Fenton-like activity and pathway modulation via single-atom sites and pollutants comediates the electron transfer process.

The studies on the origin of versatile oxidation pathways toward targeted pollutants in the single-atom catalysts (SACs)/peroxymonosulfate (PMS) systems were always associated with the coordination structures rather than the perspective of pollutant characteristics, and the analysis of mechanism commonality is lacking. In this work, a variety of single-atom catalysts (M-SACs, M: Fe, Co, and Cu) were fabricated via a pyrolysis process using lignin as the complexation agent and substrate precursor. Sixteen kinds of commonly detected pollutants in various references were selected, and their lnkobs values in M-SACs/PMS systems correlated well (R2 = 0.832 to 0.883) with their electrophilic indexes (reflecting the electron accepting/donating ability of the pollutants) as well as the energy gap (R2 = 0.801 to 0.840) between the pollutants and M-SACs/PMS complexes. Both the electron transfer process (ETP) and radical pathways can be significantly enhanced in the M-SACs/PMS systems, while radical oxidation was overwhelmed by the ETP oxidation toward the pollutants with lower electrophilic indexes. In contrast, pollutants with higher electrophilic indexes represented the weaker electron-donating capacity to the M-SACs/PMS complexes, which resulted in the weaker ETP oxidation accompanied with noticeable radical oxidation. In addition, the ETP oxidation in different M-SACs/PMS systems can be regulated via the energy gaps between the M-SACs/PMS complexes and pollutants. As a result, the Fenton-like activities in the M-SACs/PMS systems could be well modulated by the reaction pathways, which were determined by both electrophilic indexes of pollutants and single-atom sites. This work provided a strategy to establish PMS-based AOP systems with tunable oxidation capacities and pathways for high-efficiency organic decontamination.

The DESTINY+ Dust Analyser - a dust telescope for analysing cosmic dust dynamics and composition.

The DESTINY+(Demonstration and Experiment of Space Technology for INterplanetary voYage with Phaethon fLyby and dUst Science) Dust Analyser (DDA) is a state-of-the-art dust telescope for the in situ analysis of cosmic dust particles. As the primary scientific payload of the DESTINY+ mission, it serves the purpose of characterizing the dust environment within the Earth-Moon system, investigating interplanetary and interstellar dust populations at 1 AU from the Sun and studying the dust cloud enveloping the asteroid (3200) Phaethon. DDA features a two-axis pointing platform for increasing the accessible fraction of the sky. The instrument combines a trajectory sensor with an impact ionization time-of-flight mass spectrometer, enabling the correlation of dynamical, physical and compositional properties for individual dust grains. For each dust measurement, a set of nine signals provides the surface charge, particle size, velocity vector, as well as the atomic, molecular and isotopic composition of the dust grain. With its capabilities, DDA is a key asset in advancing our understanding of the cosmic dust populations present along the orbit of DESTINY+. In addition to providing the scientific context, we are presenting an overview of the instrument's design and functionality, showing first laboratory measurements and giving insights into the observation planning. This article is part of a theme issue 'Dust in the Solar System and beyond'.

Two-Dimensional Melting of Two- and Three-Component Mixtures.

We elucidate the interplay between diverse two-dimensional melting pathways and establish solid-hexatic and hexatic-liquid transition criteria via the numerical simulations of the melting transition of two- and three-component mixtures of hard polygons and disks. We show that a mixture's melting pathway may differ from its components and demonstrate eutectic mixtures that crystallize at a higher density than their pure components. Comparing the melting scenario of many two- and three-component mixtures, we establish universal melting criteria: the solid and hexatic phases become unstable as the density of topological defects, respectively, overcomes ρ_{d,s}≃0.046 and ρ_{d,h}≃0.123.

Optimal therapy for concomitant EGFR and TP53 mutated non-small cell lung cancer: a real-world study.

