Implantation of human urine stem cells promotes neural repair in spinal cord injury rats associated cadeharin-1 and integrin subunit beta 1 expression.

BACKGROUND: The aim of this study was to determine the effect of human urine-derived stem cells (HUSCs) for the treatment of spinal cord injury (SCI) and investigate associated the molecular network mechanism by using bioinformatics combined with experimental validation. METHODS: After the contusive SCI model was established, the HUSC-expressed specific antigen marker was implanted into the injury site immediately, and the Basso, Beattie and Bresnahan locomotor rating scale (BBB scale) was utilized to evaluate motor function so as to determine the effect of HUSCs for the neural repair after SCI. Then, the geneCards database was used to collect related gene targets for both HUSCs and SCI, and cross genes were merged with the findings of PubMed screen. Subsequently, protein-protein interaction (PPI) network, Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment, as well as core network construction, were performed using Cytoscape software. Lastly, real-time quantitative polymerase chain reaction (PCR) and immunofluorescence were employed to validate the mRNA expression and localization of 10 hub genes, and two of the most important, designated as cadherin 1 (CDH1) and integrin subunit beta 1 (ITGB1), were identified successfully. RESULTS: The immunophenotypes of HUSCs were marked by CD90+ and CD44+ but not CD45, and flow cytometry confirmed their character. The expression rates of CD90, CD73, CD44 and CD105 in HUSCs were 99.49, 99.77, 99.82 and 99.51%, respectively, while the expression rates of CD43, CD45, CD11b and HLA-DR were 0.08, 0.30, 1.34 and 0.02%, respectively. After SCI, all rats appeared to have severe motor dysfunction, but the BBB score was increased in HUSC-transplanted rats compared with control rats at 28 days. By using bioinformatics, we obtained 6668 targets for SCI and 1095 targets for HUSCs and identified a total of 645 cross targets between HUSCs and SCI. Based on the PPI and Cytoscape analysis, CD44, ACTB, FN1, ITGB1, HSPA8, CDH1, ALB, HSP90AA1 and GAPDH were identified as possible therapeutic targets. Enrichment analysis revealed that the involved signal pathways included complement and coagulation cascades, lysosome, systemic lupus erythematosus, etc. Lastly, quantificational real-time (qRT)-PCR confirmed the mRNA differential expression of CDH1/ITGB1 after HUSC therapy, and glial fibrillary acidic protein (GFAP) immunofluorescence staining showed that the astrocyte proliferation at the injured site could be reduced significantly after HUSC treatment. CONCLUSIONS: We validated that HUSC implantation is effective for the treatment of SCI, and the underlying mechanisms associated with the multiple molecular network. Of these, CDH1 and ITGB1 may be considered as important candidate targets. Those findings therefore provided the crucial evidence for the potential use of HUSCs in SCI treatment in future clinic trials.

Autophagy Is Essential for Neural Stem Cell Proliferation Promoted by Hypoxia.

Hypoxia as a microenvironment or niche stimulates proliferation of neural stem cells (NSCs). However, the underlying mechanisms remain elusive. Autophagy is a protective mechanism by which recycled cellular components and energy are rapidly supplied to the cell under stress. Whether autophagy mediates the proliferation of NSCs under hypoxia and how hypoxia induces autophagy remain unclear. Here, we report that hypoxia facilitates embryonic NSC proliferation through HIF-1/mTORC1 signaling pathway-mediated autophagy. Initially, we found that hypoxia greatly induced autophagy in NSCs, while inhibition of autophagy severely impeded the proliferation of NSCs in hypoxia conditions. Next, we demonstrated that the hypoxia core regulator HIF-1 was necessary and sufficient for autophagy induction in NSCs. Considering that mTORC1 is a key switch that suppresses autophagy, we subsequently analyzed the effect of HIF-1 on mTORC1 activity. Our results showed that the mTORC1 activity was negatively regulated by HIF-1. Finally, we provided evidence that HIF-1 regulated mTORC1 activity via its downstream target gene BNIP3. The increased expression of BNIP3 under hypoxia enhanced autophagy activity and proliferation of NSCs, which was mediated by repressing the activity of mTORC1. We further illustrated that BNIP3 can interact with Rheb, a canonical activator of mTORC1. Thus, we suppose that the interaction of BNIP3 with Rheb reduces the regulation of Rheb toward mTORC1 activity, which relieves the suppression of mTORC1 on autophagy, thereby promoting the rapid proliferation of NSCs. Altogether, this study identified a new HIF-1/BNIP3-Rheb/mTORC1 signaling axis, which regulates the NSC proliferation under hypoxia through induction of autophagy.

