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Purpose: The purpose of this study was to investigate the effect of circ_HLCS on age-related cataract (ARC). Methods: Circ_HLCS, microRNA (miR)-338-3p, and bisphosphate 3′-nucleotidase 1 (BPNT1) were quantified by quantitative real-time polymerase chain reaction or western blot. Cell proliferation and cell viability were assessed by the 5-Ethynyl-2′-deoxyuridinr and cell counting kit-8 assays. Cell apoptosis was detected by flow cytometry. Targeted correlations among circ_HLCS, miR-338-3p, and BPNT1 were verified by the dual-luciferase reporter and RNA pull-down assays. Results: circ_HLCS was diminished in ARC tissues and UV-treated SRA01/04 cells. Elevated content of circ_HLCS undermined UV-induced cell proliferation inhibition and apoptosis. Mechanistically, circ_HLCS directly targeted miR-338-3p, and circ_HLCS regulated BPNT1 expression through miR-338-3p. Furthermore, reduction of miR-338-3p ameliorated UV-induced SRA01/04 cell damage by increasing BPNT1 expression. Conclusion: Taken together, these data suggested that circ_HLCS inhibited apoptosis of UV-treated SRA01/04 cells by miR-338-3p/BPNT1 axis. Therefore, circ_HLCS might be a potential therapeutic target for ARC. [ABSTRACT FROM AUTHOR]

Purpose: β-asarone is the prime component of essential oil extracted from Acori graminei Rhizoma, which plays an inhibitory role in various tumors. Here, we aim to investigate the functions as well as the mechanism of β-asarone in retinoblastoma (RB). Methods: RB cell lines SO-Rb50 and HXO-Rb44 were treated with different doses of β-asarone. Then, CCK8 and BrdU experiments were adopted to examine the RB cell proliferation. Wound healing test and Transwell assay were employed to detect cell migration and invasion. RB cell apoptosis was tested by flow cytometry and Western blot. An RB cell xenograft model was constructed on nude mice for testing the role of β-asarone on RB cell growth in vivo. RT-PCR and Western blot were used to determine the effect of β-asarone on Wnt/β-catenin signaling pathway. Furthermore, the Wnt/β-catenin pathway inhibitor PNU-74654 and activator HLY78 were administered to RB cells for confirming the effects of β-asarone in Wnt/β-catenin pathway. Results: In vivo experiment showed that β-asarone attenuated SO-Rb50 cell growth in nude mice. Further research found that β-asarone significantly repressed Wnt/β-catenin canonical pathway activation. Conclusion: Prior inhibition of Wnt/β-catenin pathway abolished the antitumor effects induced by β-asarone. β-asarone exerted antitumor effects in RB cells by inactivating the Wnt/β-catenin signaling pathway. [ABSTRACT FROM AUTHOR]

The maldistribution of working medium restricts the heat transfer performance of the spiral-wound heat exchangers (SWHEs), especially when the heat exchangers are applied in floating production storage and offloading platform. Therefore, the maldistribution in the SWHEs needs to be studied under sloshing conditions. In the investigation, a novel distributor named "disc distributor" is designed and its distribution characteristic is analysed under sloshing conditions experimentally. The impacts of sloshing amplitude, sloshing periods, mass flow rate and structural parameters on flow uniformity are discussed. The results show that based on steady condition the augmentation of the sloshing amplitude makes the liquid uniformity deteriorate by 14.2–56.0%, and the enlargement of the sloshing period improves the liquid flow uniformity by 12.8–28.3%. The elevation of the mass flow rate promotes the flow uniformity by 23.8–27.0% and 13.9–32.4% under steady and sloshing conditions, respectively. The variation of hole diameter exacerbates distribution performance of the distributor by 5.3–18.4% and 2.5–22.3% under steady and sloshing conditions separately. Heave condition always has less influence on the flow uniformity of the distributor than other sloshing conditions. [ABSTRACT FROM AUTHOR]

