Development of a non-intercepting weak beam current measurement electronics for Heavy Ion Accelerator Facility in Lanzhou.

Non-destructive measurements of low-intensity charged particle beams are particularly challenging for beam diagnostics. At the Heavy Ion Accelerator Facility in Lanzhou (HIRFL), beams with weak currents below 1 µA are often provided for experiments. The detection of such low beam current is below the threshold of typical standard beam current transformers. Therefore, a low-intensity monitoring system is developed by using a sensitive capacitive pick-up (PU) and low-noise electronics. This device measures beam currents by digitally analyzing the amplitude of the PU signals using a homodyne detection scheme. During lab tests, the amplitude nonlinearity is <0.5% in the operational range of 1 nA-45 µA and the amplitude resolution is 0.94 nA. At present, four measurement systems for low beam currents are installed at HIRFL for the monitoring of standard operating conditions with low beam currents below 1 µA. After an absolute calibration with a Faraday cup, it can be used for accurate beam intensity measurement with a current resolution of about 1 nA.

Mechanism of Guigan Longmu Decoction in the Treatment of Arrhythmias Based on Network Pharmacology and Untargeted Metabolomics Assays.

BACKGROUND: Guigan longmu decoction (GGLM), a traditional Chinese medicine compound, has demonstrated efficacy in treating rapid arrhythmia clinically. Nevertheless, its mechanism of action remains elusive. This study aims to elucidate the molecular mechanism underlying the efficacy of GGLM in treating arrhythmia utilizing non-targeted metabolomics, widely-targeted metabolomics, and network pharmacology, subsequently validated through animal experiments. METHODS: Initially, network pharmacology analysis and widely-targeted metabolomics were performed on GGLM. Subsequent to that, rats were administered GGLM intervention, and nontargeted metabolomics assays were utilized to identify metabolites in rat plasma postadministration. The primary signaling pathways, core targets, and key active ingredients of GGLM influencing arrhythmia were identified. Additionally, to validate the therapeutic efficacy of GGLM on arrhythmia rat models, a rat model of rapid arrhythmia was induced via subcutaneous injection of isoproterenol, and alterations in pertinent pathogenic pathways and proteins in the rat model were assessed through qRT-PCR and Western blot following GGLM administration. RESULTS: The results of network pharmacology showed that 99 active ingredients in GGLM acted on 249 targets and 201 signaling pathways, which may be key to treating arrhythmia. Widelytargeted metabolic quantification analysis detected a total of 448 active ingredients in GGLM, while non-targeted metabolomics identified 279 different metabolites and 10 major metabolic pathways in rats. A comprehensive analysis of the above results revealed that the core key active ingredients of GGLM in treating arrhythmia include calycosin, licochalcone B, glabridin, naringenin, medicarpin, formononetin, quercetin, isoliquiritigenin, and resveratrol. These active ingredients mainly act on the relevant molecules and proteins upstream and downstream of the MAPK pathway to delay the onset of arrhythmia. Animal experimental results showed that the heart rate of rats in the model group increased significantly, and the mRNA and protein expression of p38, MAPK, JNK, ERK, NF-kb, IL-1ß, and IL-12 in myocardial tissue also increased significantly. However, after intervention with GGLM, the heart rate of rats in the drug group decreased significantly, while the mRNA and protein expression of p38 MAPK, JNK, ERK1, NF-kb, IL-1ß, and IL-12 in myocardial tissue decreased significantly. CONCLUSION: GGLM, as an adjunctive therapy in traditional Chinese medicine, exhibits favorable therapeutic efficacy against arrhythmia. This can be attributed to the abundant presence of bioactive compounds in the formulation, including verminin, glycyrrhizin B, glabridine, naringenin, ononin, quercetin, isorhamnetin, and kaempferol. The metabolites derived from these active ingredients have the potential to mitigate myocardial inflammation and decelerate heart rate by modulating the expression of proteins associated with the MAPK signaling pathway in vivo.

A comprehensive benchmark of graph-based genetic variant genotyping algorithms on plant genomes for creating an accurate ensemble pipeline.