Auxiliary Rather Than Dominant. The Role of Direct Dy-S Coordination in Single-Molecule Magnet Unveiled via ab initio Study.

The role of Dy-S coordination in a single-molecule magnet (SMM) is investigated via an ab initio study in a group of mononuclear structures. The SMM performance of this group is well interpreted via a concise criterion consisting of long quantum tunneling of magnetization (QTM) time τQTM and high effective barrier for magnetic reversal Ueff. The best SMMs in the selected group, i.e., 1Dy (CCDC refcode: PUKFAF) and 2Dy (CCDC refcode: NIKSEJ), are just those holding the longest τQTM and the highest Ueff simultaneously. Further analysis based on the crystal field model and ab initio magneto-structural exploration indicates that the influence of Dy-S coordination on the SMM performance of 1Dy is weaker than that of axial Dy-O coordination. Thus, Dy-S coordination is more likely to play an auxiliary role rather than a dominant one. However, if placed at the suitable equatorial position, Dy-S coordination could provide important support for good SMM performance. Consequently, starting from 1Dy, we built two new structures where Dy-S coordination only exists at the equatorial position and two axial positions are occupied by strong Dy-O/Dy-F coordination. Compared to 1Dy and 2Dy, these new ones are predicted to have significantly longer τQTM and higher Ueff, as well as a nearly doubled blocking temperature TB. Thus, they are probable candidates of SMM having clearly improved performance.

Bevacizumab induces ferroptosis and enhances CD8+ T cell immune activity in liver cancer via modulating HAT1 and increasing IL-9.

Bevacizumab is a recombinant humanized monoclonal immunoglobulin (Ig) G1 antibody of VEGF, and inhibits angiogenesis and tumor growth in hepatocellular carcinoma (HCC). Ferroptosis, a new form of regulated cell death function independently of the apoptotic machinery, has been accepted as an attractive target for pharmacological intervention; the ferroptosis pathway can enhance cell immune activity of anti-PD1 immunotherapy in HCC. In this study we investigated whether and how bevacizumab regulated ferroptosis and immune activity in liver cancer. Firstly, we performed RNA-sequencing in bevacizumab-treated human liver cancer cell line HepG2 cells, and found that bevacizumab significantly altered the expression of a number of genes including VEGF, PI3K, HAT1, SLC7A11 and IL-9 in liver cancer, bevacizumab upregulated 37 ferroptosis-related drivers, and downregulated 17 ferroptosis-related suppressors in particular. We demonstrated that bevacizumab triggered ferroptosis in liver cancer cells by driving VEGF/PI3K/HAT1/SLC7A11 axis. Clinical data confirmed that the expression levels of VEGF were positively associated with those of PI3K, HAT1 and SLC7A11 in HCC tissues. Meanwhile, we found that bevacizumab enhanced immune cell activity in tumor immune-microenvironment. We identified that HAT1 up-regulated miR-143 targeting IL-9 mRNA 3'UTR in liver cancer cells; bevacizumab treatment resulted in the increase of IL-9 levels and its secretion via VEGF/PI3K/HAT1/miR-143/IL-9 axis, which led to the inhibition of tumor growth in vivo through increasing the release of IL-2 and Granzyme B from activated CD8+ T cells. We conclude that in addition to inhibiting angiogenesis, bevacizumab induces ferroptosis and enhances CD8+ T cell immune activity in liver cancer. This study provides new insight into the mechanisms by which bevacizumab synergistically modulates ferroptosis and CD8+ T cell immune activity in liver cancer.

Inhibition of USP7 enhances CD8+ T cell activity in liver cancer by suppressing PRDM1-mediated FGL1 upregulation.

