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The cyclic GMP-AMP (cGAMP) synthase (cGAS)-stimulator of interferon genes (STING) pathway has a crucial role in combating pathogen infection. However, its aberrant activation is involved in several human disorders. Lysosomes are emerging as key negative regulators of cGAS-STING signaling. Here, we discuss the lysosomal control of cGAS-STING signaling and its implication in human disorders., Competing Interests: Declaration of interests No interests are declared., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

LC3 lipidation plays an important role in the regulation of macroautophagy and LC3-associated microautophagy. The E1-like enzyme ATG7 is one of the core components that are directly involved in LC3 lipidation reaction. Here, we provide evidence showing that acetylation of ATG7 tightly controls its enzyme activity to regulate the induction of macroautophagy and LC3-associated microautophagy. Mechanistically, acetylation of ATG7 disrupts its interaction with the E2-like enzyme ATG3, leading to an inhibition of LC3 lipidation in vitro and in vivo . Functionally, in response to various different stimuli, cellular ATG7 undergoes deacetylation to induce macroautophagy and LC3-associated microautophagy, which are necessary for cells to eliminate cytoplasmic DNA and degrade lysosome membrane proteins, respectively. Taken together, these findings reveal that ATG7 acetylation acts as a critical rheostat in controlling LC3 lipidation and related cellular processes. Abbreviations: AMPK: AMP-activated protein kinase; ATG: autophagy-related; cGAMP: cyclic GMP-AMP; CGAS: cyclic GMP-AMP synthase; CREBBP/CBP: CREB binding protein; EGF: epidermal growth factor; EGFR: epidermal growth factor receptor; EP300/p300: E1A binding protein p300; IFNB1: interferon beta 1; ISD: interferon stimulatory DNA; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MCOLN1/TRPML1: mucolipin TRP cation channel 1; MEF: mouse embryonic fibroblast; MTOR: mechanistic target of rapamycin kinase; NAM: nicotinamide; PE: phosphatidylethanolamine; PTM: post-translational modification; RB1CC1/FIP200: RB1 inducible coiled-coil 1; SIRT: sirtuin; SQSTM1/p62: sequestosome 1; STING1: stimulator of interferon response cGAMP interactor 1; TSA: trichostatin A; ULK1: unc-51 like autophagy activating kinase 1; WIPI2: WD repeat domain, phosphoinositide interacting 2; WT: wild-type.

Objective. The accurate automatic segmentation of tumors from computed tomography (CT) volumes facilitates early diagnosis and treatment of patients. A significant challenge in tumor segmentation is the integration of the spatial correlations among multiple parts of a CT volume and the context relationship across multiple channels. Approach. We proposed a mutually enhanced multi-view information model (MEMI) to propagate and fuse the spatial correlations and the context relationship and then apply it to lung tumor CT segmentation. First, a feature map was obtained from segmentation backbone encoder, which contained many image region nodes. An attention mechanism from the region node perspective was presented to determine the impact of all the other nodes on a specific node and enhance the node attribute embedding. A gated convolution-based strategy was also designed to integrate the enhanced attributes and the original node features. Second, transformer across multiple channels was constructed to integrate the channel context relationship. Finally, since the encoded node attributes from the gated convolution view and those from the channel transformer view were complementary, an interaction attention mechanism was proposed to propagate the mutual information among the multiple views. Main results. The segmentation performance was evaluated on both public lung tumor dataset and private dataset collected from a hospital. The experimental results demonstrated that MEMI was superior to other compared segmentation methods. Ablation studies showed the contributions of node correlation learning, channel context relationship learning, and mutual information interaction across multiple views to the improved segmentation performance. Utilizing MEMI on multiple segmentation backbones also demonstrated MEMI's generalization ability. Significance. Our model improved the lung tumor segmentation performance by learning the correlations among multiple region nodes, integrating the channel context relationship, and mutual information enhancement from multiple views., (© 2024 Institute of Physics and Engineering in Medicine.)

As one of the major acetyltransferases in mammalian cells, p300 (also known as EP300) and its highly related protein CBP (also known as CREBBP), collectively termed p300/CBP, is characterized as a key regulator in gene transcription by modulating the acetylation of histones. In recent decades, proteomic analyses have revealed that p300 is also involved in the regulation of various cellular processes by acetylating many non-histone proteins. Among the identified substrates, some are key players involved in different autophagy steps, which together establish p300 as a master regulator of autophagy. Accumulating evidence has shown that p300 activity is controlled by many distinct cellular pathways to regulate autophagy in response to cellular or environmental stimuli. In addition, several small molecules have been shown to regulate autophagy by targeting p300, suggesting that manipulation of p300 activity is sufficient for controlling autophagy. Importantly, dysfunction of p300-regulated autophagy has been implicated in a number of human disorders, such as cancer, aging and neurodegeneration, highlighting p300 as a promising target for the drug development of autophagy-related human disorders. Here, we focus on the roles of p300-mediated protein acetylation in the regulation of autophagy and discuss implications for autophagy-related human disorders., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2023. Published by The Company of Biologists Ltd.)

Background: Combined injuries of ipsilateral wrist and elbow joints are rare in clinical practice, characterized by multiple joint dislocations or/and fractures and varying manifestations. As there are still no clinical guidelines and no consensus on the standard treatment, this study aimed to explore the surgical intervention and complications of this kind of combined injuries., Methods: This retrospective study was conducted in a single center. A total of 13 patients with acute combined injuries of the ipsilateral wrist and elbow joints receiving surgical treatment from August 2013 to May 2016 were retrospectively analyzed. The fracture and joint instability and structural damages were repaired and reconstructed., Results: All 13 patients were followed up for a mean duration of 17 months (range: 14 to 22 months). The X-ray films showed good fracture reduction and joint alignment, no fixation failure, re-displacement, bone nonunion, or ischemic necrosis in all cases. According to the Mayo Elbow Performance Score (MEPS), the excellent and good rate of joint function was 84.6%. According to the Mayo Modified Wrist Score (MMWS), the excellent and good rate of joint function was 76.9%. There were no significant restrictions on elbow and wrist movements. The disabilities of the arm, shoulder, and hand (DASH) score was excellent, with an average of 18.5 points., Conclusions: The key to intervention of combined injuries of the wrist and elbow is to identify the types of injuries and conduct an overall assessment to determine the appropriate surgical methods. Early surgical intervention and rehabilitation exercise are the main principles for the treatment., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://atm.amegroups.com/article/view/10.21037/atm-22-6598/coif). The authors have no conflicts of interest to declare., (2023 Annals of Translational Medicine. All rights reserved.)