BACKGROUND: Non-small cell cancer (NSCLC) patients with concomitant epidermal growth factor receptor (EGFR) and TP53 mutations have a poor prognosis with the treatment of tyrosine kinase inhibitors (TKIs), and may benefit from a combination regimen preferentially. The present study aims to compare the benefits of EGFR-TKIs and its combination with antiangiogenic drugs or chemotherapy in patients with NSCLC harboring EGFR and TP53 co-mutation in a real-life setting. METHODS: This retrospective analysis included 124 patients with advanced NSCLC having concomitant EGFR and TP53 mutations, who underwent next-generation sequencing prior to treatment. Patients were classified into the EGFR-TKI group and combination therapy group. The primary end point of this study was progression-free survival (PFS). The Kaplan-Meier (KM) curve was drawn to analyze PFS, and the differences between the groups were compared using the logarithmic rank test. Univariate and multivariate cox regression analysis was performed on the risk factors associated with survival. RESULTS: The combination group included 72 patients who received the regimen of EGFR-TKIs combined with antiangiogenic drugs or chemotherapy, while the EGFR-TKI monotherapy group included 52 patients treated with TKI only. The median PFS was significantly longer in the combination group than in the EGFR-TKI group (18.0 months; 95% confidence interval [CI]: 12.1-23.9 vs. 7.0 months; 95% CI: 6.1-7.9; p < 0.001) with greater PFS benefit in TP53 exon 4 or 7 mutations subgroup. Subgroup analysis showed a similar trend. The median duration of response was significantly longer in the combination group than in the EGFR-TKI group. Patients with 19 deletions or L858R mutations both achieved a significant PFS benefit with combination therapy versus EGFR-TKI alone. CONCLUSION: Combination therapy had a higher efficacy than EGFR-TKI alone for patients with NSCLC having concomitant EGFR and TP53 mutations. Future prospective clinical trials are needed to determine the role of combination therapy for this patient population.

Effects of Cryptocaryon irritans infection on the histopathology, oxidative stress, immune response, and intestinal microbiota in the orange-spotted grouper Epinephelus coioides.

Cryptocaryon irritans is a parasitic ciliate of marine fish, causing serious mortality and economic loss of grouper. In this study, the orange-spotted grouper (Epinephelus coioides) were separately exposed to C. irritans infection for 72 h at a dose of 5000 or 10000 active theronts per fish, and we evaluated the changes in histopathology, oxidative stress, immune response, and intestinal microbiota composition. The results showed that C. irritans infection caused pathological alteration on the skin, gills, and liver of E. coioides. Oxidative stress responses occurred in the liver and gills, reflected in the corresponding antioxidant enzyme and gene indexes. The mRNA expression levels of inflammation-related genes (IL-1ß, IL-6, and IL-8) and the mediators of apoptosis (casp3, casp9, and cytc) were increased in the liver and gills of the fish. C. irritans infection also affected the diversity and composition of intestinal microbiota. Specifically, the relative abundance of Firmicutes was increased, whereas that of Proteobacteria was decreased. Several potentially beneficial bacteria (Pandoraea, Clostridium sensu stricto 1, Christensenellaceae R-7 group, and Weissella) were decreased, whereas pathogenic bacteria (Streptococcus and Acinetobacter) were increased. In conclusion, this study reveals that C. irritans infection caused histopathology, immune disorders, and intestinal microbial community variation in E. coioides.

Vibrio harveyi co-infected with Cryptocaryon irritans to orange-spotted groupers Epinephelus coioides.