Lymphocyte activation gene 3 (LAG3), an immune checkpoint molecule expressed on activated T cells, functions as a negative regulator of immune responses. Persistent antigen exposure in the tumor microenvironment results in sustained LAG3 expression on T cells, contributing to T cell dysfunction. Fibrinogen-like protein 1 (FGL1) has been identified as a major ligand of LAG3, and FGL1/LAG3 interaction forms a novel immune checkpoint pathway that results in tumor immune evasion. In addition, ubiquitin-specific peptidase 7 (USP7) plays a crucial role in cancer development. In this study we investigated the role of USP7 in modulation of FGL1-mediated liver cancer immune evasion. We showed that knockdown of USP7 or treatment with USP7 inhibitor P5091 suppressed liver cancer growth by promoting CD8+ T cell activity in Hepa1-6 xenograft mice and in HepG2 or Huh7 cells co-cultured with T cells, whereas USP7 overexpression produced the opposite effect. We found that USP7 upregulated FGL1 in HepG2 and Huh7 cells by deubiquitination of transcriptional factor PR domain zinc finger protein 1 (PRDM1), which transcriptionally activated FGL1, and attenuated the CD8+ T cell activity, leading to the liver cancer growth. Interestingly, USP7 could be transcriptionally stimulated by PRDM1 as well in a positive feedback loop. P5091, an inhibitor of USP7, was able to downregulate FGL1 expression, thus enhancing CD8+ T cell activity. In an immunocompetent liver cancer mouse model, the dual blockade of USP7 and LAG3 resulted in a superior antitumor activity compared with anti-LAG3 therapy alone. We conclude that USP7 diminishes CD8+ T cell activity by a USP7/PRDM1 positive feedback loop on FGL1 production in liver cancer; USP7 might be a promising target for liver cancer immunotherapy.

Palaeobotanical evidence reveals the living conditions of Miocene Lufengpithecus in East Asia.

BACKGROUND: Understanding the relationship between human evolution and environmental changes is the key to lifting the veil on human origin. The hypothesis that environmental changes triggered the divergence of humans from apes (ca. 9.3-6.5 million years ago, Ma) has been poorly tested because of limited continuous environmental data from fossil localities. Lufengpithecus (12.5-6.0 Ma) found on the southeastern margin of the Tibetan Plateau (SEMTP) across the ape-human split provides a good chance for testing this hypothesis. RESULTS: Here, we reconstructed the habitats of L. keiyuanensis (12.5-11.6 Ma) with comprehensive vegetation, climate, and potential food web data by palaeobotanical evidence, together with other multidisciplinary data and partly tested the environment-driven hypothesis by revealing the living conditions of Lufengpithecus. CONCLUSION: A detailed comparison of hominoids on different continents reveals their behaviour and fate divergence across the ape-human split against the background of global climate change, i.e., the stable living conditions of SEMTP not only provided a so-called 'refuge' for arboreal Lufengpithecus but also acted as a 'double-edged sword', preventing their further evolution while vegetation shifts in East Africa probably stimulated the emergence of human bipedalism, and the intense climatic changes in Europe possibly prevented those hominoids from surviving that time interval. Our findings provide interesting insight into the environmental impacts on the behavioural evolution of hominoids.

New insights into the origin of buckwheat cultivation in southwestern China from pollen data.

Buckwheat is an important crop which originated in China and spread widely across Eurasia. However, exactly where in China domestication took place remains controversial. Archaeological and palynological records suggest a longer cultivation history of buckwheat in northern China than in southwestern China, but this conflicts with phylogenetic evidence implicating southwestern China as the centre of origin and diversity of buckwheat. We investigate alternative methodologies for inferring the occurrence of buckwheat cultivation and suggest that relative abundance could provide a reliable measure for distinguishing between wild and cultivated buckwheat in both present-day and fossil samples. Approximately 12 800-yr palaeoecological record shows that Fagopyrum pollen occurred only infrequently before the early Holocene. As southwestern China entered the early agricultural period, c. 8000-7000 yr ago, a slight increase in abundance of Fagopyrum pollen was observed. Approximately 4000 yr ago, concurrent with the Pu minority beginning to develop dry-land agriculture, the abundance of Fagopyrum pollen increased significantly, suggesting the cultivation of this crop. Fagopyrum pollen rose to a maximum value c. 1270 yr ago, suggesting an intensification of agricultural activity. These findings fill a gap in the Fagopyrum pollen record in southwestern China and provide new indications that early cultivation may have occurred in this region.