BACKGROUND: Although sequencing technologies have boosted the measurement of the genomic diversity of plant crops, it remains challenging to accurately genotype millions of genetic variants, especially structural variations, with only short reads. In recent years, many graph-based variation genotyping methods have been developed to address this issue and tested for human genomes. However, their performance in plant genomes remains largely elusive. Furthermore, pipelines integrating the advantages of current genotyping methods might be required, considering the different complexity of plant genomes. RESULTS: Here we comprehensively evaluate eight such genotypers in different scenarios in terms of variant type and size, sequencing parameters, genomic context, and complexity, as well as graph size, using both simulated and real data sets from representative plant genomes. Our evaluation reveals that there are still great challenges to applying existing methods to plants, such as excessive repeats and variants or high resource consumption. Therefore, we propose a pipeline called Ensemble Variant Genotyper (EVG) that can achieve better genotyping performance in almost all experimental scenarios and comparably higher genotyping recall and precision even using 5× reads. Furthermore, we demonstrate that EVG is more robust with an increasing number of graphed genomes, especially for insertions and deletions. CONCLUSIONS: Our study will provide new insights into the development and application of graph-based genotyping algorithms. We conclude that EVG provides an accurate, unbiased, and cost-effective way for genotyping both small and large variations and will be potentially used in population-scale genotyping for large, repetitive, and heterozygous plant genomes.

Aflatoxin B1-exposed hepatocyte-derived extracellular vesicles: Initiating hepatic stellate cell-mediated liver fibrosis through a p53-Parkin-dependent mitophagy pathway.

Environmental aflatoxin B1 (AFB1) exposure has been proposed to contribute to hepatocellular carcinoma by promoting liver fibrosis, but the potential mechanisms remain to be further elucidated. Extracellular vesicles (EVs) were recognized as crucial traffickers for hepatic intercellular communication and play a vital role in the pathological process of liver fibrosis. The AFB1-exposed hepatocyte-derived EVs (AFB1-EVs) were extracted, and the functional effects of AFB1-EVs on the activation of hepatic stellate cells (HSCs) were explored to investigate the molecular mechanism of AFB1 exposure-induced liver fibrogenesis. Our results revealed that an environment-level AFB1 exposure induced liver fibrosis via HSCs activation in mice, while the AFB1-EVs mediated hepatotoxicity and liver fibrogenesis in vitro and in vivo. AFB1 exposure in vitro increased PINK1/Parkin-dependent mitophagy in hepatocytes, where upregulated transcription of the PARK2 gene via p53 nuclear translocation and mitochondrial recruitment of Parkin, and promoted AFB1-EVs-mediated mitochondria-trafficking communication between hepatocytes and HSCs. The knockdown of Parkin in HepaRG cells reversed HSCs activation by blocking the mitophagy-related AFB1-EVs trafficking. This study further revealed that the hepatic fibrogenesis of AFB1 exposure was rescued by genetic intervention with siPARK2 or p53's Pifithrin-α (PFTα) inhibitors. Furthermore, AFB1-EVs-induced HSCs activation was relieved by GW4869 pharmaceutic inhibition of EVs secretion. These results revealed a novel mechanism that AFB1 exposure-induced p53-Parkin signal axis regulated mitophagy-dependent hepatocyte-derived EVs to mediate the mitochondria-trafficking intercellular communication between hepatocytes and HSCs in the local hepatotoxic microenvironment to promote the activated HSCs-associated liver fibrogenesis. Our study provided insight into p53-Parkin-dependent pathway regulation and promised an advanced strategy targeting intervention to EVs-mediated mitochondria trafficking for preventing xenobiotics-induced liver fibrosis.

Selective efficient photocatalytic degradation of antibiotics and direct Z-type migration pathway for hierarchical core-shell TiO2/g-C3N4 composites.