Porous ceramics with lightweight, high strength, thermal insulation, and decoration integration were prepared using red mud, construction waste, polished tile waste, and kaolin as raw materials. The influences of the content of red mud, sintering temperature, and blowing agent on the microstructure, mechanical, and thermal properties of porous ceramic were investigated. According to bulk density, pore morphology, compressive strength, and thermal conductivity, the optimum preparation condition of porous ceramic was determined after selecting the raw materials formulations and process parameters. Multi-functional wall insulation materials have been prepared when the content of red mud was 40%, blowing agent was 3%, and sintering temperature was 1080 °C. The bulk density, porosity, compressive strength, thermal conductivity, and softening temperature of porous ceramics were 0.25 g/cm3, 72.15%, 7.26 MPa, 0.058 W/(m K), and 1160 °C respectively. Their corresponding influence mechanisms of pore structure on mechanical and thermal properties were discussed in detail. It was found from the section images of pore morphology that pore distribution and size were significantly uniform in porous ceramic. [ABSTRACT FROM AUTHOR]

Astrocytes respond to all forms of central nervous system (CNS) insults by a process referred to as reactive astrogliosis. Inhibition of astrocyte growth and activation is an important strategy for promoting injured CNS repair. STAT3 (signal transducer and activator of transcription 3) is reported to be a critical regulator of astrogliosis, and resveratrol (RES, a dietary polyphenol) is considered to be a natural inhibitor of STAT3 expression and phosphorylation. In this study, we investigated the effects of RES on STAT3 expression and phosphorylation, and then on the proliferation and activation of astrocytes, a critical process in reactive astrogliosis, in rat primary cultured astrocytes and an in vitro scratch-wound model. RES downregulated the expression levels of STAT3, P-STAT3 and GFAP (glial fibrillary acidic protein) in cultured astrocytes. The positive index of Ki67 was apparently reduced in cultured astrocytes after RES treatment. Meanwhile, cultured astrocyte proliferation and activation were attenuated by RES. Moreover, in the established in vitro scratch-wound model the increased expression levels of STAT3, P-STAT3 and GFAP induced by scratching injury were also clearly inhibited by RES. In addition, the inhibitory effect of RES on cell proliferation was similar to that of AG490 (a selective inhibitor of STAT3 phosphorylation) and abrogated by Colivelin (a STAT3 activator) stimuli. Taken together, our data suggest that RES is able to inhibit reactive astrocyte proliferation and activation mainly via deactivating STAT3 pathway. So RES may have a therapeutic benefit for the treatment of the injured CNS. [ABSTRACT FROM AUTHOR]

Purpose: Recent researches are attempting to verify that the 3D cell models can provide a gap bridge between in vitro and in vivo for anticancer drug evaluations. The aim of this study was to continue the development of novel in vitro 3D cell models and the investigation of the cellular uptake mechanism of camptothecin (CPT) and its derivatives [FL118 (10,11-methylenedioxy-20(S)-camptothecin), 9-Q20 (9-p-trifluoromethylphenyl-10,11-methylenedioxy-20(S)-camptothecin)] in 2D and 3D cell models.Methods: The 3D cell models were established using ultralow attachment 96-well plates. The cytotoxicity of CPT, FL118, and 9-Q20 was evaluated by MTT method. The effects of compound concentration, incubation time, temperature, and transporter inhibitors on the cellular uptake of CPT, FL118, and 9-Q20 were examined in 2D and 3D cell models.Results: The cytotoxicity of CPT, FL118, and 9-Q20 was lower in 3D cell models than 2D cell models. In 2D Caco-2 cell model, the uptake rate of CPT, FL118, and 9-Q20 was faster during the early time of incubation. In 3D Caco-2 cell model, the uptake capacity of CPT, FL118, and 9-Q20 was significantly improved over time. In 3D Caco-2 cell model, Verapamil (P-gp inhibitor) and Gefitinib (BCRP inhibitor) more significantly increased the uptake of CPT and 9-Q20. In contrast, P-gp and BCRP did not affect the accumulation of FL118 in 2D and 3D Caco-2 cell models. The accumulation of CPT, FL118, and 9-Q20 was greater in HepG2 cells than HCT116 cells.Conclusion: The 3D cell models provided more potency information on the process of cellular uptake of CPT, FL118, and 9-Q20, which more objectively reflected the drug sensitivity and drug resistance in vivo compared with the 2D cell models. [ABSTRACT FROM AUTHOR]