Multiple Stimulus Response 2D Framework Constructed by a Flexible Cyclotriphosphazene-Derived Carboxylic Acid Linker: Synthesis, Characterization, and Fluorescence Sensing to Phenolic Pollutants and Small-Molecule Drugs.

Hexachlorocyclotriphosphazene is one of the most representative phosphazene compounds which have been proved to have broad application prospects in many fields. However, it is an emerging research perspective to combine cyclotriphosphazene-derived polycarboxylic acid compounds with lanthanides for the construction of Tb-DPCP metal-organic framework (MOF) materials. Herein, a Tb-DPCP MOF, (CH3)2NH2[Tb3(HDPCP)(DMF)(H2O)3]·6DMF (1), was successfully prepared via the reaction of H12HDPCP [hexa(4-carboxyphenoxy) cyclotriphosphazene] and Tb(NO3)3·6H2O under the solvothermal condition. Through fluorescence sensing experiments, it was found that both nitrophenols and chlorophenols could cause the fluorescence quenching of compound 1. At the same time, the compound also exhibited nice trace detection ability for small-molecule drugs (moxifloxacin hydrochloride, balsalazide disodium, and colchicine); the limits of detection were all lower than 0.2 µM. These experimental results fully demonstrated the potential application value of 1 as a multifunctional fluorescent sensor.

Ab initio prediction of key parameters and magneto-structural correlation of tetracoordinated lanthanide single-ion magnets.

Single-molecule magnets (SMMs) have great potential in becoming revolutionary materials for micro-electronic devices. As one type of SMM and holding the performance record, lanthanide single-ion magnets (Ln-SIMs) stand at the forefront of the family. Lowering the coordination number (CN) is an important strategy to improve the performance of Ln-SIMs. Here, we report a theoretical study on a typical group of low-CN Ln-SIMs, i.e., tetracoordinated structures. Our results are consistent with those of experiments and they identify the same three best Ln-SIMs via a concise criterion, i.e., the co-existence of long τQTM and high Ueff. Compared to the record-holding dysprosocenium systems, the best SIMs here possess τQTM values that are shorter by several orders of magnitude and Ueff values that are lower by ∼1000 Kelvin (K). These are important reasons for the fact that the tetracoordinated Ln-SIMs are clearly inferior to dysprosocenium. A simple but intuitive crystal-field analysis leads to several routes to improve the performance of a given Ln-SIM, including compression of the axial bond length, widening the axial bond angle, elongation of the equatorial bond length and usage of weaker equatorial donor ligands. Although these routes are not brand-new, the most efficient option and the degree of improvement resulting from it are not known in advance. Consequently, a theoretical magneto-structural study, covering various routes, is carried out for the best Ln-SIM here and the most efficient route is shown to be widening the axial ∠O-Dy-O angle. The most optimistic case, having a ∠O-Dy-O of 180°, could have a τQTM (up to 103 s) and Ueff (∼2400 K) close to those of the record-holders. Subsequently, a blocking temperature (TB) of 64 K is predicted to be possible for it. A more practical case, with ∠O-Dy-O being 160°, could have a τQTM of up to 400 s, Ueff of around 2200 K and the possibility of a TB of 57 K. Although having an inherent precision limit, these predictions provide a guide to performance improvement, starting from an existing system.

Aspirin modulates succinylation of PGAM1K99 to restrict the glycolysis through NF-κB/HAT1/PGAM1 signaling in liver cancer.