Constructing superior Z-type photocatalytic heterojunction is beneficial to effectively enlarge interface contact, improve the photo-generated carrier separation rate, and retain the high redox ability. In this work, we designed a hierarchical core-shell g-C3N4/TiO2 structure to build Z-type heterojunction via combining simple template method and pyrolysis process. A close-knit Z-type heterojunction was constructed using TiO2 as a thick core and g-C3N4 as an ultra-thin shell. The effects of lamp source, wavelength, tetracycline (TC) concentration, and photocatalyst dose on the degradation performance on TC of g-C3N4/TiO2 were inspected. 0.1TiO2/g-C3N4 photocatalyst had the best degradation rate and highest removal rate within 30 min, and its degradation rate was about 49, 23, and 5 times than pure g-C3N4, TiO2, and commercial TiO2/g-C3N4 in respect. Moreover, compared with degradation ability under Xenon lamp, LED irradiation for g-C3N4/TiO2 composites showed a remarkable selective degradation. The fast and efficient Z-type transfer pathway of 0.1 g-C3N4/TiO2 was realized by forming an optimized interface and abundant surface active sites ascribed to the combined action of thick TiO2 core and ultra-thin g-C3N4 shell. In addition, the degradation intermediates were analyzed by LC-MS and suggested pathways of degradation. The work could provide novel design concept to obtain reliable Z-type photocatalysts with hierarchical core-shell structure applied in degradation of antibiotic wastewater.

DNA methylation-activated full-length EMX1 facilitates metastasis through EMX1-EGFR-ERK axis in hepatocellular carcinoma.

Altered DNA methylation is a crucial epigenetic event in hepatocellular carcinoma (HCC) development and progression. Through methylation-transcriptomic analysis, we identified a set of sixty potential DNA methylation-based epidriver genes. In this set of genes, we focused on the hypermethylation of EMX1, which is frequently observed in hepatobiliary tumors. Despite of its frequent occurrence, the function of EMX1 remains largely unknown. By utilizing bisulfite-next-generation sequencing, we have detected EMX1 DNA hypermethylation on the gene body, which is positively correlated with EMX1 mRNA expression. Further analysis revealed that EMX1 mRNA terminal exon splicing in HCC generated two protein isoforms: EMX1 full length (EMX1-FL) and alternative terminal exon splicing isoform (EMX1-X1). Cellular functional assays demonstrated that gain-of-function EMX1-FL, but not EMX1-X1, induced HCC cells migration and invasion while silencing EMX1-FL inhibited HCC cells motility. This result was further validated by in vivo tumor metastasis models. Mechanistically, EMX1-FL bound to EGFR promoter, promoting EGFR transcription and activating EGFR-ERK signaling to trigger tumor metastasis. Therefore, EGFR may be a potential therapeutic target for EMX1-high expression HCC. Our work illuminated the crucial role of gene body hypermethylation-activated EMX1-FL in promoting tumorigenesis and metastasis in HCC. These findings pave the way for targeting the EMX1-EGFR axis in HCC tumorigenicity and metastasis.

Stochastic cooling notch filter developments for the high-precision spectrometer ring in the high intensity heavy-ion accelerator facility project.

Stochastic cooling of the high-precision spectrometer ring (SRing) at the High Intensity Heavy-Ion Accelerator Facility (HIAF) project in China, which is used mainly for experiments with radioactive fragment beams, is applied to speed up the cooling process of a stored ion beam. In this article, a new coaxial-type notch filter with an amplitude equalizer in the long branch and an optical-type notch filter with phase-stabilized optical fiber are discussed and evaluated for the SRing stochastic cooling system. Both prototypes of coaxial and optical notch filters are fabricated and tested. The minimum notch depth of coaxial and optical notch filters reaches to 26 and 40 dB, respectively. The performance of both coaxial notch filter and optical fiber notch filter is presented in this work. These developments will be used not only for the longitudinal stochastic cooling system but also have potential for the beam feedback system.

Protein phosphatase 2A-B55ß mediated mitochondrial p-GPX4 dephosphorylation promoted sorafenib-induced ferroptosis in hepatocellular carcinoma via regulating p53 retrograde signaling.