The orange-spotted grouper (Epinephelus coioides) is a high economic value aquacultural fish in China, however, it often suffers from the outbreak of parasitic ciliate Cryptocaryon irritans as well as bacterium Vibrio harveyi which bring great loss in grouper farming. In the present study, we established a high dose C. irritans local-infected model which caused the mortality of groupers which showed low vitality and histopathological analysis demonstrated inflammatory response and degeneration in infected skin, gill and liver. In addition, gene expression of inflammatory cytokines was detected to assist the estimate of inflammatory response. Furthermore, we also found that the activity of Na+/K+ ATPase in gill was decreased in groupers infected C. irritans and the concentration of Na+/Cl- in blood were varied. Base on the morbidity symptom occurring in noninfected organs, we hypothesized that the result of morbidity and mortality were due to secondary bacterial infection post parasitism of C. irritans. Moreover, four strains of bacteria were isolated from the infected site skin and liver of local-infected groupers which were identified as V. harveyi in accordance of phenotypic traits, biochemical characterization and molecular analysis of 16S rDNA genes, housekeeping genes (gyrB and cpn60) and species-specific gene Vhhp2. Regression tests of injecting the isolated strain V. harveyi has showed high pathogenicity to groupers. In conclusion, these findings provide the evidence of coinfections with C. irritans and V. harveyi in orange-spotted grouper.

Ultra-fine SnO2nanocrystals anchored on reduced graphene oxide as a high-performance anode material for sodium-ion batteries.

SnO2has attracted extensive research attentions as a promising anode material for sodium-ion batteries (SIBs) due to its high theoretical capacity. However, its application is largely hindered by sluggish sodium ion diffusion and drastic volume change during the conversion reaction and alloying process. Herein, ultra-fine SnO2nanocrystals (3-5 nm) anchored on reduced graphene oxide (rGO) is demonstrated as a promising anode material for SIBs. Ultra-fine SnO2nanocrystals are uniformly grown on rGO sheets by a facile one-step hydrothermal process. Nano-scaled SnO2grains tolerate volume expansion and provide shortened diffusion pathway for sodium ions, and meanwhile rGO acts as an excellent conductive matrix, thus endowing the composite electrode with excellent electrochemical performance. More importantly, the ratio of SnO2to rGO in the composite is optimized. The optimized sample delivers an initial charge capacity of 518 mAh g-1at a current density of 50 mA g-1, and 504 mAh g-1after 300 cycles at a current density of 100 mA g-1. Furthermore, a capacity of 287 mAh g-1can be maintained after 1000 cycles at a current density of 1000 mA g-1.

Scalable synthesis of N/S co-doped hard carbon microspheres as a high-performance anode material for sodium-ion batteries.

Hard carbon is a promising anode material for sodium-ion batteries (SIBs) due to its abundance. However, it exhibits low reversible capacity and slow kinetics if inappropriate microstructural features are developed during synthesis. Herein, N/S co-doped phenolic resin-based hard carbon microspheres are prepared by a scalable strategy, and the electrochemical performance is assessed both in half cells and full cells. We demonstrate that the expanded interlayer spacing, the increased active sites, and the enhanced capacitive behavior result in the enhanced reversible capacity and promoted kinetics for Na+storage. The sample with appropriate doping amount exhibits an initial charge capacity of 536.8 mAh g-1at 50 mA g-1and maintains 445.9 mAh g-1after 1000 cycles at a current density of 1 A g-1in a Na-metal half cell. Coupled with a carbon-coated Na4Fe3(PO4)2P2O7(NFPP) cathode, the full cell exhibits a capacity of 92.5 mAh g-1after 90 cycles, with a capacity retention of 91.6%. This work provides a facile and scalable method for synthesizing high-performance hard carbon anode materials for SIBs.

Impacts of QM region sizes and conformation numbers on modelling enzyme reactions: a case study of polyethylene terephthalate hydrolase.