Aspirin as a chemopreventive agent is able to restrict the tumor growth. Phosphoglycerate mutase 1 (PGAM1) is a key enzyme of glycolysis, playing an important role in the development of cancer. However, the underlying mechanism by which aspirin inhibits the proliferation of cancer cells is poorly understood. This study aims to identify the effects of aspirin on modulating PGAM1 enzymatic activities in liver cancer. Here, we found that aspirin attenuated the PGAM1 succinylation to suppress the PGAM1 enzymatic activities and glycolysis in hepatoma cells. Mechanically, aspirin remarkably reduced the global succinylation levels of hepatoma cells, including the PGAM1 succinylation, which led to the block of conversion from 3-phosphoglycerate (3-PG) to 2-phosphoglycerate (2-PG) in cells. Interestingly, RNA-seq analysis identified that aspirin could significantly decrease the levels of histone acetyltransferase 1 (HAT1), a writer of PGAM1 succinylation, in liver cancer. As a target of aspirin, NF-κB p65 could effectively up-regulate the expression of HAT1 in the system, resulting in the increase of PGAM1 enzymatic activities. Moreover, we observed that the PGAM1-K99R mutant failed to rescue the aspirin-induced inhibition of PGAM1 activities, glycolysis, and proliferation of hepatoma cells relative to PGAM1-WT. Functionally, aspirin down-regulated HAT1 and decreased the PGAM1 succinylation levels in the tumor tissues from mice treated with aspirin in vivo. Thus, we conclude that aspirin modulates PGAM1K99 succinylation to restrict the PGAM1 activities and glycolysis through NF-κB p65/HAT1/PGAM1 signaling in liver cancer. Our finding provides new insights into the mechanism by which aspirin inhibits glycolysis in hepatocellular carcinoma.

Aspirin triggers ferroptosis in hepatocellular carcinoma cells through restricting NF-κB p65-activated SLC7A11 transcription.

A number of studies have shown that aspirin, as commonly prescribed drug, prevents the development of hepatocellular carcinoma (HCC). Ferroptosis as a dynamic tumor suppressor plays a vital role in hepatocarcinogenesis. In this study we investigated whether aspirin affected ferroptosis in liver cancer cells. RNA-seq analysis revealed that aspirin up-regulated 4 ferroptosis-related drivers and down-regulated 5 ferroptosis-related suppressors in aspirin-treated HepG2 cells. Treatment with aspirin (4 mM) induced remarkable ferroptosis in HepG2 and Huh7 cells, which was enhanced by the ferroptosis inducer erastin (10 µM). We demonstrated that NF-κB p65 restricted ferroptosis in HepG2 and Huh7 cells through directly binding to the core region of SLC7A11 promoter and activating the transcription of ferroptosis inhibitor SLC7A11, whereas aspirin induced ferroptosis through inhibiting NF-κB p65-activated SLC7A11 transcription. Overexpression of p65 rescued HepG2 and Huh7 cells from aspirin-induced ferroptosis. HCC patients with high expression levels of SLC7A11 and p65 presented lower survival rate. Functionally, NF-κB p65 blocked the aspirin-induced ferroptosis in vitro and in vivo, which was attenuated by erastin. We conclude that aspirin triggers ferroptosis by restricting NF-κB-activated SLC7A11 transcription to suppress the growth of HCC. These results provide a new insight into the mechanism by which aspirin regulates ferroptosis in hepatocarcinogenesis. A combination of aspirin and ferroptosis inducer may provide a potential strategy for the treatment of HCC in clinic.

Heat shock protein family A member 8 serving as a co-activator of transcriptional factor ETV4 up-regulates PHLDA2 to promote the growth of liver cancer.

Heat shock protein family A member 8 (HSPA8) participates in the folding or degradation of misfolded proteins under stress and plays critical roles in cancer. In this study, we investigated the function of HSPA8 in the development of liver cancer. By analyzing the TCGA transcriptome dataset, we found that HSPA8 was upregulated in 134 clinical liver cancer tissue samples, and positively correlated with poor prognosis. IHC staining showed the nuclear and cytoplasmic localization of HSPA8 in liver cancer cells. Knockdown of HSPA8 resulted in a decrease in the proliferation of HepG2 and Huh-7 cells. ChIP-seq and RNA-seq analysis revealed that HSPA8 bound to the promoter of pleckstrin homology-like domain family A member 2 (PHLDA2) and regulated its expression. The transcription factor ETV4 in HepG2 cells activated PHLDA2 transcription. HSPA8 and ETV4 could interact with each other in the cells and colocalize in the nucleus. From a functional perspective, we demonstrated that HSPA8 upregulated PHDLA2 through the coactivating transcription factor ETV4 to enhance the growth of liver cancer in vitro and in vivo. From a therapeutic perspective, we identified both HSPA8 and PHDLA2 as novel targets in the treatment of HCC. In conclusion, this study demonstrates that HSPA8 serves as a coactivator of ETV4 and upregulates PHLDA2, leading to the growth of HCC, and is a potential therapeutic target in HCC treatment.

