antioxidant activity, holds significant potential for application in nutraceuticals, aquaculture, and cosmetics. The increasing market demand necessitates a higher production of astaxanthin using Phaffia rhodozyma. Despite extensive research efforts focused on optimizing fermentation conditions, employing mutagenesis treatments, and utilizing genetic engineering technologies to enhance astaxanthin yield in P. rhodozyma, progress in this area remains limited. This review provides a comprehensive summary of the current understanding of rough metabolic pathways, regulatory mechanisms, and preliminary strategies for enhancing astaxanthin yield. However, further investigation is required to fully comprehend the intricate and essential metabolic regulation mechanism underlying astaxanthin synthesis. Specifically, the specific functions of key genes, such as crtYB, crtS, and crtI, need to be explored in detail. Additionally, a thorough understanding of the action mechanism of bifunctional enzymes and alternative splicing products is imperative. Lastly, the regulation of metabolic flux must be thoroughly investigated to reveal the complete pathway of astaxanthin synthesis. To obtain an in-depth mechanism and improve the yield of astaxanthin, this review proposes some frontier methods, including: omics, genome editing, protein structure-activity analysis, and synthetic biology. Moreover, it further elucidates the feasibility of new strategies using these advanced methods in various effectively combined ways to resolve these problems mentioned above. This review provides theory and method for studying the metabolic pathway of astaxanthin in P. rhodozyma and the industrial improvement of astaxanthin, and provides new insights into the flexible combined use of multiple modern advanced biotechnologies.

Gut-Derived Trimethylamine N-Oxide Promotes CCR2-Mediated Macrophage Infiltration in acute kidney injury.

BACKGROUND: Inflammation is crucial in the development of AKI and subsequent CKD following renal ischemia-reperfusion (IR) injury. Gut microbiota metabolites trigger inflammation and affect IR-induced renal damage. Yet, the driving factors and mechanisms are unclear. Trimethylamine N-oxide (TMAO), a gut-derived choline metabolite, is a strong pro-inflammatory factor that increases in patients with AKI and CKD. We hypothesized that TMAO can promote renal injury caused by IR. METHODS: Mice subjected to unilateral renal IR to induce AKI and CKD were fed a high-choline diet to observe the effects of TMAO on kidney inflammation, fibrosis, and macrophage dynamics. RESULTS: A choline-rich diet altered the gut microbiota and elevated TMAO levels, which exacerbated IR-induced AKI and subsequent CKD. Single-cell analysis identified a distinct subset of CCR2+ macrophages derived from monocytes as key responders to TMAO, intensifying immune cell interactions and worsening renal injury. TMAO promoted sustained CCR2 expression after IR, increasing macrophage infiltration. CCR2 deletion and antagonist RS-102895 improved TMAO-induced inflammation and fibrosis, alleviated renal injury induced by IR. CONCLUSIONS: Our study provides valuable insights into the link between TMAO and IR-incited renal inflammation and fibrosis, emphasizing the critical role of TMAO-mediated macrophage infiltration via CCR2 as a key therapeutic target in the acute and chronic phase after IR.

Water rights trading planning and its application in water resources management: A water-ecology-food nexus perspective.

Nexus approach provides an effective perspective for implementing synergetic management of water resources. In this study, an interval two-stage chance-constrained water rights trading planning model under water-ecology-food nexus perspective (ITCWR-WEF) is proposed to analyze the interaction between water trading and water-ecology-food (WEF) nexus, which fills in the water resources management gaps from a novel nexus perspective. ITCWR-WEF incorporates hydrological simulation with soil and water assessment tool (SWAT), water rights configuration with interval two-stage chance-constrained programming (ITCP), and multi-criterion analysis with Technique for Order Preference by Similarity to an Ideal Solution (TOPSIS). The developed ITCWR-WEF is applied to a real case of Daguhe watershed, which has characteristics of water scarcity, food producing areas and fragile ecosystem. Initial water rights allocation is addressed before the trading. Mechanisms analysis is designed to reveal mutual effect of water rights trading and WEF nexus. Optimal water management scenario is identified through multi-criterion analysis. Results reveal that the mechanism of water rights trading with WEF nexus under low constraint-violation risk level of water availability and environment capacity is recommended to promote the rational water resources allocation to balance the economic goals, water environment and water supply security, as well as ecological and food water demand guarantees.