Post-translational modifications, such as phosphorylation, ubiquitination and acetylation, play crucial roles in the regulation of autophagy. Acetylation has emerged as an important regulatory mechanism for autophagy. Acetylation regulates autophagy initiation and autophagosome formation by targeting core components of the ULK1 complex, the BECN1-PIK3C3 complex, and the LC3 lipidation system. Recent studies have shown that acetylation occurs on the key proteins participating in autophagic cargo assembly and autophagosome-lysosome fusion, such as SQSTM1/p62 and STX17. In addition, acetylation controls autophagy at the transcriptional level by targeting histones and the transcription factor TFEB. Here, we review the current knowledge on acetylation of autophagy proteins and their regulations and functions in the autophagy pathway with focus on recent findings. Abbreviations : ACAT1: acetyl-CoA acetyltransferase 1; ACSS2: acyl-CoA synthetase short chain family member 2; AMPK: AMP-activated protein kinase; ATG: autophagy-related; CALCOCO2/NDP52: calcium binding and coiled-coil domain 2; CCAR2/DBC1: cell cycle and apoptosis regulator 2; BECN1: beclin 1; CMA: chaperone-mediated autophagy; CREBBP/CBP: CREB binding protein; EP300/p300: E1A binding protein p300; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; GSK3: glycogen synthase kinase 3; HDAC6: histone deacetylase 6; HSPA8/HSC70: heat shock protein family A (Hsp70) member 8; KAT2A/GCN5: lysine acetyltransferase 2A; KAT2B/PCAF: lysine acetyltransferase 2B; KAT5/TIP60: lysine acetyltransferase 5; KAT8/MOF: lysine acetyltransferase 8; LAMP2A: lysosomal associated membrane protein 2A; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MTOR: mechanistic target of rapamycin kinase; NBR1: NBR1 autophagy cargo receptor; OPTN: optineurin; PD: Parkinson disease; PE: phosphatidylethanolamine; PIK3C3/VPS34: phosphatidylinositol 3-kinase catalytic subunit type 3; PKM2: pyruvate kinase M1/2; PtdIns3P: phosphatidylinositol-3-phosphate; PTM: post-translational modification; RB1CC1/FIP200: RB1 inducible coiled-coil 1; RUBCN/Rubicon: rubicon autophagy regulator; RUBCNL/Pacer: rubicon like autophagy enhancer; SIRT1: sirtuin 1; SNAP29: synaptosome associated protein 29; SNARE: soluble N-ethylamide-sensitive factor attachment protein receptor; SQSTM1/p62: sequestosome 1; STX17: syntaxin 17; TFEB: transcription factor EB; TP53/p53: tumor protein p53; TP53INP2/DOR: tumor protein p53 inducible nuclear protein 2; UBA: ubiquitin-associated; ULK1: unc-51 like autophagy activating kinase 1; VAMP8: vesicle associated membrane protein 8; WIPI2: WD repeat domain, phosphoinositide interacting 2.

Autophagy has emerged as a key regulator of cell metabolism. Recently, we have demonstrated that autophagy is involved in RNA metabolism by regulating ribosomal RNA (rRNA) synthesis. We found that autophagy-deficient cells display much higher 47S precursor rRNA level, which is caused by the accumulation of SQSTM1/p62 (sequestosome 1) but not other autophagy receptors. Mechanistically, SQSTM1 accumulation potentiates the activation of MTOR (mechanistic target of rapamycin kinase) complex 1 (MTORC1) signaling, which facilitates the assembly of RNA polymerase I pre-initiation complex at ribosomal DNA (rDNA) promoter regions and leads to the activation of rDNA transcription. Finally, we showed that SQSTM1 accumulation is responsible for the increase in protein synthesis, cell growth and cell proliferation in autophagy-deficient cells. Taken together, our findings reveal a regulatory role of autophagy and autophagy receptor SQSTM1 in rRNA synthesis and may provide novel mechanisms for the hyperactivated rDNA transcription in autophagy-related human diseases. Abbreviations: 5-FUrd: 5-fluorouridine; LAP: MAP1LC3/LC3-associated phagocytosis; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MTOR: mechanistic target of rapamycin kinase; PIC: pre-initiation complex; POLR1: RNA polymerase I; POLR1A: RNA polymerase I subunit A; rDNA: ribosomal DNA; RRN3: RRN3 homolog, RNA polymerase I transcription factor; rRNA: ribosomal RNA; SQSTM1/p62: sequestosome 1; TP53INP2: tumor protein p53 inducible nuclear protein 2; UBTF: upstream binding transcription factor.