High-Symmetry Co/Ni Triazine Polycarboxylate Diverse Frameworks Constructed by Mx(COO)y Building Blocks: Characterization and Catalytic Performance Evaluation of p-Nitrophenol.

Three new triazine compounds [Co1.5(H3TDPAT)(H2O)3]·6H2O (1), [Co2(TCPT)(µ2-H2O)2]·OH (2), and [Ni3(TCPT)]·3OH (3) were designed and synthesized via the reaction of the symmetrical triazine ligand connected by C-N-C and C-O-C bonds with triazine poly(carboxylic acid)s ligands as the side arms: H6TDPAT (H6TDPAT = 2,4,6-tris(3,5-dicarboxylphenylamino)-1,3,5-triazine) and H3TCPT (H3TCPT = 2,4,6-tris(4-carboxyphenoxy)-1,3,5-triazine) as well as the corresponding metal salts under the solvothermal condition. Three triazine polycarboxylate frameworks were characterized by elemental analysis, infrared spectroscopy, ultraviolet spectroscopy, thermogravimetric analysis, X-ray powder diffraction, and solid fluorescent spectra in detail. The structural analysis results showed that the three-dimensional porous cage framework of compound 1 was constructed by three different polyhedral cages connected with [Co(COO)4(H2O)2] building blocks. One of the compounds, 2, is formed by twin propeller Co2(µ2-H2O)(COO)3 building blocks connecting two-dimensional layers and the intermolecular π-π interactions involved the triazine rings between the layers. While the structure of compound 3 is similar to that of 2, assembly is by Ni(COO)3 building blocks and adjacent layers of the face-to-face π-π interaction between the triazine rings. In order to explore functional properties, the catalytic reduction of p-nitrophenol (PNP) of compounds 1-3 was investigated. They exhibit excellent catalytic activity of more than 95% for reduction of PNP with a dose of 2.5 mg of the compounds.

PRMT5 confers lipid metabolism reprogramming, tumour growth and metastasis depending on the SIRT7-mediated desuccinylation of PRMT5 K387 in tumours.

The protein arginine methyltransferase 5 (PRMT5), which is highly expressed in tumour tissues, plays a crucial role in cancer development. However, the mechanism by which PRMT5 promotes cancer growth is poorly understood. Here, we report that PRMT5 contributes to lipid metabolism reprogramming, tumour growth and metastasis depending on the SIRT7-mediated desuccinylation of PRMT5 K387 in tumours. Mass spectrometric analysis identified PRMT5 lysine 387 as its succinylation site. Moreover, the desuccinylation of PRMT5 K387 enhances the methyltransferase activity of PRMT5. SIRT7 catalyses the desuccinylation of PRMT5 in cells. The SIRT7-mediated dessuccinylation of PRMT5 lysine 387 fails to bind to STUB1, decreasing PRMT5 ubiquitination and increasing the interaction between PRMT5 and Mep50, which promotes the formation of the PRMT5-Mep50 octamer. The PRMT5-Mep50 octamer increases PRMT5 methyltransferase activity, leading to arginine methylation of SREBP1a. The symmetric dimethylation of SREBP1a increases the levels of cholesterol, fatty acid, and triglyceride biogenesis in the cells, escaping degradation through the ubiquitin-proteasome pathway. Functionally, the desuccinylation of PRMT5 K387 promotes lipid metabolism reprogramming, tumour growth and metastasis in vitro and in vivo in tumours.

IFN-α inhibits HBV transcription and replication by promoting HDAC3-mediated de-2-hydroxyisobutyrylation of histone H4K8 on HBV cccDNA minichromosome in liver.