Rationale: As a key endogenous negative regulator of ferroptosis, glutathione peroxidase 4 (GPX4) can regulate its antioxidant function through multiple post-translational modification pathways. However, the effects of the phosphorylation/dephosphorylation status of GPX4 on the regulation of inducible ferroptosis in hepatocellular carcinoma (HCC) remain unclear. Methods: To investigate the effects and molecular mechanism of GPX4 phosphorylation/dephosphorylation modification on ferroptosis in HCC cells. Sorafenib (Sora) was used to establish the ferroptosis model in HCC cells in vitro. Using the site-directed mutagenesis method, we generated the mimic GPX4 phosphorylation or dephosphorylation HCC cell lines at specific serine sites of GPX4. The effects of GPX4 phosphorylation/dephosphorylation modification on ferroptosis in HCC cells were examined. The interrelationships among GPX4, p53, and protein phosphatase 2A-B55ß subunit (PP2A-B55ß) were also explored. To explore the synergistic anti-tumor effects of PP2A activation on Sora-administered HCC, we established PP2A-B55ß overexpression xenograft tumors in a nude mice model in vivo. Results: In the Sora-induced ferroptosis model of HCC in vitro, decreased levels of cytoplasmic and mitochondrial GPX4, mitochondrial dysfunction, and enhanced p53 retrograde signaling occurred under Sora treatment. Further, we found that mitochondrial p53 retrograded remarkably into the nucleus and aggravated Sora-induced ferroptosis. The phosphorylation status of GPX4 at the serine 2 site (GPX4Ser2) revealed that mitochondrial p-GPX4Ser2 dephosphorylation was positively associated with ferroptosis, and the mechanism might be related to mitochondrial p53 retrograding into the nucleus. In HCC cells overexpressing PP2A-B55ß, it was found that PP2A-B55ß directly interacted with mitochondrial GPX4 and promoted Sora-induced ferroptosis in HCC. Further, PP2A-B55ß reduced the interaction between mitochondrial GPX4 and p53, leading to mitochondrial p53 retrograding into the nucleus. Moreover, it was confirmed that PP2A-B55ß enhanced the ferroptosis-mediated tumor growth inhibition and mitochondrial p53 retrograde signaling in the Sora-treated HCC xenograft tumors. Conclusion: Our data uncovered that the PP2A-B55ß/p-GPX4Ser2/p53 axis was a novel regulatory pathway of Sora-induced ferroptosis. Mitochondrial p-GPX4Ser2 dephosphorylation triggered ferroptosis via inducing mitochondrial p53 retrograding into the nucleus, and PP2A-B55ß was an upstream signal modulator responsible for mitochondrial p-GPX4Ser2 dephosphorylation. Our findings might serve as a potential theranostic strategy to enhance the efficacy of Sora in HCC treatment through the targeted intervention of p-GPX4 dephosphorylation via PP2A-B55ß activation.

Aflatoxin B1 exposure triggers hepatic lipotoxicity via p53 and perilipin 2 interaction-mediated mitochondria-lipid droplet contacts: An in vitro and in vivo assessment.

Aflatoxin B1 (AFB1) is one of the most toxic mycotoxins widely found in food contaminants, and its target organ is the liver. It poses a major food security and public health threat worldwide. However, the lipotoxicity mechanism of AFB1 exposure-induced liver injury remains unclear and requires further elucidation. Herein, we investigated the potential hepatic lipotoxicity of AFB1 exposure using in vitro and in vivo models to assess the public health hazards of high dietary AFB1 exposure. We demonstrated that low-dose of AFB1 (1.25 µM for 48 h, about one-fifth of the IC50 in HepG2 and HepaRG cells, IC50 are 5.995 µM and 5.266 µM, respectively) exposure significantly induced hepatic lipotoxicity, including abnormal lipid droplets (LDs) growth, mitochondria-LDs contacts increase, lipophagy disruption, and lipid accumulation. Mechanistically, we showed that AFB1 exposure promoted the mitochondrial p53 (mito-p53) and LDs-associated protein perilipin 2 (PLIN2) interaction-mediated mitochondria-LDs contacts, resulting in lipid accumulation in hepatocytes. Mito-p53-targeted inhibition, knockdown of PLIN2, and rapamycin application efficiently promoted the lysosome-dependent lipophagy and alleviated the hepatic lipotoxicity and liver injury induced by AFB1 exposure. Overall, our study found that mito-p53 and PLIN2 interaction mediates three organelles-mitochondria, LDs, and lysosomal networks to regulate lipid homeostasis in AFB1 exposure-induced hepatotoxicity, revealing how this unique trio of organelles works together and provides a novel insight into the targeted intervention in inter-organelle lipid sensing and trafficking for alleviating hazardous materials-induced hepatic lipotoxicity.