It is well known that the small intestinal epithelial cells of mammals rapidly undergo differentiation, maturation, and apoptosis. However, few studies have defined the physiological state and gene expression changes of enterocytes along the crypt-villus axis in suckling piglets. In the present study, we obtained the intestinal upper villus epithelial cells (F1) and crypt epithelial cells (F3) of 21-day suckling piglets using the divalent chelation and precipitation technique. The activities of alkaline phosphatase, sucrase, and lactase of F1 were significantly higher (p < 0.05) than those of F3. To explore the differences at the gene transcription level, we compared the global transcriptional profiles of F1 and F3 using RNA-seq analysis technology. A total of 672 differentially expressed genes (DEGs) were identified between F1 and F3, including 224 highly expressed and 448 minimally expressed unigenes. Functional analyses indicated that some DEGs were involved in the transcriptional regulation of nutrient transportation (SLC15A1, SLC5A1, and SLC3A1), cell differentiation (LGR5, HOXA5 and KLF4), cell proliferation (PLK2 and TGFB3), transcriptional regulation (JUN, FOS and ATF3), and signaling transduction (WNT10B and BMP1), suggesting that these genes were related to intestinal epithelial cell maturation and cell renewal. Gene Ontology (GO) enrichment analysis showed that the DEGs were mainly associated with binding, catalytic activity, enzyme regulator activity, and molecular transducer activity. Furthermore, KEGG pathway analysis revealed that the DGEs were categorized into 284 significantly enriched pathways. The greatest number of DEGs enriched in signal transduction, some of which (Wnt, Hippo, TGF-beta, mTOR, PI3K-Akt, and MAPK signaling pathways) were closely related to the differentiation, proliferation, maturation and apoptosis of intestinal epithelial cells. We validated the expression levels of eight DEGs in F1 and F3 using qRT-PCR. The present study revealed temporal and regional changes in mRNA expression between F1 and F3 of suckling piglets, which provides insights into the regulatory mechanisms underlying intestinal epithelial cell renewal and the rapid repair of intestinal mucosal damage.

Macroautophagy/autophagy, a highly conserved lysosome-dependent degradation pathway, has been intensively studied in regulating cell metabolism by degradation of intracellular components. In this study, we link autophagy to RNA metabolism by uncovering a regulatory role of autophagy in ribosomal RNA (rRNA) synthesis. Autophagy-deficient cells exhibit much higher 47S precursor rRNA level, which is caused by the accumulation of SQSTM1/p62 (sequestosome 1) but not other autophagy receptors. Mechanistically, SQSTM1 accumulation potentiates the activation of MTOR (mechanistic target of rapamycin kinase) complex 1 (MTORC1) signaling and promotes the assembly of RNA polymerase I pre-initiation complex at ribosomal DNA (rDNA) promoters, which leads to an increase of 47S rRNA transcribed from rDNA. Functionally, autophagy deficiency promotes protein synthesis, cell growth and cell proliferation, both of which are dependent on SQSTM1 accumulation. Taken together, our findings suggest that autophagy deficiency is involved in RNA metabolism by activating rDNA transcription and provide novel mechanisms for the reprogramming of cell metabolism in autophagy-related diseases including multiple types of cancers. Abbreviations: 5-FUrd: 5-fluorouridine; AMPK: AMP-activated protein kinase; ATG: autophagy related; CALCOCO2/NDP52: calcium binding and coiled-coil domain 2; ChIP: chromatin immunoprecipitation; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MAPK/ERK: mitogen-activated protein kinase; MTOR: mechanistic target of rapamycin kinase; NBR1: NBR1 autophagy cargo receptor; NFKB/NF-κB: nuclear factor kappa B; NFE2L2/NRF2: nuclear factor, erythroid 2 like 2; OPTN: optineurin; PIC: pre-initiation complex; POLR1: RNA polymerase I; POLR1A/RPA194: RNA polymerase I subunit A; POLR2A: RNA polymerase II subunit A; rDNA: ribosomal DNA; RPS6KB1/S6K1: ribosomal protein S6 kinase B1; rRNA: ribosomal RNA; RUBCN/Rubicon: rubicon autophagy regulator; SQSTM1/p62: sequestosome 1; STX17: syntaxin 17; SUnSET: surface sensing of translation; TAX1BP1: Tax1 binding protein 1; UBTF/UBF1: upstream binding transcription factor; WIPI2: WD repeat domain, phosphoinositide interacting 2; WT: wild-type.

TIGIT is an emerging novel checkpoint target that is expressed on both tumor-infiltrating T cells and NK cells. Some current investigational antibodies targeting TIGIT have also achieved dramatic antitumor efficacy in late clinical research. Most recently, the relevance of NK cell-associated TIGIT signaling pathway to tumors' evasion of the immune system has been clearly revealed, which endows NK cells with a pivotal role in the therapeutic effects of TIGIT blockade. In this article, we describe a novel anti-TIGIT monoclonal antibody, AET2010, which was acquired from a phage-displayed human single-chain antibody library through a cell panning strategy. With emphasis on its regulation of NK cells, we confirmed the excellent ex vivo and in vivo antitumor immunity of AET2010 mediated by the NK-92MI cells. Intriguingly, our work also revealed that AET2010 displays a lower affinity but parallel avidity and activity relative to MK7684, an investigational monoclonal antibody from MSD, implying a reasonable balance of potency and potential side effects for AET2010. Together, these results are promising and warrant further development of AET2010., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Degradation solutions containing atrazine need to be further purified before they are discharged into the aquatic environment. With the objectives of evaluating removal capacity of the microalga Chlorella sp. toward atrazine in degradation solutions and toxicity of the degradation products, we investigated the removal efficiency (RE) and bioaccumulation of atrazine in the microalgae after an 8 d exposure to diluted degraded solutions containing 40 μg/L and 80 μg/L of atrazine as well as degradation products in the present study. Moreover, pure atrazine solutions with similar concentrations were simultaneously inoculated with the microalgae in order to distinguish the influence of the products. The photocatalytic degradation results showed that 31.4% of atrazine was degraded after 60 min, and three degradation products, desisopropyl-atrazine (DIA), desethyl-atrazine (DEA), and desethyl-desisopropyl-atrazine (DEIA) were detected. After an 8-d exposure, 83.0% and 64.3% of atrazine were removed from the degraded solutions containing 40 μg/L and 80 μg/L of atrazine, respectively. In comparison with the control, i.e., pure atrazine solution with equal concentration, Chlorella sp. in the degraded atrazine solution showed lower RE and growth rate. The photosynthetic parameters, especially performance index (PI ABS ), clearly displayed the differences between treatments. The values of PI ABS of Chlorella sp. cultured in degradation atrazine for 8 days were significantly lower (P < 0.01) than that in the corresponding pure atrazine, suggesting potential inhibitory effect of degradation products on the microalgae. Atrazine and the degradation products inhibited algal photosynthesis via depressed light absorption and electron transport, and reduced utilization of light energy via energy dissipation. Our results demonstrated that microalgae Chlorella sp. had an encouraging atrazine removal potential and the degradation products of atrazine may inhibit algal growth and removal capability. This study may be useful for the application of microalgae in herbicide wastewater treatment and understanding algal removal of atrazine in natural aquatic environment., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Ribosomal DNA (rDNA) transcription drives cell growth and cell proliferation via the product ribosomal RNA (rRNA), the essential component of ribosome. Given the fundamental role of rRNA in ribosome biogenesis, rDNA transcription has emerged as one of the effective targets for a number of human diseases including various types of cancers. In this study, we identify curcumin, an ancient drug, as a novel natural inhibitor of rDNA transcription. Curcumin treatment impairs the assembly of the RNA polymerase I preinitiation complex at rDNA promoters and represses rDNA promoter activity, which leads to the decrease of rRNA synthesis. In addition, curcumin treatment stimulates autophagosome formation and promotes autophagic degradation in cells. Mechanistically, curcumin inactivates the mechanistic target of rapamycin complex 1 (mTORC1), the upstream regulator of rDNA transcription and autophagy induction, by inhibiting mTOR lysosomal localization. Functionally, curcumin treatment inhibits protein synthesis, cell growth and cell proliferation. Taken together, these findings identify curcumin as an effective inhibitor of rDNA transcription and provide novel mechanisms for the anticancer properties of curcumin. Abbreviations: Atg: autophagy-related; GFP: green fluorescent protein; LAMP2: lysosomal associated membrane protein 2; LC3: microtubule-associated protein 1 light chain 3; MEF: mouse embryonic fibroblast; mTORC1: mechanistic target of rapamycin complex 1; rDNA: ribosomal DNA; rRNA: ribosomal RNA; TP53INP2: tumor protein p53 inducible nuclear protein 2.