The epigenetic modification of hepatitis B virus (HBV) covalently closed circular DNA (cccDNA) plays a crucial role in cccDNA transcription and viral persistence. Interferon-α (IFN-α) is a pivotal agent against HBV cccDNA. However, the mechanism by which IFN-α modulates the epigenetic regulation of cccDNA remains poorly understood. In this study, we report that IFN-α2b enhances the histone deacetylase 3 (HDAC3)-mediated de-2-hydroxyisobutyrylation of histone H4 lysine 8 (H4K8) on HBV cccDNA minichromosome to restrict the cccDNA transcription in liver. By screening acetyltransferases and deacetylases, we identified that HDAC3 was an effective restrictor of HBV transcription and replication. Moreover, we found that HDAC3 was able to mediate the de-2-hydroxyisobutyrylation of H4K8 in HBV-expressing hepatoma cells. Then, the 2-hydroxyisobutyrylation of histone H4K8 (H4K8hib) was identified on the HBV cccDNA minichromosome, promoting the HBV transcription and replication. The H4K8hib was regulated by HDAC3 depending on its deacetylase domain in the system. The low level of HDAC3 and high level of H4K8hib were observed in the liver tissues from HBV-infected human liver-chimeric mice. The levels of H4K8hib on HBV cccDNA minichromosome were significantly elevated in the liver biopsy specimens from clinical hepatitis B patients, which was consistent with the high transcriptional activity of cccDNA. Strikingly, IFN-α2b effectively facilitated the histone H4K8 de-2-hydroxyisobutyrylation mediated by HDAC3 on the HBV cccDNA minichromosome in primary human hepatocytes and hepatoma cells, leading to the inhibition of HBV transcription and replication. Our finding provides new insights into the mechanism by which IFN-α modulates the epigenetic regulation of HBV cccDNA minichromosome.

[Application of "kindergarten effect" in radiotherapy for children with tumor aged 3-5 years]. / "幼儿园效应"在3~5å²å„¿ç«¥è‚¿ç˜¤æ”¾ç–—ä¸­çš„åº”ç”¨ç ”ç©¶.

OBJECTIVES: To study the clinical application effect of "kindergarten effect" in radiotherapy for children with tumor based on the psychology of preschool children aged 3-5 years. METHODS: A total of 30 children, aged 3-5 years, who were admitted to the Department of Radiotherapy, Tianjin Medical University Cancer Institute and Hospital, from January 2020 to August 2021 were enrolled in this prospective study. The children were randomly divided into a control group and a test group, with 15 children in each group. The children in the test group were treated in "kindergarten mode", i.e., all children were treated together at a specified time and left together after all children completed treatment. Those in the control group were treated alternately with adult patients according to the treatment time based on the type of radiotherapy fixation device. The treatment compliance was evaluated for both groups, and the two groups were compared in terms of the setup errors in the superior-inferior (SI), left-right (LR), and anterior-posterior (AP) directions. RESULTS: Compared with the control group, the test group showed a significantly shorter time for finishing the treatment (P<0.05) and a significantly lower proportion of children with treatment interruption (P<0.05). Compared with the control group, the test group showed smaller mean errors in the SI, LR and AP directions after image-guided radiotherapy, with significant differences in the mean errors in the SI and LR directions (P<0.05). CONCLUSIONS: With the application of the "kindergarten effect", most children can actively cooperate in radiotherapy, and it can also improve the accuracy and repeatability of positioning and help to achieve the desired treatment outcome.

Aspirin modulates 2-hydroxyisobutyrylation of ENO1K281 to attenuate the glycolysis and proliferation of hepatoma cells.

Aspirin can efficiently inhibit the glycolysis and proliferation of cancer cells, however, the underlying mechanism is poorly understood. Here, we report that aspirin attenuates the glycolysis and proliferation of hepatoma cells through modulating the levels of lysine 2-hydroxyisobutyrylation (Khib) of enolase 1 (ENO1). We found that aspirin decreased the levels of glucose consumption and lactate production in hepatoma cells. Moreover, 4 mM aspirin reduced the activities of ENO1, a key enzyme of glycolysis, and decreased the levels of ENO1 Khib in the cells. Interestingly, we identified that 4 mM aspirin could decrease the levels of Khib on many proteins by using pan Khib antibody in the cells. Interestingly, the activities of ENO1 could be rescued by the transient overexpression of ENO1, but not by ENO1 mutant (K281R). Moreover, we identified that the C646, an inhibitor of p300 which is a writer of Khib, could reduce the levels of ENO1 Khib, resulting in the decrease of ENO1 activities. The treatment with PDTC, an inhibitor of NF-κB which is a target of aspirin, could work well as C646 in the cells. Both of aspirin and C646 (or PDTC) displayed a stronger effect than the single treatment in the system. Functionally, ENO1, but not ENO1 mutant (K281R), could rescue the aspirin-induced inhibition of proliferation of liver cancer cells in vitro, suggesting that ENO1K281 is involved in the aspirin-mediated inhibition of liver cancer. Our finding provides new insights into the mechanism by which aspirin attenuates the glycolysis and proliferation of hepatoma cells.