Temperature measurement and error analysis of the transverse plane of oil-jet-lubrication herringbone gear with infrared pyrometers.

Frictional power losses of high-speed and heavy-load herringbone gearboxes increase the temperature of the gearbox. Thus, real-time surface temperature measurement is significant for evaluating the gearbox lubrication design. A rotating gear test rig with an infrared pyrometer is developed in this paper to conduct real-time and accurate temperature measurements of the transverse plane of the oil-jet-lubrication herringbone gear. First, the influencing factors and measuring errors of surface temperature are analyzed using the infrared pyrometer. The emissivity of the measured surface of a gear tooth painted with matte black is experimentally calibrated. Second, the temperature measurement tests of the oil-jet-lubrication herringbone gear under different conditions are carried out. Measurement errors resulting from purge air pressure, purge air temperature, and oil-jet temperature are also experimentally studied. The results indicate that the purge gas flow can reduce the measurement errors of the infrared pyrometer resulting from oil mist with an appropriate purge air pressure and purge air temperature. Finally, a mathematical curve-fitting of the measurement results between the infrared pyrometer and thermocouple is carried out. The calculated temperatures by the curve-fitting formula are compared with the measured thermocouple temperature, with the relative differences being less than 1 °C. Thus, the curve-fitting formula is credible for the real-time measurement of surface temperature, while the relevant measuring method is also valuable for engineering applications of high-speed gear systems under oil-jet-lubrication conditions.

Removal of As(V) from aqueous solution using modified Fe3O4 nanoparticles.

The removal of arsenic contamination from the aqueous environment is of great importance in the conservation of the Earth's water resources, and surfactants are a promising material used to modify magnetic nanoparticles to improve adsorption properties. Therefore, it is important to develop efficient and selective adsorbents for arsenic. Surface modification of Fe3O4 was carried out using anionic, cationic and zwitterionic surfactants to obtain composite Fe3O4@SDS, Fe3O4@CTAB, Fe3O4@SNC 16 and Fe3O4@NPC 16 (collectively referred to as Fe3O4@surfactants). The synthesized composite Fe3O4@surfactants magnetic nanoparticles were characterized by XRD, TEM and FTIR. The As(V) removal characteristics of the composite magnetic nanoparticles from the aqueous solution were evaluated by adsorption batch experiments which indicated the possibility of effective application of the surfactant-modified Fe3O4 magnetic nanoparticles for the removal of As(V) from aqueous solution. The adsorption equilibrium of the composites was reached in 30 min and the kinetic data followed the pseudo-second-order model. Langmuir equation could represent the adsorption isotherm data very well. Moreover, under the identical conditions, Fe3O4@CTAB showed maximum capacity of adsorption for As(V) (55.671 mg g-1), with its removal efficiency being much higher than that of the other composites. In addition, the Fe3O4@surfactants composite magnetic nanoparticles retained 93.5% of its initial arsenic removal efficiency even after re-using it five times. The mechanism of arsenic adsorption by Fe3O4@surfactants composite magnetic nanoparticles was proved to be complexation via electrostatic attraction, which was mainly innersphere in nature.

A novel nano material for anti-cerebral ischaemia: preparation and application of borneol angelica polysaccharide liposomes.