Background: Osteosarcoma (OS) is the most common primary malignancy of bone with a high incidence in children. Circular RNAs (circRNAs) play crucial roles in the carcinogenesis and chemoresistance of OS. In the current work, we focused on the function and mechanism of hsa&#95;circ&#95;0003496 (circ&#95;0003496) in OS progression and chemoresistance., Materials and Methods: The expression levels of circ&#95;0003496, miR-370 and Krüppel-like factor 12 (KLF12) mRNA were measured by quantitative real-time polymerase chain reaction (qRT-PCR). The Cell Counting Kit-8 (CCK-8) assay was used to assess the 50% inhibitory concentration (IC50) value and cell proliferation. Cell migration, invasion and apoptosis were detected by transwell assay and flow cytometry, respectively. Western blot analysis was performed to assess the protein level. Targeted relationships among circ&#95;0003496, miR-370 and KLF12 were validated by dual-luciferase reporter, RNA immunoprecipitation (RIP) and RNA pull-down assays. Animal studies were carried out to observe the role of circ&#95;0003496 in vivo., Results: Our results indicated that circ&#95;0003496 up-regulation was associated with doxorubicin (DXR) resistance of OS. Circ&#95;0003496 knockdown repressed DXR-resistant OS cell proliferation, migration and invasion, and enhanced apoptosis and DXR sensitivity. Circ&#95;0003496 functioned as a sponge of miR-370, and miR-370 mediated the regulatory effect of circ&#95;0003496 depletion on DXR-resistant OS cell progression and DXR sensitivity. KLF12 was a direct target of miR-370, and miR-370 overexpression suppressed cell progression and enhanced DXR sensitivity by KLF12. Moreover, circ&#95;0003496 protected against KLF12 repression through sponging miR-370. Additionally, circ&#95;0003496 knockdown hampered tumor growth and promoted DXR sensitivity in vivo., Conclusion: Our present work suggested that the knockdown of circ&#95;0003496 suppressed OS progression and enhanced DXR sensitivity at least partially through modulating KLF12 expression via functioning as a miR-370 sponge, highlighting new opportunities for OS management., Competing Interests: The authors report no funding and no conflicts of interest for this work., (© 2020 Xie et al.)

Cells integrate intracellular and extracellular cues to precisely control the balance of anabolic and catabolic processes, which is essential for cells to maintain homeostasis. The nuclear protein TP53INP2 (tumor protein p53 inducible nuclear protein 2) has emerged as one of the key players participating in both anabolic and catabolic processes. In the nucleus including the nucleolus, TP53INP2 binds to multiple transcription-related factors to modulate transcription, such as the transcription of thyroid hormone-related genes and ribosomal DNA. Interestingly, upon nutrient deprivation, TP53INP2 rapidly moves from the nucleus to the cytoplasm and participates in the regulation of macroautophagy/autophagy. By acting as a nutrient status sensor, TP53INP2 switches its role between transcription and autophagy by changing its subcellular localization and helps the cell to cope with environmental changes., Abbreviations: Atg: autophagy related; LIR: LC3-interacting region; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; MTORC1: mechanistic target of rapamycin kinase complex 1; rDNA: ribosomal DNA; TP53INP2: tumor protein p53 inducible nuclear protein 2; UIM: ubiquitin-interacting motif.