OTOR in breast carcinoma as a potent prognostic predictor correlates with cell proliferation, migration, and invasiveness.

Otoraplin (OTOR), recognized as an important cochlear gene, has a predicted secretory signal peptide sequence and harbors a high degree of cross-species conservation. However, its role in tumor progression is relatively unclear, especially in breast carcinoma (BC). This study investigated the clinicopathological significance of OTOR in breast infiltrating ductal carcinoma (IDC) with high metastasis to uncover its biological function in BC. OTOR was highly overexpressed in BC tissues and cells compared with normal samples. OTOR overexpression was associated with certain clinicopathological characteristics and poorer prognosis (overall survival; OS) of patients with breast IDC. As determined using CCK-8, colony formation, wound-healing, and Transwell assays, silencing OTOR using siRNA impeded BC-cell proliferation, migration, and invasiveness, which may have resulted from inactivating the mitogen-activated protein kinase - extracellular-signal-regulated kinase pathway. These results indicate that OTOR plays a crucial role in the progression of and prognosis for BC, which could help to identify future therapeutic targets for treating BC patients.

Fossil evidence reveals how plants responded to cooling during the Cretaceous-Paleogene transition.

BACKGROUND: Around the Cretaceous-Paleogene (K-Pg) boundary, an obvious global cooling occurred, which resulted in dramatic changes in terrestrial ecosystems and the evolutionary trends of numerous organisms. However, how plant lineages responded to the cooling has remained unknown until now. Between ca. 70-60 Ma Mesocyparis McIver & Basinger (Cupressaceae), an extinct conifer genus, was distributed from eastern Asia to western North America and provides an excellent opportunity to solve this riddle. RESULTS: Here we report a new species, Mesocyparis sinica from the early Paleocene of Jiayin, Heilongjiang, northeastern China. By integrating lines of evidence from phylogeny and comparative morphology of Mesocyparis, we found that during ca.70-60 Ma, the size of seed cone of Mesocyparis more than doubled, probably driven by the cooling during the K-Pg transition, which might be an effective adaptation for seed dispersal by animals. More importantly, we discovered that the northern limit of this genus, as well as those of two other arboreal taxa Metasequoia Miki ex Hu et Cheng (gymnosperm) and Nordenskioldia Heer (angiosperm), migrated ca.4-5° southward in paleolatitude during this time interval. CONCLUSIONS: Our results suggest that the cooling during the K-Pg transition may have been responsible for the increase in size of the seed cone of Mesocyparis and have driven the migration of plants southwards.

Influence of the Neonicotinoid Insecticide Thiamethoxam on miRNA Expression in the Honey Bee (Hymenoptera: Apidae).

MicroRNAs (miRNAs) are small endogenous noncoding single-stranded RNAs regulating gene expression in eukaryotes. They play important roles in regulating caste differentiation, behavior development, and immune defences in the honey bee, Apis mellifera (Linnaeus) (Hymenoptera: Apidae). In this study, we explored the effect of the neonicotinoid insecticide, thiamethoxam, on miRNA expression in this species using deep small RNA sequencing. The results showed that seven miRNAs were significantly differentially expressed (q-value <0.01 and |log2(fold-change)| >1) upon exposure to 10 ppb thiamethoxam over 10 d. Some candidate target genes were related to behavior, immunity, and neural function. Several miRNAs, including ame-miR-124, ame-miR-981, ame-miR-3791, and ame-miR-6038, were selected and further validated using real-time quantitative PCR analysis. The findings expand our understanding of the effects of neonicotinoid insecticides on honey bees at the molecular level.