Drug uptake and efflux are two of the critical factors required in order to be able to define drug efficacy. This study aims to investigate cytotoxicity and uptake mechanisms of two FL118 analogues (7-Q20 and val-FL118) in parallel with FL118 in three-dimensional multi-cellular spheroids model. The influence of compound concentration, time, temperature, cell lines, and the inhibitors of P-gp, BCRP and LAT1 on drug uptake and efflux were investigated. In vitro cytotoxicity studies revealed that FL118, 7-Q20 and val-FL118 exhibited sensitive cytotoxicity to the HCT-116 cell line and the water-soluble compound 7-Q20 showed the lowest IC50. Cellular uptake and efflux of FL118 was independent of efflux pump proteins. Uptake and efflux of 7-Q20 were affected by P-gp, which was one of reasons that caused a lower uptake at 37 °C than at 4 °C. The carrier protein LAT1 played a role in the cellular intakes of val-FL118. These findings provided basic information for FL118 and the two novel FL118 derivatives for further development. [ABSTRACT FROM AUTHOR]

We propose a theoretical method to enhance the entanglement between two mechanical resonators in two optomechanical cavities, which are coupled by the photon-hopping process, and each opto-mechanical cavity are consisted of a Fabry-Perot cavity and a mechanical oscillator by applying N atomic medium. We explore the effect of the entanglement between two mechanical oscillators with two atomic mediums and without them, respectively. The results show that the introduction of atoms can effectively increase the entanglement between the two oscillator modes. [ABSTRACT FROM AUTHOR]

The tumor suppressor Merlin/NF2 functions upstream of the core Hippo pathway kinases Lats1/2 and Mst1/2, as well as the nuclear E3 ubiquitin ligase CRL4DCAF1. Numerous mutations of Merlin have been identified in Neurofibromatosis type 2 and other cancer patients. Despite more than two decades of research, the upstream regulator of Merlin in the Hippo pathway remains unknown. Here we show by high-resolution crystal structures that the Lats1/2-binding site on the Merlin FERM domain is physically blocked by Merlin's auto-inhibitory tail. Angiomotin binding releases the auto-inhibition and promotes Merlin's binding to Lats1/2. Phosphorylation of Ser518 outside the Merlin's auto-inhibitory tail does not obviously alter Merlin's conformation, but instead prevents angiomotin from binding and thus inhibits Hippo pathway kinase activation. Cancer-causing mutations clustered in the angiomotin-binding domain impair angiomotin-mediated Merlin activation. Our findings reveal that angiomotin and Merlin respectively interface cortical actin filaments and core kinases in Hippo signaling, and allow construction of a complete Hippo signaling pathway. [ABSTRACT FROM AUTHOR]

RNA-dependent protein kinase (PKR) is crucial for the innate immune response, cell growth, proliferation, signal transduction and apoptosis. The activation process of PKR has been studied for many years and is still under debate. To obtain new insight into the mechanism of PKR activation, we solved the crystal structure of a latent mutant of the PKR kinase domain (PKR-KD) in the apo form at a resolution of 2.9 Å. The overall structure of PKR-KD is similar to previously reported structures. Structural analysis revealed a classical back-to-back dimer and a newly defined face-to-face dimer. Analytical ultracentrifugation experiments, electrostatic surface maps and the model of PKR-KD in complex with the eIF2α substrate all support that the face-to-face dimer is more reflective of PKR in solution. Our results provide new information on PKR dimerization and its activation mechanism. [ABSTRACT FROM AUTHOR]