A quantum mechanics/molecular mechanics (QM/MM) approach is a broadly used tool in computational enzymology. Treating the QM region with a high-level DFT method is one of the important branches. Here, taking leaf-branch compost cutinase-catalyzed polyethylene terephthalate depolymerization as an example, the convergence behavior of energy barriers as well as key structural and charge features with respect to the size of the QM region (up to 1000 atoms) is systematically investigated. BP86/6-31G(d)//CHARMM and M06-2X/6-311G(d,p)//CHARMM level of theories were applied for geometry optimizations and single-point energy calculations, respectively. Six independent enzyme conformations for all the four catalytic steps (steps (i)-(iv)) were considered. Most of the twenty-four cases show that at least 500 QM atoms are needed while only two rare cases show that ∼100 QM atoms are sufficient for convergence when only a single conformation was considered. This explains why most previous studies showed that 500 or more QM atoms are required while a few others showed that ∼100 QM atoms are sufficient for DFT/MM calculations. More importantly, average energy barriers and key structural/charge features from six conformations show an accelerated convergence than that in a single conformation. For instance, to reach energy barrier convergence (within 2.0 kcal mol-1) for step (ii), only ∼100 QM atoms are required if six conformations are considered while 500 or more QM atoms are needed with a single conformation. The convergence is accelerated to be more rapid if hundreds and thousands of conformations were considered, which aligns with previous findings that only several dozens of QM atoms are required for convergence with semi-empirical QM/MM MD simulations.

Production of virus-like particles of porcine circovirus 2 in baculovirus expression system and its application for antibody detection.

BACKGROUND: Porcine circovirus 2 (PCV-2) is one of the pathogens that leads to a growing and persistent threat in pigs. Thus, the development of serological detection methods for PCV-2 is of great necessity for clinical diagnosis as well as epidemiological investigations. This study aimed to establish an indirect enzyme-linked immunosorbent assay (ELISA) to examine antibodies against PCV-2 based on virus-like particles (VLPs). RESULTS: Recombinant PCV-2 Cap protein was expressed in the baculovirus-insect cells system and PCV-2 VLPs were observed over transmission electron microscopy (TEM). The PCV-2 VLPs were shown to have good immunogenicity in mice and stimulated a high level of PCV-2 antibody titers. Using PCV-2 VLPs as coating antigen, the indirect ELISA can detect PCV-2 antibodies in animals with diagnostic sensitivity and specificity of 98.33% and 93.33% compared to immunofluorescence assay (IFA), respectively. The intra- and inter-assay coefficient variations (CVs) were < 10% in a batch, and < 15% in different batches, indicating good repeatability. There was no cross-reaction of this ELISA with antibodies against other porcine viruses. A total of 170 serum samples collected from different pig farms in China were tested for PCV-2 antibodies, and 151 (88.8%) samples were PCV-2 antibody positive. CONCLUSION: Our findings suggest that this ELISA was rapid, specific, and reproducible and can be used for large-scale serological investigations of PCV-2 antibodies in pigs.

Systematic evaluation of membrane-camouflaged nanoparticles in neutralizing Clostridium perfringens ε-toxin.

Clostridium perfringens ε-toxin (ETX) is the main toxin leading to enterotoxemia of sheep and goats and is classified as a potential biological weapon. In addition, no effective treatment drug is currently available in clinical practice for this toxin. We developed membrane-camouflaged nanoparticles (MNPs) with different membrane origins to neutralize ETX and protect the host from fatal ETX intoxication. We evaluated the safety and therapeutic efficacy of these MNPs in vitro and in vivo. Compared with membranes from karyocytes, such as Madin-Darby canine kidney (MDCK) cells and mouse neuroblastoma N2a cells (N2a cells), membrane from erythrocytes, which do not induce any immune response, are superior in safety. The protective ability of MNPs was evaluated by intravenous injection and lung delivery. We demonstrate that nebulized inhalation is as safe as intravenous injection and that both modalities can effectively protect mice against ETX. In particular, pulmonary delivery of nanoparticles more effectively treated the challenge of inhaled toxins than intravenously injected nanoparticles. Moreover, MNPs can alter the biological distribution of ETX among different organs in the body, and ETX was captured, neutralized and slowly delivered to the liver and spleen, where nanoparticles with ETX could be phagocytized and metabolized. This demonstrates how MNPs treat toxin infections in vivo. Finally, we injected the MNPs into mice in advance to find out whether MNPs can provide preventive protection, and the results showed that the long-cycle MNPs could provide at least a 3-day protection in mice. These findings demonstrate that MNPs provide safe and effective protection against ETX intoxication, provide new insights into membrane choices and delivery routes of nanoparticles, and new evidence of the ability of nanoparticles to provide preventive protection against infections.