Due to their unique structure and properties, carbon nanotubes (CNTs) released into the aquatic environment can potentially influence the behavior of other coexisting pollutants, thereby altering their toxicity to aquatic organisms. In this study, the toxicities of multi-walled CNTs and three heavy metals, copper (Cu), cadmium (Cd) and zinc (Zn) were determined individually. Following this, CNTs with low concentrations (1 and 5 mg/L) were co-exposed with Cu, Cd or Zn to the microalgae Scenedesmus obliquus, to investigate the effects and underlying mechanisms of CNTs on metal toxicity. Results showed that CNTs, especially at a concentration of 5 mg/L, promoted algae growth and enhanced photosynthetic efficiency via increasing exciton trap efficiency and quantum yield for electron transport. Introduction of CNTs appeared to alleviate the adverse effects of Cu, Cd or Zn on microalgae, indicated by algae growth, total chlorophyll content and photosynthetic indices. However, these effects differed greatly for different metals, depending on both the toxicity of each metal and the exposure period (4 day and 8 day). Enhancement of photosynthesis and interference of metal uptake by CNTs, have a crucial role in the effects of CNTs on metal toxicity., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Atrazine is a widely-applied herbicide used primarily to control weeds, which can persist in the ecosystem and exert potential toxicity to phytoplankton in the aquatic environment. In this study, acute toxicity of atrazine on microalgae Chlorella sp. was investigated with different initial cell densities (1 × 10 5 and 1 × 10 6  cells mL -1 ) and exposure periods (4 d and 8 d). Both growth rate and photosynthetic parameters of the microalgae in response of atrazine stress were determined to find out the sensitive indices and toxicological mechanisms. Because of the independence of initial cell density as well as the high sensitivity and reliability, the performance index PI ABS was verified as the most convincing photosynthetic parameter for indicating IC 50 of atrazine on Chlorella sp., being superior to the traditional parameters of growth rate and F V /F M . The IP amplitude (ΔF IP , fluorescence amplitude of the I-to-P-rise in the OJIP curve) was another sensitive biomarker to reflect atrazine stress. Results from chlorophyll fluorescence transient revealed that atrazine damaged the photosystem II (PS II) reaction center, suppressed the electron transport at the donor and receptor sides, and acted on the absorption, transfer, and utilization of light energy. Our results provide confirmatory references for understanding the toxicity and mechanisms of atrazine on freshwater microalgae., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Inflammation and insomnia are medical problems that may severely affect work and health, thereby necessitating strategies for their effective treatment. Icartin (ICT) is a major active monomeric component of icariin  . Studies have revealed that ICT possesses several pharmacological properties such anti-inflammatory, anti-tumor, anti-fibrotic, anti-osteoporotic and neuroprotective effects. The present research was carried out to investigate the anti-inflammatory, analgesic and sedative/hypnotic effects of ICT. The results obtained revealed that ICT exerted a good anti-inflammatory effect related to the downregulations of inflammatory cytokines and the inhibition of COX-2 signaling pathway. Moreover, ICT enhanced Cl- influx in mouse cortical cells in a concentration-dependent manner. These data suggest that ICT exerts a hypnotic effect in mice through a mechanism associated with increased Cl- influx in cortical cells.

The tumor protein p53-inducible nuclear protein 2 (TP53INP2) has been reported to participate in autophagy by interacting with autophagosome-localized autophagy-related protein 8 (Atg8) family proteins, including LC3. Here, we uncover a novel function for TP53INP2 in the autophagic degradation of proteins. We identify the ubiquitin-interacting motif (UIM) of TP53INP2 that mediates its binding to ubiquitin and ubiquitinated proteins. TP53INP2 lacking the UIM is able to displace autophagic adaptor p62 from LC3, which leads to accumulation of ubiquitinated proteins in cells. Furthermore, overexpression of TP53INP2 lacking the UIM sensitizes cells to chloroquine treatment. Our findings indicate that TP53INP2 may act as a novel autophagic adaptor through recruiting ubquitinated substrates to autophagosomes for degradation., (© 2019 Federation of European Biochemical Societies.)

TP53INP2/DOR (tumor protein p53-inducible nuclear protein 2) contributes to mammalian macroautophagy/autophagy by carrying nuclear deacetylated MAP1LC3/LC3 to the cytoplasm. Here, we report that in the cytoplasm, TP53INP2 further functions in autophagosome biogenesis by promoting LC3B-ATG7 interaction. Cytoplasmic expression of the N-terminal region of TP53INP2, which includes the LC3-interacting region, effectively triggered LC3B-PE production and autophagosome formation. In the cytoplasm, TP53INP2 colocalized to early autophagic membrane structures containing ATG14, ZFYVE1/DFCP1 or WIPI2. While knockdown of TP53INP2 did not affect the formation of these autophagic structures, deletion of BECN1 or Atg5 , or mutations preventing TP53INP2 from LC3 interaction, disrupted the membrane binding of TP53INP2. TP53INP2 interacted directly with ATG7 to form a LC3B-TP53INP2-ATG7 complex in the cytoplasm. Loss of TP53INP2-LC3 or TP53INP2-ATG7 interaction significantly reduced LC3B-ATG7 binding. Together, these results suggest that after shifting from the nucleus, cytoplasmic TP53INP2 is targeted to early autophagic membranes accompanied by LC3, where it contributes to autophagosome biogenesis by mediating LC3-ATG7 interaction. Abbreviations : 3-MA, 3-methyladenine; 3NES, 3 repeated nuclear export signal; 3NLS, 3 repeated nuclear localization signal; ACTB, actin beta; ATG, autophagy related; BECN1, Beclin 1; mCherry, monomeric red fluorescent protein mCherry; GFP, green fluorescent protein; GST, glutathione S-transferase; KO, knockout; LC3B/MAP1LC3B, microtubule-associated protein 1 light chain 3 beta; LC3B[G120], LC3B mutant lacking amino acids after glycine 120; LDH, lactate dehydrogenase; LMNB1, lamin B1; LIR, LC3-interacting region; MTORC1, mechanistic target of rapamycin complex 1; PE, phosphatidylethanolamine; PtdIns3K, phosphatidylinositol 3-kinase; PtdIns3P, phosphatidylinositol 3-phosphate; rDNA, ribosomal DNA; RFP, red fluorescent protein; RNAi, RNA interference; SQSTM1, sequestosome 1; TP53INP2, tumor protein p53-inducible nuclear protein 2; TP53INP2[1-28], TP53INP2 mutant containing amino acids 1 to 28; TP53INP2[28-45], TP53INP2 mutant containing amino acids 28 to 45; TP53INP2[LIRΔ], TP53INP2 mutant lacking amino acids 1 to 144; TP53INP2[NLSΔ], TP53INP2 mutant lacking amino acids 145 to 221; TP53INP2 W35,I38A , TP53INP2 mutant in which tryptophan 35 and isoleucine 38 are replaced with alanine; TP53INP2 W35,I38A [NLSΔ], TP53INP2 mutant lacking amino acids 145 to 221, and tryptophan 35 and isoleucine 38 are replaced with alanine; TP53INP2 W35,I38A [Δ1-28],[NLSΔ], TP53INP2 mutant lacking amino acids 1 to 28 and amino acids 145 to 221, and tryptophan 35 and isoleucine 38 are replaced with alanine; TP53INP2[Δ1-28],[NLSΔ], TP53INP2 mutant lacking amino acids 1 to 28 and amino acids 145 to 221; TP53INP2[Δ67-111],[NLSΔ], TP53INP2 mutant lacking amino acids 67 to 111 and amino acids 145 to 221; TP53INP2[Δ112-144],[NLSΔ], TP53INP2 mutant lacking amino acids 112 to 144 and amino acids 145 to 221; TUBB, tubulin beta class I; ULK1, unc-51 like autophagy activating kinase 1; VMP1, vacuole membrane protein 1; WIPI2, WD repeat domain phosphoinositide-interacting 2; WT, wild-type; ZFYVE1/DFCP1, zinc finger FYVE-type containing 1.