OBJECTIVE: To investigate the preparation of novel nanoliposomes (Borneol Angelica Polysaccharide Liposomes, BAPL) for anti-cerebral ischaemia and verify its curative effects and mechanism. METHODS: By applying a uniform experiment design to investigate the fitting combination of BAPL. Encapsulation Efficiency Evaluation of BAPL Preparation; Particle Size and Surface Potential Evaluation of BAPL Biological activity; Cerebral ischaemia models of rats Evaluation of BAPL curative effects and mechanism. RESULTS: (1) The fitting combination of lecithin, Cholesterol, AP mass and the borneol mass was 60 mg, 60 mg, 45 mg and 5 mg. the highest encapsulation efficiency was 80.4%, the particle size was 179.1 nm, and the surface zeta potential was -17.2 mV. It conforms to the nano-material standards. (2) The results of animal experiments show that: In the BAPL group, the infarct volume of TTC staining was significantly decreased, and the expression levels of NF-κBp65, TLR-4, IL-8, IL-6, IL-1ß in brain tissue were significantly decreased, while the expression levels of ZO-1, ZO-2, IL-10 were significantly increased after cerebral ischaemia-reperfusion. CONCLUSION: BAPL is a novel nano and effective material for anti-cerebral ischaemia.

Efficient Visible-Light-Driven Hydrogen Production over Cu-Modified Polyoxotungstate Hybrids.

Hydrogen energy is a renewable and clean source, which makes a great difference in future sustainable energy systems. Visible-light-driven photocatalysis reaction involves harnessing the abundance of sunlight for hydrogen production among many catalytic technologies. However, the fabrication of photocatalysts that have distinctive performance in visible light is still the primary challenge. Herein, two new Cu-modified polyoxotungstate hybrids, {[Cu2(bim)4(H2O)2](HBW12O40)2·(H2bim)2·8H2O} (1) (bim = [1,1'-methylenebis(1H-imidazole)]) and {[Cu2(bim)4(H2O)2](H3PW10Ti2O40)2·(H2bim)2·8H2O} (2), have been successfully isolated by bridging two saturated Keggin polyoxotungstates and copper-azole complexes. Not surprisingly, 2 holds higher reduction activity due to the more negative charge and stronger basicity on the terminal oxygen of Ti═O and bridge oxygen of Ti-O-W. The H2 yield was 17075 µmol g-1 h-1 for 2 in the tunable light-driven H2 production system, which is promising in the field of photocatalysis.

[Preliminary Study on the Effect of Whole-Process Case Management Based on Service Process Design on the Function and Satisfaction of Patients Undergoing Total Knee Arthroplasty].

Objective: To investigate the effect of whole-process case management based on service process design on patients undergoing total knee arthroplasty (TKA) in areas including pain, function, satisfaction, and complications. Methods: A total of 204 patients who underwent unilateral TKA between April 2021 and March 2022 at the Department of Orthopedics, West China Hospital, Sichuan University were enrolled. By using a random number table, the patients were randomly assigned to two groups, 102 in the general case management group (group G) and 102 in the whole-process case management group (group W). Patients in group G received traditional perioperative case management, while those in the whole-process case management group received integrated case management optimized on the basis of the service process design. The two groups of patients were studied through comparison of their general data, Visual Analogue Scale (VAS) pain score, knee flexion and range of motion, Hospital for Special Surgery (HSS) knee score, the 18-item Patient Satisfaction Questionnaire Short Form (PSQ-18), ability to climb stairs, and complications at 3 days and 3, 8, and 12 weeks after TKA. Results: There was no significant difference between the two groups in patient general information or baseline data collected at the time of enrollment ( P>0.05). There was no significant difference in HSS score, joint range of motion, and VAS pain score between the two groups before the surgery and 3 days after the surgery ( P>0.05). However, the HSS score, joint range of motion, and VAS pain scores of group W were significantly superior to those of group G at 3, 8 and 12 weeks after the surgery (all P<0.05). In addition, group W demonstrated significantly better ability to climb up and down stairs than that of group G at 12 weeks after the surgery ( P< 0.001). In terms of satisfaction, patients in group W were significantly more satisfied than those in group G at 3 days, and 3, 8, and 12 weeks after the surgery ( P<0.001). Conclusion: Whole-process case management based on service process design has a positive effect of relieving pain, increasing range of motion, improving function, increasing satisfaction, and reducing complications in patients undergoing TKA.

