Multiscale 3D genome organization underlies duck fatty liver with no adipose inflammation or serious injury

Non-alcoholic fatty liver disease (NAFLD) is the most common form of chronic liver disease. Little is known about how gene expression and chromatin structure are regulated in NAFLD due to lack of suitable model. Ducks naturally develop fatty liver similar to serious human non-alcoholic fatty liver (NAFL) without adipose inflammation and liver fibrosis, thus serves as a good model for investigating molecular mechanisms of adipose metabolism and anti-inflammation. Here, we constructed a NAFLD model without adipose inflammation and liver fibrosis in ducks. By performing dynamic pathological and transcriptomic analyses, we identified critical genes involving in regulation of the NF-κB and MHCII signaling, which usually lead to adipose inflammation and liver fibrosis. We further generated dynamic three-dimensional chromatin maps during liver fatty formation and recovery. This showed that ducks enlarged hepatocyte cell nuclei to reduce inter-chromosomal interaction, decompress chromatin structure, and alter strength of intra-TAD and loop interactions during fatty liver formation. These changes partially contributed to the tight control the NF-κB and the MHCII signaling. Our analysis uncovers duck chromatin reorganization might be advantageous to maintain liver regenerative capacity and reduce adipose inflammation. These findings shed light on new strategies for NAFLD control.</p

A new chromosome-scale duck genome shows a major histocompatibility complex with several expanded multigene families

BACKGROUND: The duck (Anas platyrhynchos) is one of the principal natural hosts of influenza A virus (IAV), harbors almost all subtypes of IAVs and resists to many IAVs which cause extreme virulence in chicken and human. However, the response of duck's adaptive immune system to IAV infection is poorly characterized due to lack of a detailed gene map of the major histocompatibility complex (MHC).RESULTS: We herein reported a chromosome-scale Beijing duck assembly by integrating Nanopore, Bionano, and Hi-C data. This new reference genome SKLA1.0 covers 40 chromosomes, improves the contig N50 of the previous duck assembly with highest contiguity (ZJU1.0) of more than a 5.79-fold, surpasses the chicken and zebra finch references in sequence contiguity and contains a complete genomic map of the MHC. Our 3D MHC genomic map demonstrated that gene family arrangement in this region was primordial; however, families such as AnplMHCI, AnplMHCIIβ, AnplDMB, NKRL (NK cell receptor-like genes) and BTN underwent gene expansion events making this area complex. These gene families are distributed in two TADs and genes sharing the same TAD may work in a co-regulated model.CONCLUSIONS: These observations supported the hypothesis that duck's adaptive immunity had been optimized with expanded and diversified key immune genes which might help duck to combat influenza virus. This work provided a high-quality Beijing duck genome for biological research and shed light on new strategies for AIV control.</p

High-fat diets enhance and delay ursodeoxycholic acid absorption but elevate circulating hydrophobic bile salts

Background: Ursodeoxycholic acid (UDCA) is a natural drug essential for the treatment of cholestatic liver diseases. The food effects on the absorption of UDCA and the disposition of circulating bile salts remain unclear despite its widespread global uses. This study aims to investigate the effects of high-fat (HF) diets on the pharmacokinetics of UDCA and disclose how the circulated bile salts were simultaneously perturbed.Methods: After an overnight fast, a cohort of 36 healthy subjects received a single oral dose (500 mg) of UDCA capsules, and another cohort of 31 healthy subjects received the same dose after consuming a 900 kcal HF meal. Blood samples were collected from 48 h pre-dose up to 72 h post-dose for pharmacokinetic assessment and bile acid profiling analysis.Results: The HF diets significantly delayed the absorption of UDCA, with the Tmax of UDCA and its major metabolite, glycoursodeoxycholic acid (GUDCA), changing from 3.3 h and 8.0 h in the fasting study to 4.5 h and 10.0 h in the fed study, respectively. The HF diets did not alter the Cmax of UDCA and GUDCA but immediately led to a sharp increase in the plasma levels of endogenous bile salts including those hydrophobic ones. The AUC0–72h of UDCA significantly increased from 25.4 μg h/mL in the fasting study to 30.8 μg h/mL in the fed study, while the AUC0–72h of GUDCA showed no difference in both studies. As a result, the Cmax of total UDCA (the sum of UDCA, GUDCA, and TUDCA) showed a significant elevation, while the AUC0–72h of total UDCA showed a slight increase without significance in the fed study compared to the fasting study.Conclusion: The HF diets delay UDCA absorption due to the extension of gastric empty time. Although UDCA absorption was slightly enhanced by the HF diets, the beneficial effect may be limited in consideration of the simultaneous elevation of circulating hydrophobic bile salts