Revisiting the hormonal control of sexual dimorphism in chicken feathers.

Sexual dimorphism in plumage is widespread among avian species. In chickens, adult females exhibit countershading, characterized by dull-colored round feathers lacking fringe on the saddle, while adult males display vibrant plumage with deeply fringed bright feathers. This dimorphism is estrogen-dependent, and administering estrogen to males transforms their showy plumage into cryptic female-like plumage. Extensive studies have shown that estrogen's role in female plumage formation requires thyroid hormone; however, the precise mechanisms of their interaction remain unclear. In this study, we investigated the roles of estrogen and thyroid hormone in creating sexual dimorphism in the structure and coloration of saddle feathers by administering each hormone to adult males and observing the resulting changes in regenerated feathers induced by plucking. RT-PCR analysis revealed that the expression of type 3 deiodinase (DIO3), responsible for thyroid hormone inactivation, correlates with fringing. Estrogen suppressed DIO3 and agouti signaling protein (ASIP) expression while stimulating BlSK1, a marker of barbule cells, resulting in female-like feathers with mottled patterns and lacking fringes. Administration of thyroxine (T4) stimulated BlSK1 and proopiomelanocortin (POMC) expression, with no effect on ASIP, leading to the formation of solid black feathers lacking fringes. Triiodothyronine (T3) significantly increased POMC expression in pulp cells in culture. Taken together, these findings suggest that estrogen promotes the formation of solid vanes by suppressing DIO3 expression, while also inducing the formation of mottled patterns through inhibition of ASIP expression and indirect stimulation of melanocortin expression via changes in local T3 concentration. This is the first report describing molecular mechanism underlying hormonal crosstalk in creating sexual dimorphism in feathers.

The role of cellular senescence in neurodegenerative diseases.

Increasing evidence has revealed that cellular senescence drives NDs, including Alzheimer's disease (AD) and Parkinson's disease. Different senescent cell populations secrete senescence-associated secretory phenotypes (SASP), including matrix metalloproteinase-3, interleukin (IL)-1α, IL-6, and IL-8, which can harm adjacent microglia. Moreover, these cells possess high expression levels of senescence hallmarks (p16 and p21) and elevated senescence-associated ß-galactosidase activity in in vitro and in vivo ND models. These senescence phenotypes contribute to the deposition of ß-amyloid and tau-protein tangles. Selective clearance of senescent cells and SASP regulation by inhibiting p38/mitogen-activated protein kinase and nuclear factor kappa B signaling attenuate ß-amyloid load and prevent tau-protein tangle deposition, thereby improving cognitive performance in AD mouse models. In addition, telomere shortening, a cellular senescence biomarker, is associated with increased ND risks. Telomere dysfunction causes cellular senescence, stimulating IL-6, tumor necrosis factor-α, and IL-1ß secretions. The forced expression of telomerase activators prevents cellular senescence, yielding considerable neuroprotective effects. This review elucidates the mechanism of cellular senescence in ND pathogenesis, suggesting strategies to eliminate or restore senescent cells to a normal phenotype for treating such diseases.

Free-space coupled, large-active-area superconducting microstrip single-photon detector for photon-counting time-of-flight imaging.

Numerous applications at the photon-starved regime require a free-space coupling single-photon detector with a large active area, low dark count rate (DCR), and superior time resolutions. Here, we developed a superconducting microstrip single-photon detector (SMSPD), with a large active area of 260 µm in diameter, a DCR of ∼5k c p s, and a low time jitter of ∼171p s, operated at a near-infrared of 1550 nm and a temperature of ∼2.0K. As a demonstration, we applied the detector to a single-pixel galvanometer scanning system and successfully reconstructed the object information in depth and intensity using a time-correlated photon counting technology.

Association of frequent intradialytic hypotension with the clinical outcomes of patients on hemodialysis: a prospective cohort study.