Survivin is a unique member of the inhibitor of apoptosis protein family, and its expression is regulated by p53. Recent identification of several functionally divergent survivin variants augments the complexity of survivin action as well as its regulation. Here we report that survivin-2B (retaining a part of intron 2 as a cryptic exon) is positively regulated by p53, and its overexpression plays a role in sensitizing leukemia cells to chemotherapeutic drug doxorubicin. Doxorubicin treatment activated p53, downregulated survivin and survivin-?Ex3 but upregulated survivin-2B in EU-3, an acute lymphocytic leukemia (ALL) cell line with wild-type (wt)-p53 phenotype. In contrast, doxorubicin treatment failed to induce these alterations in EU-6 cells, a mutant-p53 ALL cell line. To specify the role of wt-p53 in regulating survivin and its variants, a temperature-sensitive p53 mutant plasmid p53-143 was transfected into EU-4, a p53-null ALL cell line, to establish a subline EU-4/p53-143. When EU-4/p53-143 cell culture was shifted from 37.5°C to the wt-p53-permissive temperature (32.5°C), the expression of survivin and survivin-?Ex3 was decreased whereas survivin-2B expression was increased, confirming the distinct regulatory effect of p53 on survivin and its variants. To clarify the role of survivin-2B in the process of apoptosis, survivin-2B cDNA was cloned into pcDNA3HA vector and transfected into EU-4 cells. Enforced expression of survivin-2B in EU-4 cells inhibited cell growth and sensitized these cells to doxorubicin-induced apoptosis. These results suggest that survivin-2B variant is a proapoptotic factor and its expression is upregulated by p53.Oncogene (2004) 23, 7545-7551. doi:10.1038/sj.onc.1208038 Published online 30 August 2004 [ABSTRACT FROM AUTHOR]

It has been demonstrated that survivin, a novel member of the inhibitor of apoptosis (IAP) protein family, is expressed in human cancers but is undetectable in normal differentiated tissues. We employed a recombinant adenoviral vector (reAdGL3BSurvivin) in which a tumor-specific survivin promoter and a luciferase reporter gene were inserted into the E1-deleted region of adenovirus vector. Luciferase activity was measured in both multiple tumor cell lines and two primary melanoma cells infected with reAdGL3BSurvivin. Human fibroblast and mammary epithelial cell lines were used as negative controls. A reAdGL3CMV, containing the CMV promoter and luciferase gene, was used as a positive control to normalize the luciferase activity generated by the survivin promoter. Our data revealed that the survivin promoter showed high activity in both established tumor cell lines and the primary melanoma cells. In contrast, the in vivo studies indicated that the activities of survivin promoter were extremely low in the major mouse organs. The survivin promoter appears to be a promising tumor-specific promoter exhibiting a “tumor on” and “liver off” profile, and therefore, it may prove to be a good candidate for transcriptional targeting of cancer gene therapy in a wide variety of tumors.Cancer Gene Therapy (2004) 11, 256-262. doi:10.1038/sj.cgt.7700679 Published online 12 March 2004 [ABSTRACT FROM AUTHOR]

We have previously shown that the clinically relevant polyamine analog N1,N11-diethylnorspermine (DENSPM) causes rapid apoptosis in human melanoma SK-MEL-28 cells via a series of events that include mitochondrial release of cytochrome c and activation of the caspase cascade. Upstream to these events, DENSPM downregulates polyamine biosynthesis and potently upregulates polyamine catabolism at the level of spermidine/spermine N1-acetyltransferase (SSAT). In searching for downstream effectors that either contribute to or abrogate the apoptotic response, we observed that DENSPM treatment of SK-MEL-28 cells for 30?h led to cytosolic release of Smac/Diablo, a mitochondrial protein known to bind and inhibit the function of inhibitor of apoptosis proteins (IAPs). Subsequently, we found that DENSPM markedly lowered survivin and ML-IAP protein (but not XIAP) levels by 18?h via an apparently Smac/Diablo-independent pathway. Proteasome inhibitors fully prevented survivin and ML-IAP protein loss as well as apoptosis, suggesting that the proteasome-mediated degradation of survivin and ML-IAP is causally linked to the cellular outcome. We also observed that structural analogs of DENSPM which differentially induced SSAT and apoptosis lowered survivin and ML-IAP levels in a manner that correlated with enzyme activity. The linkage between IAPs and SSAT was more directly established by the finding that selective prevention of SSAT induction by small interfering RNA prevented survivin and ML-IAP loss as well as apoptosis during DENSPM treatment. Among the melanoma cell lines (SK-MEL-28, MALME-3M, A375 and LOX), survivin degradation correlated temporally with the onset of DENSPM induced apoptosis or growth inhibition. By contrast, ML-IAP degradation occurred only during rapid apoptosis seen in SK-MEL-28 cells. These data suggest a sequence of events whereby DENSPM induction of SSAT leads to loss of IAP proteins and a more fulminate apoptotic response. The findings implicate survivin and ML-IAP as important determinants of polyamine analog drug action in melanoma cells.Oncogene (2003) 22, 4964-4972. doi:10.1038/sj.onc.1206725 [ABSTRACT FROM AUTHOR]