Ubiquitin ligase RNF125 targets PD-L1 for ubiquitination and degradation

As a critical immune checkpoint molecule, PD-L1 is expressed at significantly higher levels in multiple neoplastic tissues compared to normal ones. PD-L1/PD-1 axis is a critical target for tumor immunotherapy, blocking the PD-L1/PD-1 axis is recognized and has achieved unprecedented success in clinical applications. However, the clinical efficacy of therapies targeting the PD-1/PD-L1 pathway remains limited, emphasizing the need for the mechanistic elucidation of PD-1/PD-L1 expression. In this study, we found that RNF125 interacted with PD-L1 and regulated PD-L1 protein expression. Mechanistically, RNF125 promoted K48-linked polyubiquitination of PD-L1 and mediated its degradation. Notably, MC-38 and H22 cell lines with RNF125 knockout, transplanted in C57BL/6 mice, exhibited a higher PD-L1 level and faster tumor growth than their parental cell lines. In contrast, overexpression of RNF125 in MC-38 and H22 cells had the opposite effect, resulting in lower PD-L1 levels and delayed tumor growth compared with parental cell lines. In addition, immunohistochemical analysis of MC-38 tumors with RNF125 overexpression showed significantly increased infiltration of CD4+, CD8+ T cells and macrophages. Consistent with these findings, analyses using The Cancer Genome Atlas (TCGA) public database revealed a positive correlation of RNF125 expression with CD4+, CD8+ T cell and macrophage tumor infiltration. Moreover, RNF125 expression was significantly downregulated in several human cancer tissues, and was negatively correlated with the clinical stage of these tumors, and patients with higher RNF125 expression had better clinical outcomes. Our findings identify a novel mechanism for regulating PD-L1 expression and may provide a new strategy to increase the efficacy of immunotherapy

Sustainable Agriculture in the Face of Climate Change: Exploring Farmers’ Risk Perception, Low-Carbon Technology Adoption, and Productivity in the Guanzhong Plain of China

Agriculture is a significant contributor to global greenhouse gas emissions, and reducing carbon emissions in this sector is essential for mitigating global warming. To achieve China’s targets of carbon peak by 2030 and carbon neutrality by 2060, promoting low-carbon agricultural technology (LCAT) is fundamental. This study examines the impact of farmers’ risk perception on LCAT adoption behavior and its productivity effects with the Ordered Probit regression method, using micro survey data from 531 farmers in Shaanxi Province, China. The results show that farmers with stronger risk perceptions were more likely to adopt LCAT, based on their loss aversion characteristics. Additionally, farmers’ perceptions of yield, market, and climate risks positively influence the adoption of LCAT, with market risk perception having the strongest effect. Adopting LCAT has significant production and spillover effects, improving the output rate of farmers’ operating farmland and neighboring plots by 2.4% and 1.2%, respectively, for each additional measure adopted. This study contributes to the perception and loss aversion literature by examining farmers’ adoption of low-carbon agricultural practices. This study sheds light on the importance of risk perception in the adoption of sustainable agricultural practices and can inform policies aimed at promoting the adoption of LCAT for achieving sustainable agriculture and mitigating climate change, highlighting the crucial role of sustainable environmental management in the agricultural sector

Uncovering the role of nanoscale Si particles on the thermal stability of a lamellar-nanostructured Al–1%Si alloy

This study investigates particle governed thermal stability in lamellar-nanostructured Al–1.0%Si using in-situ transmission electron microscopy and post-mortem observations. Microstructural coarsening, dominated by Y-junction motion, is correlated with dispersed Si nanoparticles. Si particles within lamellae efficiently hinder dislocation movement during deformation, fostering a configuration with Si particles along incidental dislocation boundaries (IDBs). This particle–IDB configuration significantly impedes Y-junction motion, retarding lamellar coarsening. The enhanced pinning force from particle–IDB synergy, combined with direct pinning by Si particles, contributes to improved thermal stability in lamellar-nanostructured Al–1.0%Si

Uncovering the role of nanoscale Si particles on the thermal stability of a lamellar-nanostructured Al–1%Si alloy

This study investigates particle governed thermal stability in lamellar-nanostructured Al–1.0%Si using in-situ transmission electron microscopy and post-mortem observations. Microstructural coarsening, dominated by Y-junction motion, is correlated with dispersed Si nanoparticles. Si particles within lamellae efficiently hinder dislocation movement during deformation, fostering a configuration with Si particles along incidental dislocation boundaries (IDBs). This particle–IDB configuration significantly impedes Y-junction motion, retarding lamellar coarsening. The enhanced pinning force from particle–IDB synergy, combined with direct pinning by Si particles, contributes to improved thermal stability in lamellar-nanostructured Al–1.0%Si.</p