Intradialytic hypotension (IDH) is a common complication of hemodialysis (HD), but there is no consensus on its definition. In 2015, Flythe proposed a definition of IDH (Definition 1 in this study): nadir systolic blood pressure (SBP) <90 mmHg during hemodialysis for patients with pre-dialysis SBP <159 mmHg, and nadir SBP <100 mmHg during hemodialysis for patients with pre-dialysis SBP ≥160 mmHg. This prospective observational cohort study investigated the association of frequent IDH based on Definition 1 with clinical outcomes and compared Definition 1 with a commonly used definition (nadir SBP <90 mmHg during hemodialysis, Definition 2). The incidence of IDH was observed over a 3-month exposure assessment period. Patients with IDH events ≥30% were classified as 'frequent IDH'; the others were 'infrequent IDH'. All-cause mortality, cardiovascular mortality, and all-cause hospitalization events were followed up for 36 months. This study enrolled 163 HD patients. The incidence of IDH was 11.1% according to Definition 1 and 10.5% according to Definition 2. The Kaplan-Meier curves showed that frequent IDH patients had higher risks of all-cause mortality (p = 0.009, Definition 1; p = 0.002, Definition 2) and cardiovascular mortality (p = 0.021, Definition 1). Multivariable Cox regression analysis indicated that frequent IDH was independently associated with a higher risk of all-cause mortality (Model 1: HR = 2.553, 95%CI 1.334-4.886, p = 0.005; Model 2: HR = 2.406, 95%CI 1.253-4.621, p = 0.008). In conclusion, HD patients classified as frequent IDH are at a greater risk of all-cause mortality. This highlights the significance of acknowledging and proactively managing frequent IDH within the HD patients.

The QTL and Candidate Genes Regulating the Early Tillering Vigor Traits of Late-Season Rice in Double-Cropping Systems.

Rice effective panicle is a major trait for grain yield and is affected by both the genetic tiller numbers and the early tillering vigor (ETV) traits to survive environmental adversities. The mechanism behind tiller bud formation has been well described, while the genes and the molecular mechanism underlying rice-regulating ETV traits are unclear. In this study, the candidate genes in regulating ETV traits have been sought by quantitative trait locus (QTL) mapping and bulk-segregation analysis by resequencing method (BSA-seq) conjoint analysis using rice backcross inbred line (BIL) populations, which were cultivated as late-season rice of double-cropping rice systems. By QTL mapping, seven QTLs were detected on chromosomes 1, 3, 4, and 9, with the logarithm of the odds (LOD) values ranging from 3.52 to 7.57 and explained 3.23% to 12.98% of the observed phenotypic variance. By BSA-seq analysis, seven QTLs on chromosomes 1, 2, 4, 5, 7, and 9 were identified using single-nucleotide polymorphism (SNP) and insertions/deletions (InDel) index algorithm and Euclidean distance (ED) algorithm. The overlapping QTL resulting from QTL mapping and BSA-seq analysis was shown in a 1.39 Mb interval on chromosome 4. In the overlap interval, six genes, including the functional unknown genes Os04g0455650, Os04g0470901, Os04g0500600, and ethylene-insensitive 3 (Os04g0456900), sialyltransferase family domain containing protein (Os04g0506800), and ATOZI1 (Os04g0497300), showed the differential expression between ETV rice lines and late tillering vigor (LTV) rice lines and have a missense base mutation in the genomic DNA sequences of the parents. We speculate that the six genes are the candidate genes regulating the ETV trait in rice, which provides a research basis for revealing the molecular mechanism behind the ETV traits in rice.

CPNE1 regulates myogenesis through the PERK-eIF2α pathway mediated by endoplasmic reticulum stress.

Sarcopenia is characterized by a progressive reduction in muscle mass or muscle physiological function associated with aging, but the relevant molecular mechanisms are not clear. Here, we identify the role of the myogenesis modifier CPNE1 in sarcopenia. CPNE1 is upregulated in aged skeletal muscles and young skeletal muscle satellite cells with palmitate-induced atrophy. The overexpression of CPNE1 hinders proliferation and differentiation and increases muscle atrophy characteristics in young skeletal muscle-derived satellite cells. In addition, CPNE1 overexpression disrupts the balance of mitochondrial fusion and division and causes endoplasmic reticulum stress. We found that the effects of CPNE1 on mitochondrial function are dependent on the PERK/eIF2α/ATF4 pathway. The overexpression of CPNE1 in young muscles alters membrane lipid composition, reduces skeletal muscle fibrosis regeneration, and exercise capacity in mice. These effects were reversed by PERK inhibitor GSK2606414. Moreover, immunoprecipitation indicates that CPNE1 overexpression greatly increased the acetylation of PERK. Therefore, CPNE1 is an important modifier that drives mitochondrial homeostasis to regulate myogenic cell proliferation and differentiation via the PERK-eIF2α pathway, which could be a valuable target for age-related sarcopenia.