Regioselective oxidation of heterocyclic aromatic hydrocarbons catalyzed by cytochrome P450: A case study of carbazole.

Recently there are increasing interests in accurately evaluating the health effects of heterocyclic PAHs. However, the activation mechanism and possible metabolites of heterocyclic PAHs catalyzed by human CYP1A1 is still elusive to a great extent. Here, leveraged to high level QM/MM calculations, the corresponding activation pathways of a representative heterocyclic PAHs, carbazole, were systematically explored. The first stage is electrophilic addition or hydrogen abstraction from N-H group. Electrophilic addition was evidenced to be more feasible and regioselectivity at C3 and C4 sites were identified. Correlations between energy barriers and key structural/electrostatic parameters reveal that O-Cα distance and Fe-O-Cα angle are the main origin for the catalytic regioselectivity. Electrophilic addition was determined as the rate-determining step and the subsequent possible reactions include epoxidation, NIH shift (the hydrogen migration from the site of hydroxylation to the adjacent carbon) and proton shuttle. The corresponding products are epoxides, ketones and hydroxylated carbazoles, respectively. The main metabolites (hydroxylated carbazoles) are estimated to be more toxic than carbazole. The regioselectivity of carbazole activated by CYP1A1 is different from the environmental processes (gas and aqueous phase). Collectively, these results will inform the in-depth understanding the metabolic processes of heterocyclic PAHs and aid the accurate evaluation of their health effects.

Hepatotoxicity assessment investigations on PFASs targeting L-FABP using binding affinity data and machine learning-based QSAR model.

Per- and polyfluoroalkyl substances (PFASs) are persistent organic pollutants that have been detected in various environmental media and human serum, but their safety assessment remains challenging. PFASs may accumulate in liver tissues and cause hepatotoxicity by binding to liver fatty acid binding protein (L-FABP). Therefore, evaluating the binding affinity of PFASs to L-FABP is crucial in assessing the potential hepatotoxic effects. In this study, two binding sites of L-FABP were evaluated, results suggested that the outer site possessed high affinity to polyfluoroalkyl sulfates and the inner site preferred perfluoroalkyl sulfonamides, overall, the inner site of L-FABP was more sensitive to PFASs. The binding affinity data of PFASs to L-FABP were used as training set to develop a machine learning model-based quantitative structure-activity relationship (QSAR) for efficient prediction of potentially hazardous PFASs. Further Bayesian Kernel Machine Regression (BKMR) model disclosed flexibility as the determinant molecular property on PFASs-induced hepatotoxicity. It can influence affinity of PFASs to target protein through affecting binding conformations directly (individual effect) as well as integrating with other molecular properties (joint effect). Our present work provided more understanding on hepatotoxicity of PFASs, which could be significative in hepatotoxicity gradation, administration guidance, and safer alternatives development of PFASs.

Statins as Potential Preventative Treatment of ETX and Multiple Pore-Forming Toxin-Induced Diseases.

Epsilon toxin (ETX), produced by type B and D strains of Clostridium perfringens, can cause fatal enterotoxaemia in ruminant animals, particularly sheep, cattle, and goats. Previous studies show that the cytotoxicity of ETX is dependent on the integrity of lipid rafts, the maintenance of which is ensured by cholesterol. Zaragozic acid (ZA) is a statin drug that reduces the synthesis of squalene, which is responsible for cholesterol synthesis. In this study, ZA significantly reduced the toxicity of ETX in Madin-Darby canine kidney (MDCK) cells. We show that ZA does not affect the binding of ETX to MDCK cells, but propidium iodide staining (PI) and Western blotting confirmed that ZA significantly disrupts the ability of ETX to form pores or oligomers in MDCK cells. Additionally, ZA decreased the phosphatidylserine exposure on the plasma membrane and increased the Ca2+ influx of the cells. Results of density gradient centrifugation suggest that ZA decreased the number of lipid rafts in MDCK membranes, which probably contributed to the attenuation of pore-formation. Moreover, ZA protected mice against ETX in vivo. All mice pre-treated with ZA for 48 h before exposure to an absolute lethal dose of ETX (6400 ng/kg) survived. In summary, these findings provide an innovative method to prevent ETX intoxication. Considering many pore-forming toxins require lipid rafts, we tested and found ZA also inhibited the toxicity of other toxins such as Clostridium perfringens Net B and ß-toxin (CPB) and Staphylococcus aureus α-hemolysin (Hla). We expect ZA can thus be developed as a broad-spectrum medicine for the treatment of multiple toxins. In addition, other statins, such as lovastatin (LO), also reduced the toxicity of ETX. These findings indicate that statin medicines are potential candidates for preventing and treating multiple toxin-induced diseases.