Intracellular antibody targeting HBx suppresses invasion and metastasis in hepatitis B virus-related hepatocarcinogenesis via protein phosphatase 2A-B56γ-mediated dephosphorylation of protein kinase B.

OBJECTIVES: Hepatitis B virus X (HBx) is closely associated with HBV-related hepatocarcinogenesis via the inactivation of tumour suppressors. Protein phosphatase 2A (PP2A) regulatory subunit B56 gamma (B56γ), as a tumour suppressor, plays a critical role in regulating cellular phosphorylation signals via dephosphorylation of signalling proteins. However, the underlying mechanism that B56γ involved in regulating HBx-associated hepatocarcinogenesis phenotypes and mediating anti-HBx antibody-mediated tumour suppression remains unknown. MATERIALS AND METHODS: We used bioinformatics analysis, paired HCC patient specimens, HBx transgenic (HBx-Tg) mice, xenograft nude mice, HBV stable replication in the HepG2.2.15 cells, and anti-HBx antibody intervention to systematically evaluate the biological function of protein kinase B (AKT) dephosphorylation through B56γ in HBx-associated hepatocarcinogenesis. RESULTS: Bioinformatics analysis revealed that AKT, matrix metalloproteinase 2 (MMP2), and MMP9 were markedly upregulated, while cell migration and viral carcinogenesis pathways were activated in HBV-infected liver tissues and HBV-associated HCC tissues. Our results demonstrated that HBx-expression promotes AKT phosphorylation (p-AKTThr308/Ser473 ), mediating the migration and invasion phenotypes in vivo and in vitro. Importantly, in clinical samples, HBx and B56γ were downregulated in HBV-associated HCC tumour tissues compared with peritumor tissues. Moreover, intervention with site-directed mutagenesis (AKTT308A , AKTS473A ) of p-AKTThr308/Ser473 mimics dephosphorylation, genetics-based B56γ overexpression, and intracellular anti-HBx antibody inhibited cell growth, migration, and invasion in HBx-expressing HCC cells. CONCLUSIONS: Our results demonstrated that B56γ inhibited HBV/HBx-dependent hepatocarcinogenesis by regulating the dephosphorylation of p-AKTThr308/Ser473 in HCC cells. The intracellular anti-HBx antibody and the activator of B56γ may provide a multipattern chemopreventive strategy against HBV-related HCC.

Protein phosphatase 2A-B56γ-Drp1-Rab7 signaling axis regulates mitochondria-lysosome crosstalk to sensitize the anti-cancer therapy of hepatocellular carcinoma.

Mitochondria-lysosome crosstalk is an intercellular communication platform regulating mitochondrial quality control (MQC). Activated dynamin-related protein 1 (Drp1) with phosphorylation at serine 616 (p-Drp1Ser616) plays a critical role in mitophagy-dependent cell survival and anti-cancer therapy for hepatocellular carcinoma (HCC). However, the underlying mechanisms that p-Drp1Ser616 involved in regulating mitochondria-lysosome crosstalk and mediating anti-HCC therapy remain unknown. HCC cells and mouse xenograft models were conducted to evaluate the relationship between p-Drp1Ser616 and Ras-associated protein 7 (Rab7) and the underlying mechanism by protein phosphatase 2A (PP2A)-B56γ regulating mitophagy via dephosphorylation of p-Drp1Ser616 in HCC. Herein, we found that Drp1 was frequently upregulated and was associated with poor prognosis in HCC. Mitochondrial p-Drp1Ser616 was a novel inter-organelle tethering protein localized to mitochondrion and lysosome membrane contact sites (MCSs) via interaction with Rab7 to trigger an increase in the mitochondria-lysosome crosstalk, resulting in PINK1-Parkin-dependent mitophagy and anti-apoptosis in HCC cells under the treatment of chemotherapy drugs. Moreover, we demonstrate that B56γ-mediated direct dephosphorylation of p-Drp1Ser616 inhibited mitophagy and thus increased mitochondria-dependent apoptosis. Overall, our findings demonstrated that activation of B56γ sensitizes the anti-cancer effect of HCC chemoprevention via dephosphorylated regulation of p-Drp1Ser616 in inhibiting the interaction between p-Drp1Ser616 and Rab7, which may provide a novel mechanism underlying the theranostics for targeting intervention in HCC.