mTORC1, the major homeostatic sensor and responder, regulates cell catabolism mainly by targeting autophagy. Here, we show that mTORC1 directly controls autophagosome formation via phosphorylation of WIPI2, a critical protein in isolation membrane growth and elongation. mTORC1 phosphorylates Ser395 of WIPI2, directing WIPI2 to interact specifically with the E3 ubiquitin ligase HUWE1 for ubiquitination and proteasomal degradation. Physiological or pharmacological inhibition of mTORC1 in cells promotes WIPI2 stabilization, autophagosome formation, and autophagic degradation. In mouse liver, fasting significantly increases the WIPI2 protein level, while silencing HUWE1 enhances autophagy, and introducing WIPI2 improves lipid clearance. Thus, regulation of the intracellular WIPI2 protein level by mTORC1 and HUWE1 is a key determinant of autophagy flux and may coordinate the initiation, progression, and completion of autophagy., (Copyright © 2018 Elsevier Inc. All rights reserved.)

In the present study, a new strain, Bacillus cereus ZY12, producing phospholipase D (PLD) was identified. The expression of PLD in this strain was found to be induced by its substrate, phosphatidylcholine (PC), and completely silenced by other carbon sources, such as glucose, fructose, and maltose, which are generally used in microbial growth cultures, thus presenting a unique expression pattern different from other PLD-producing microorganisms. This study is the first to report on the ability of B. cereus to produce PLD, and successfully clone its PLD-coding gene and identify its function, extending the knowledge on PLD distribution and evolution in microorganisms.

Acetylation is increasingly recognized as one of the major post-translational mechanisms for the regulation of multiple cellular functions in mammalian cells. Acetyltransferase p300, which acetylates histone and non-histone proteins, has been intensively studied in its role in cell growth and metabolism. However, the mechanism underlying the activation of p300 in cells remains largely unknown. Here, we identify the homeostatic sensor mTORC1 as a direct activator of p300. Activated mTORC1 interacts with p300 and phosphorylates p300 at 4 serine residues in the C-terminal domain. Mechanistically, phosphorylation of p300 by mTORC1 prevents the catalytic HAT domain from binding to the RING domain, thereby eliminating intra-molecular inhibition. Functionally, mTORC1-dependent phosphorylation of p300 suppresses cell-starvation-induced autophagy and activates cell lipogenesis. These results uncover p300 as a direct target of mTORC1 and suggest that the mTORC1-p300 pathway plays a pivotal role in cell metabolism by coordinately controlling cell anabolism and catabolism., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: The purpose of this study was to evaluate whether PFNA-II (Asia proximal femoral nail anti-rotation) and DHS (dynamic hip screw) carry substantial post-operative hidden blood loss and to compare PFNA-II with DHS in terms of post-operative hidden blood loss in elderly high-risk patients with intertrochanteric femur fractures(IFFs)., Methods: The clinical data from Jan 2005 to Apr 2015 of 186 patients with PFNA-II and 177 patients with DHS were analyzed retrospectively. Indexes including pre- and post-operative blood routine, intra- and post-operative blood loss and blood transfusion situation were analyzed. The situation of perioperative blood loss (visible and hidden) was assessed., Results: The intra-operative blood loss in the PFNA-II group was 34.7 ± 2.5 ml, the post-operative visible blood loss was 54.7 ± 2.5 ml, and the hidden blood loss was 277.2 ± 7.6 ml. In the DHS group, the intra-operative blood loss was 102.0 ± 7.0 ml, the post-operative visible blood loss was 78.8 ± 4.7 ml, and the hidden blood loss was 139.3 ± 9.6 ml. The intra-operative blood loss and the post-operative visible blood loss in the PFNA-II group were significantly less than in the DHS group (p < 0.01). However, the post-operative hidden blood loss and the total blood loss in the PFNA-II group were larger than in the DHS group (p < 0.01)., Conclusion: This study demonstrated that with PFNA-II and DHS, much post-operative hidden blood loss exists in the treatment of intertrochanteric fractures in elderly high-risk patients and DHS is more favourable than PFNA-II in terms of post-operative hidden blood loss.

Cells control their metabolism through modulating the anabolic and catabolic pathways. TP53INP2/DOR (tumor protein p53 inducible nuclear protein 2), participates in cell catabolism by serving as a promoter of autophagy. Here we uncover a novel function of TP53INP2 in protein synthesis, a major biosynthetic and energy-consuming anabolic process. TP53INP2 localizes to the nucleolus through its nucleolar localization signal (NoLS) located at the C-terminal domain. Chromatin immunoprecipitation (ChIP) assays detected an association of TP53INP2 with the ribosomal DNA (rDNA), when exclusion of TP53INP2 from the nucleolus repressed rDNA promoter activity and the production of ribosomal RNA (rRNA) and proteins. The removal of TP53INP2 also impaired the association of the POLR1/RNA polymerase I preinitiation complex (PIC) with rDNA. Further, TP53INP2 interacts directly with POLR1 PIC, and is required for the assembly of the complex. These data indicate that TP53INP2 promotes ribosome biogenesis through facilitating rRNA synthesis at the nucleolus, suggesting a dual role of TP53INP2 in cell metabolism, assisting anabolism on the nucleolus, and stimulating catabolism off the nucleolus.