RVG Peptide-Functionalized Favipiravir Nanoparticle Delivery System Facilitates Antiviral Therapy of Neurotropic Virus Infection in a Mouse Model.

Neurotropic viruses severely damage the central nervous system (CNS) and human health. Common neurotropic viruses include rabies virus (RABV), Zika virus, and poliovirus. When treating neurotropic virus infection, obstruction of the blood-brain barrier (BBB) reduces the efficiency of drug delivery to the CNS. An efficient intracerebral delivery system can significantly increase intracerebral delivery efficiency and facilitate antiviral therapy. In this study, a rabies virus glycopeptide (RVG) functionalized mesoporous silica nanoparticle (MSN) packaging favipiravir (T-705) was developed to generate T-705@MSN-RVG. It was further evaluated for drug delivery and antiviral treatment in a VSV-infected mouse model. The RVG, a polypeptide consisting of 29 amino acids, was conjugated on the nanoparticle to enhance CNS delivery. The T-705@MSN-RVG caused a significant decrease in virus titers and virus proliferation without inducing substantial cell damage in vitro. By releasing T-705, the nanoparticle promoted viral inhibition in the brain during infection. At 21 days post-infection (dpi), a significantly enhanced survival ratio (77%) was observed in the group inoculated with nanoparticle compared with the non-treated group (23%). The viral RNA levels were also decreased in the therapy group at 4 and 6 dpi compared with that of the control group. The T-705@MSN-RVG could be considered a promising system for CNS delivery for treating neurotropic virus infection.

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OBJECTIVES: To study the impact of the home literacy environment on children's emotional regulation skills and the mediating role of the parent-child relationship between them. METHODS: A stratified cluster sampling approach was employed to select 1 626 preschool children from five kindergartens in Nanjing. Questionnaires were used to collect detailed information on the home literacy environment, children's emotional regulation skills, and the parent-child relationship. A mediation model was established using the Process program in SPSS macro, and the significance of the mediation effect was tested using the Bootstrap method. RESULTS: The findings revealed a positive correlation between the home literacy environment and children's emotional regulation skills (r=0.217, P<0.001), as well as parent-child intimacy (r=0.065, P<0.01). Conversely, a negative correlation was found between the home literacy environment and parent-child conflict (r=-0.129, P<0.001). Additionally, parent-child conflict demonstrated a negative correlation with children's emotional regulation skills (r=-0.443, P<0.001), while parent-child intimacy exhibited a positive correlation (r=0.247, P<0.001). The home literacy environment exerted a significant direct effect on children's emotional regulation skills (ß=0.162, P<0.001), and the mediating effect of the parent-child relationship accounted for 25.54% of the total effect. CONCLUSIONS: The home literacy environment significantly influences children's emotional regulation skills, with the parent-child relationship partially mediating this relationship.

Long-read genome assembly and genetic architecture of fruit shape in the bottle gourd.