Millimeter-scale active area superconducting microstrip single-photon detector fabricated by ultraviolet photolithography.

The effective and convenient detection of single photons via advanced detectors with a large active area is becoming significant for quantum and classical applications. This work demonstrates the fabrication of a superconducting microstrip single-photon detector (SMSPD) with a millimeter-scale active area via the use of ultraviolet (UV) photolithography. The performances of NbN SMSPDs with different active areas and strip widths are characterized. SMSPDs fabricated by UV photolithography and electron beam lithography with small active areas are also compared from the aspects of the switching current density and line edge roughness. Furthermore, an SMSPD with an active area of 1 mm × 1 mm is obtained via UV photolithography, and during operation at 0.85 K, it exhibits near-saturated internal detection efficiency at wavelengths up to 800 nm. At a wavelength of 1550 nm, the detector exhibits a system detection efficiency of ∼5% (7%) and a timing jitter of 102 (144) ps, when illuminated with a light spot of ∼18 (600) µm in diameter, respectively.

Detection of Entangled States Supported by Reinforcement Learning.

Discrimination of entangled states is an important element of quantum-enhanced metrology. This typically requires low-noise detection technology. Such a challenge can be circumvented by introducing nonlinear readout process. Traditionally, this is realized by reversing the very dynamics that generates the entangled state, which requires a full control over the system evolution. In this Letter, we present nonlinear readout of highly entangled states by employing reinforcement learning to manipulate the spin-mixing dynamics in a spin-1 atomic condensate. The reinforcement learning found results in driving the system toward an unstable fixed point, whereby the (to be sensed) phase perturbation is amplified by the subsequent spin-mixing dynamics. Working with a condensate of 10 900 ^{87}Rb atoms, we achieve a metrological gain of 6.97_{-1.38}^{+1.30} dB beyond the classical precision limit. Our work will open up new possibilities in unlocking the full potential of entanglement caused quantum enhancement in experiments.

Context-specific roles of diphthamide deficiency in hepatocellular carcinogenesis.

Diphthamide biosynthesis protein 1 (DPH1) is biochemically involved in the first step of diphthamide biosynthesis, a post-translational modification of eukaryotic elongation factor 2 (EEF2). Earlier studies showed that DPH1, also known as ovarian cancer-associated gene 1 (OVCA1), is involved in ovarian carcinogenesis. However, the role of DPH1 in hepatocellular carcinoma (HCC) remains unclear. To investigate the impact of DPH1 in hepatocellular carcinogenesis, we performed data mining from The Cancer Genome Atlas Liver Hepatocellular Carcinoma (TCGA-LIHC) dataset. We found that reduced DPH1 levels were associated with advanced stages and poor survival of patients with HCC. Also, we generated hepatocyte-specific Dph1-deficient mice and showed that diphthamide-deficient EEF2 resulted in a reduced translation elongation rate in the hepatocytes and led to mild liver damage with fatty accumulation. After N-diethylnitrosamine (DEN)-induced acute liver injury, p53-mediated pericentral hepatocyte death was increased, and compensatory proliferation was reduced in Dph1-deficient mice. Consistent with these effects, Dph1 deficiency decreased the incidence of DEN-induced pericentral-derived HCC and revealed a protective effect against p53 loss. In contrast, Dph1 deficiency combined with Trp53- or Trp53/Pten-deficient hepatocytes led to increased tumor loads associated with KRT19 (K19)-positive periportal-like cell expansion in mice. Further gene set enrichment analysis also revealed that HCC patients with lower levels of DPH1 and TP53 expression had enriched gene-sets related to the cell cycle and K19-upregulated HCC. Additionally, liver tumor organoids obtained from 6-month-old Pten/Trp53/Dph1-triple-mutant mice had a higher frequency of organoid re-initiation cells and higher proliferative index compared with those of the Pten/Trp53-double-mutant. Pten/Trp53/Dph1-triple-mutant liver tumor organoids showed expression of genes associated with stem/progenitor phenotypes, including Krt19 and Prominin-1 (Cd133) progenitor markers, combined with low hepatocyte-expressed fibrinogen genes. These findings indicate that diphthamide deficiency differentially regulates hepatocellular carcinogenesis, which inhibits pericentral hepatocyte-derived tumors and promotes periportal progenitor-associated liver tumors. © 2022 The Pathological Society of Great Britain and Ireland.