Background: Dynamic hip screws (DHSs) and proximal femoral nails anti-rotation (PFNAs) are well-documented implants for stable intertrochanteric femur fractures(IFFs); however, there is no consensus regarding which type of implant is the better option for stable IFFs. This study aimed to compare DHSs with PFNAs in the management of stable intertrochanteric fractures., Methods: A retrospective study was performed in our institution. Between June, 2005 and November, 2015, 267 patients (267 hips) with stable IFFs (AO/OTA Type 3.1A1) were treated with a DHS or a PFNA. Inclusion and exclusion criteria were designed to focus on isolated stable IFFs in ambulatory patients. Follow-up was undertaken at 1, 3, 12, 15, 18, 21, 24, 36, 48 postoperative months, and at final follow-up. Radiograph outcomes were obtained at all visits. The primary outcome measure was re-operation rate. The secondary outcome was patient function, evaluated using Harris hip score (HHS). Tertiary outcomes included: intra- and post-operative orthopaedic complications., Results: Two hundred twenty two patients (110 in the PFNA group and 112 in the DHS group) were evaluated with a mean follow-up period of 53 months (range, 48-60 months). There was an increased risk of reoperation after DHS in one-year follow-up: 0 % and 5.4 % for PFNA and DHS, respectively (P = 0.029). The difference persisted with time: 6.4 % and 13.4 % at last follow-up (P < 0.05). There are statistical differences in postoperative HHS at 12, 15, 18, 21, 24, 36, 48 months postoperatively and at final follow-up. No statistical differences in medical complications was observed between the two groups. The orthopaedic complications were more in the DHS group (n = 42) compared with the PFNA group (n = 18) (P <0.05)., Conclusion: Compared with PFNA device, DHS device might not be the preferred implant for stable intertrochanteric femur fractures.

Aryl methyl thioethers and methylene-bridged arylamines were synthesized via highly regioselective para-methylthiolation/bridging methylenation of arylamines using DMSO as the methylthio or methylene source in the presence of NH4I under metal-free conditions. For the substrates with both electron-donating and electron-withdrawing substituents, the reaction proceeded smoothly and gave moderate to good yields.

Shuttling of macromolecules between different cellular compartments helps regulate the timing and extent of different cellular activities. Here, we report that LC3, a key initiator of autophagy that cycles between the nucleus and cytoplasm, becomes selectively activated in the nucleus during starvation through deacetylation by the nuclear deacetylase Sirt1. Deacetylation of LC3 at K49 and K51 by Sirt1 allows LC3 to interact with the nuclear protein DOR and return to the cytoplasm with DOR, where it is able to bind Atg7 and other autophagy factors and undergo phosphatidylethanolamine conjugation to preautophagic membranes. The association of deacetylated LC3 with autophagic factors shifts LC3's distribution from the nucleus toward the cytoplasm. Thus, an acetylation-deacetylation cycle ensures that LC3 effectively redistributes in an activated form from nucleus to cytoplasm, where it plays a central role in autophagy to enable the cell to cope with the lack of external nutrients., (Copyright © 2015 Elsevier Inc. All rights reserved.)

A palladium-catalyzed direct sulfonylation of 2-aryloxypyridines on the ortho-position of the benzene ring was developed using 2-pyridyloxyl as the directing group and sulfonyl chlorides as sulfonylation reagents. The protocol was available for both electron-rich and electron-deficient substrates. The ortho-sulfonylated phenol was synthesized expediently from the sulfonylation product by the removal of the pyridyl group.

This paper investigates semi-online scheduling problems on two parallel machines under a grade of service (GoS) provision subject to minimize the makespan. We consider three different semi-online versions with knowing the total processing time of the jobs with higher GoS level, knowing the total processing time of the jobs with lower GoS level, or knowing both in advance. Respectively, for the three semi-online versions, we develop algorithms with competitive ratios of 3/2, 20/13, and 4/3 which are shown to be optimal.

Objective: To evaluate the biomechanical effect of a self-made iliac screw plate on the stability of lumbo-iliac fixation construct before and after fatigue loading., Methods: Twelve fresh lumbo-pelvic specimens from donated adult cadavers with formalin embalm were used in the study. According to whether use the iliac screw plate or not, the specimens were randomly assigned into group A (with iliac screw plate, n=6) and group B (without iliac screw plate, n=6). The bone mineral density (BMD) of L(t-4) was measured using dual-energy radiograph absorptiometry. The pedicle screw and iliac screw fixation were given at L3-5, and bilateral facetectomy and diskectomy at L5, S1 level were performed to prepare the model of the intervertebral destabilization. The biomechanical testing was conducted on a material testing machine under 0-600 N compression and -7-7 N.m torsion loading modes for the initial compressive stiffness and torsional stiffness evaluation. And then 20 000 cyclic compressive loading of 40-400 N was given to the specimen, the stiffness evaluation was repeated. Then the maximum pull-out strength of screws at every level was measured and compared. Gross observation and radiological observation were performed during experiment., Results: The BMD values of groups A and B were (1.15 +/-0.13) g/cm(2) and (1.12 +/-0.11) g/cm(2) respectively, showing no significant difference between 2 groups (t=0.428, P=0.678). All pedicle screws and iliac screws were inserted in good position; no loosening or breaking of screw was observed during loading. After fatigue loading, the incidence of halo ring around the iliac screws of groups A and B was 16.7% (1/6) and 50.0% (3/6), respectively. The compressive stiffness and torsional stiffness after fatigue loading were significantly lower than those in initial state in groups A and B (P < 0.05); there was no significant difference in compressive stiffness and torsional stiffness between groups A and B before fatigue loading (P > 0.05). However, group A had higher compressive stiffness than group B (t=2.664, P=0.024) after fatigue loading, and there was no significant difference in torsional stiffness between 2 groups (t=0.410, P=0.690). No significant difference was found in screw pull-out strength of pedicle screws at L3, L4, and L5 levels between groups A and B (P > 0.05); however, the pull-out strength of the iliac screws in group A was significantly higher than that in group B (t=3.398, P=0.007). In groups A and B, the pull-out strength of L3 screw was significantly lower than that of L4 and L5 screws (P < 0.05). In group A, pull-out strength of the iliac screws was significantly higher than that of L3, L4, and L5 screws (P < 0.05); in group B, the pull-out strength of iliac screws was significantly lower than that of L4 and L5 screws (P < 0.05)., Conclusion: In the lumbo-iliac reconstruction, the use of iliac screw plate could resist iliac screw loosening, therefore, it has the potential to increase the stability oflumbo-iliac fixation construct.