The bottle gourd (Lagenaria siceraria, Cucurbitaceae) is an important horticultural crop exhibiting tremendous diversity in fruit shape. The genetic architecture of fruit shape variation in this species remains unknown. We assembled a long-read-based, high-quality reference genome (ZAAS_Lsic_2.0) with a contig N50 value over 390-fold greater than the existing reference genomes. We then focused on dissection of fruit shape using a one-step geometric morphometrics-based functional mapping approach. We identified 11 quantitative trait loci (QTLs) responsible for fruit shape (fsQTLs), reconstructed their visible effects and revealed syntenic relationships of bottle gourd fsQTLs with 12 fsQTLs previously reported in cucumber, melon or watermelon. Homologs of several well-known and newly identified fruit shape genes, including SUN, OFP, AP2 and auxin transporters, were comapped with bottle gourd QTLs.

Layered Cathode Materials: Precursors, Synthesis, Microstructure, Electrochemical Properties, and Battery Performance.

The exploitation of clean energy promotes the exploration of next-generation lithium-ion batteries (LIBs) with high energy-density, long life, high safety, and low cost. Ni-rich layered cathode materials are one of the most promising candidates for next-generation LIBs. Numerous studies focusing on the synthesis and modifications of the layered cathode materials are published every year. Many physical features of precursors, such as density, morphology, size distribution, and microstructure of primary particles pass to the resulting cathode materials, thus significantly affecting their electrochemical properties and battery performance. This review focuses on the recent advances in the controlled synthesis of hydroxide precursors and the growth of particles. The essential parameters in controlled coprecipitation are discussed in detail. Some innovative technologies for precursor modifications and for the synthesis of novel precursors are highlighted. In addition, future perspectives of the development of hydroxide precursors are presented.

Local Plastic Response and Slow Heterogeneous Dynamics of Supercooled Liquids.

We demonstrate, via numerical simulations, that the relaxation dynamics of supercooled liquids correlates well with a plastic length scale measuring a particle's response to impulsive localized perturbations and weakly to measures of local elasticity. We find that the particle averaged plastic length scale vanishes linearly in temperature and controls the super-Arrhenius temperature dependence of the relaxation time. Furthermore, we show that the plastic length scale of individual particles correlates with their typical displacement at the relaxation time. In contrast, the local elastic response only correlates with the dynamics on the vibrational timescale.

Targeted inhibition of PPARα ameliorates CLA-induced hypercholesterolemia via hepatic cholesterol biosynthesis reprogramming.

BACKGROUND & AIMS: Disruption of lipid metabolism is largely linked to metabolic disorders, such as hypercholesterolemia (HCL) and liver steatosis. While cholesterol metabolic re-programmers can serve as targets for relevant interventions. Here we explored the dietary conjugated linoleic acids (CLA)-induced HCL in mice and the molecular regulation behind it. METHODS: A high dose of CLA supplementation in the diet was used to induce HCL in mice and was found to cause a hyper-activated cholesterol biosynthesis programme in the liver, leading to cholesterol metabolism dysregulation. The effects of a small-molecule drug targeting PPARα, i.e., GW6471 were studied in vivo in mice fed diets with CLA supplementation for 28 days, and in primary hepatocytes derived from HCL-mice in vitro. RESULTS: We demonstrate that CLA induced HCL and liver steatosis through multiple pathways. Among which was the PPARα-mediated cholesterogenesis. It was found to cooperate with SREBP2 via binding to Hmgcr and Dhcr7 (genes encoding key enzymes of the cholesterol biosynthetic pathway) and recruits the histone marks H3K27ac and H3K4me1 and cofactors. PPARα inhibition disrupts its physical association with SREBP2 by blocking cobinding of PPARα and SREBP2 to the genomic DNA response element. We showed that NR RORγ functions as an essential mediator that facilitates the interaction of PPARα and SREBP2 to modulate the cholesterol biosynthesis genes expression. CONCLUSIONS: Our study unravels that the small-molecule compound GW6471 exerts an attractive therapeutic effect for CLA-induced HCL, involving multiple pathways with the "PPARα-RORγ-SREBP2" being a potential complex player in this hepatic cholesterol biosynthesis programming.