Analysis of rare thalassemia genetic variants based on third-generation sequencing.

Thalassemia is a group of common hereditary anemias that cause significant morbidity and mortality worldwide. However, precisely diagnosing thalassemia, especially rare thalassemia variants, is still challenging. Long-range PCR and long-molecule sequencing on the PacBio Sequel II platform utilized in this study could cover the entire HBA1, HBA2 and HBB genes, enabling the diagnosis of most of the common and rare types of thalassemia variants. In this study, 100 cases of suspected thalassemia were subjected to traditional thalassemia testing and third-generation sequencing for thalassemia genetic diagnosis. Compared with traditional diagnostic methods, an additional 10 cases of rare clinically significant variants, including 3 cases of structure variants and 7 cases of single nucleotide variations (SNVs) were identified, of which a case with - α3.7 subtype III (- α3.7III) was first identified and validated in the Chinese population. Other rare variants of 11.1 kb deletions (- 11.1/αα), triplicate α-globin genes (aaa3.7/αα) and rare SNVs have also been thoroughly detected. The results showed that rare thalassemia variants are not rare but have been misdiagnosed by conventional methods. The results further validated third-generation sequencing as a promising method for rare thalassemia genetic testing.

Rhythm disturbance in osteoarthritis.

Osteoarthritis (OA) is one of the main causes of disabilities among older people. To date, multiple disease-related molecular networks in OA have been identified, including abnormal mechanical loadings and local inflammation. These pathways have not, however, properly elucidated the mechanism of OA progression. Recently, sufficient evidence has suggested that rhythmic disturbances in the central nervous system (CNS) and local joint tissues affect the homeostasis of joint and can escalate pathological changes of OA. This is accompanied with an exacerbation of joint symptoms that interfere with the rhythm of CNS in reverse. Eventually, these processes aggravate OA progression. At present, the crosstalk between joint tissues and biological rhythm remains poorly understood. As such, the mechanisms of rhythm changes in joint tissues are worth study; in particular, research on the effect of rhythmic genes on metabolism and inflammation would facilitate the understanding of the natural rhythms of joint tissues and the OA pathology resulting from rhythm disturbance. Video Abstract.

The Association Between Vitamin C and Cancer: A Two-Sample Mendelian Randomization Study.

In recent years, many studies have indicated that vitamin C might be negatively associated with the risk of cancer, but the actual relationship between vitamin C and cancer remains ambivalent. Therefore, we utilized a two-sample Mendelian randomization (MR) study to explore the causal associations of genetically predicted vitamin C with the risk of a variety of cancers. Single-nucleotide polymorphisms (SNPs) associated with vitamin C at a significance level of p < 5 × 10-8 and with a low level of linkage disequilibrium (LD) (r2 < 0.01) were selected from a genome-wide association study (GWAS) meta-analysis of plasmid concentration of vitamin C consisting of 52,018 individuals. The data of the GWAS outcomes were obtained from United Kingdom Biobank, FinnGen Biobank and the datasets of corresponding consortia. In the inverse-variance weight (IVW) method, our results did not support the causal association of genetically predicted vitamin C with the risk of overall cancer and 14 specific types of cancer. Similar results were observed in sensitivity analyses where the weighted median and MR-Egger methods were adopted, and heterogeneity and pleiotropy were not observed in statistical models. Therefore, our study suggested that vitamin C was not causally associated with the risk of cancer. Further studies are warranted to discover the potential protective and therapeutic effects of vitamin C on cancer, and its underlying mechanisms.