In mammalian cells, the Golgi apparatus undergoes extensive fragmentation during mitosis; this is required not only for the partitioning of the complex but also for the process of mitosis. However, the molecular mechanism underlying the mitotic fragmentation of the Golgi is far from clear. Here, we show that AMP-activated protein kinase (AMPK) is phosphorylated and activated when cells enter mitosis. Activated AMPK phosphorylates GBF1, a guanine nucleotide exchange factor (GEF) for Arf-GTPases, disassociating GBF1 from the Golgi membrane and abolishing the action of GBF1 as an Arf1-GEF. We further demonstrate that the phosphorylation of AMPK and GBF1 is essential for Golgi disassembly and subsequent mitosis entry. These data suggest that AMPK-GBF1-Arf1 signaling is involved in the regulation of Golgi fragmentation during mitosis.

Unlabelled: Human MxA, an interferon-inducible cytoplasmic dynamin-like GTPase, possesses antiviral activity against multiple RNA viruses. Recently, MxA has also been demonstrated to have activity against the hepatitis B virus (HBV), a well-known DNA virus responsible for acute and chronic liver disease in humans. We investigated the molecular mechanism for the anti-HBV activity of MxA. Our results demonstrated that in HepG2.2.15 cells, MxA GTPase independently suppressed the production of hepatitis B surface antigen and HBV DNA without changing the level of hepatitis B core antigen (HBcAg) and the distribution of HBV mRNA. MxA significantly reduced the level of the encapsidated pregenomic RNA. Through its central interactive domain, MxA interacted with HBcAg, causing accumulation of the proteins in perinuclear compartments. MxA-HBcAg interaction significantly affected the dynamics of HBcAg by immobilizing HBcAg in the perinuclear structures., Conclusion: MxA displays antiviral activity against HBV involving a mechanism of MxA-HBcAg interaction that may interfere with core particle formation., (Copyright © 2012 American Association for the Study of Liver Diseases.)

Objective: To observe the systemic and local immune response after repair of nerve defect with acellular nerve xenograft laden with allogenic adipose-derived stem cells (ADSCs) in rhesus monkey so as to evaluate the safety of the proposed material for nerve reconstruction., Methods: Bilateral tibial nerves were taken from a healthy adult male landrace (weighing 48 kg) to prepare acellular nerve xenograft by chemical extraction. ADSCs were isolated from a healthy adult male rhesus monkey (weighing 4.5 kg), and were seeded into the acellular nerve grafts. The radial nerve defect models with 25 mm in length were established in 10 healthy adult female rhesus monkeys (weighing 3-5 kg), and they were divided into cell-laden group (n = 5) and non-cell-laden group (n = 5) randomly. Defect was repaired with acellular nerve xenograft laden with allogenic ADSCs in cell-laden group, with acellular nerve xenograft only in non-cell-laden group. The blood samples were taken from peripheral vein preoperatively and at 14, 60, and 90 days after operation for lymphocyte analysis; at 5 months after operation, the grafts were harvested to perform histological examination for local immune response and nerve regeneration. The nerve autograft in rhesus monkey was used as control., Results: In cell-laden group and non-cell-laden group, no significant difference was found in the count of lymphocytes and T lymphocytes, the percentage ofT lymphocytes, CD8+ T lymphocytes, as well as the ratio of CD4+ T lymphocytes to CD8+ T lymphocytes between pre- and post-operation (P > 0.05); in cell-laden group, the percentage of CD4+ T lymphocytes at 14 days was significantly lower than that at 60 and 90 days postoperatively (P < 0.05). The percentage of CD4+ T lymphocytes in cell-laden group was significantly lower than that in non-cell-laden group at 14 days (P < 0.05), but no significant difference was found in the other indexes at the other time between 2 groups (P > 0.05). At 5 months after operation, mild adhesion was found on the surface of nerve xenografts; the epineurium of nerve xenografts was thicker than that of nerve autografts; and neither necrosis nor fibrosis was found. CD3+, CD4+, CD8+, CD68+, and CD163+ T lymphocytes were scattered within the grafts, in which regenerative axons were revealed. CD3+, CD4+, CD8+, CD68+, and CD163+ T lymphocytes were comparable in cell-laden group, non-cell-laden group, and autograft group., Conclusion: Repair of nerve defect with acellular nerve xenograft elicits neither systemic nor local immune response in rhesus monkeys. Implantation of allogenic ADSCs might result in transient depression of CD4+ T lymphocytes proliferation early after surgery, no immune response can be found.

In contrast with the stability effects of trapped energetic ions on tearing modes, the effects of circulating energetic ions (CEI) on tearing modes depend on the toroidal circulating direction, and are closely related to the momentum of energetic ions. CEI provide an additional source or sink of momentum to affect tearing modes. For co-CEI, tearing modes can be stabilized if the momentum of energetic ions is large enough. On the other hand, the growth of tearing modes can be enhanced by counter-CEI. Further, a possibility to suppress the island growth of neoclassical tearing modes by co-CEI is pointed out.