Next location prediction has aroused great interests in the era of internet of things (IoT). With the ubiquitous deployment of sensor devices, e.g., GPS and Wi-Fi, IoT environment offers new opportunities for proactively analyzing human mobility patterns and predicting user's future visit in low cost, no matter outdoor and indoor. In this paper, we consider the problem of next location prediction in IoT environment via a session-based manner. We suggest that user's future intention in each session can be better inferred for more accurate prediction if patterns hidden inside both trajectory and signal strength sequences collected from IoT devices can be jointly modeled, which however existing state-of-the-art methods have rarely addressed. To this end, we propose a trajectory and sIgnal sequence (TSIS) model, where the trajectory transition regularities and signal temporal dynamics are jointly embedded in a neural network based model. Specifically, we employ gated recurrent unit (GRU) for capturing the temporal dynamics in the multivariate signal strength sequence. Moreover, we adapt gated graph neural networks (gated GNNs) on location transition graphs to explicitly model the transition patterns of trajectories. Finally, both the low-dimensional representations learned from trajectory and signal sequence are jointly optimized to construct a session embedding, which is further employed to predict the next location. Extensive experiments on two real-world Wi-Fi based mobility datasets demonstrate that TSIS is effective and robust for next location prediction compared with other competitive baselines. [ABSTRACT FROM AUTHOR]

Here we investigate the role of the control of apoptosis in normal cell division. We show that interference with the expression or function of the apoptosis inhibitor survivin causes caspase-dependent cell death in the G2/M phase of the cell cycle, and a cell-division defect characterized by centrosome dysregulation, multipolar mitotic spindles and multinucleated, polyploid cells. Use of a dominant-negative survivin mutant or antisense survivin complementary DNA disrupts a supramolecular assembly of survivin, caspase-3 and the cyclin-dependent-kinase inhibitor p21[sup Waf1/Cip1] within centrosomes, and results in caspase-dependent cleavage of p21. Polyploidy induced by survivin antagonists is accentuated in p21-deficient cells, and corrected by exogenous expression of p21. These findings show that control of apoptosis and preservation of p21 integrity within centrosomes by survivin are required for normal mitotic progression. [ABSTRACT FROM AUTHOR]

Reports on an inhibitor of apoptosis, called survivin, that is expressed in the G2/M phase of the cell cycle in a cycle-regulated manner. Background about survivin distribution; Interaction between survivin and tubulin; Methods used in the study.

We present the result of our research on the tumorigenic ability of single cell clones isolated from an aggressive murine breast cancer cell line in a matched allografting mouse model. Tumor formation is basically dependent on the cell numbers injected per location. We argue that in vivo tumor formation from single cell clones, isolated in vivo from cancer cell lines, may not provide conclusive evidence to disprove the cancer stem cell (CSC) theory without additional data. [ABSTRACT FROM AUTHOR]

It is known that tRNAs play an essential role in genetic information transfer from DNA to protein. The maturation of tRNA precursors is performed by the endoribonuclease RNase P, which classically consists of a main RNA segment and accessory proteins. However, the newly identified human mitochondrial RNase P-like protein (MRPP123) complex is unique in that it is composed of three proteins without RNA. Here, we determined the crystal structure of MRPP123 complex subunit 3 (MRPP3), which is thought to carry out the catalytic reaction. A detailed structural analysis in combination with biochemical assays suggests that MRPP3 is in an auto-inhibitory conformation in which metal ions that are essential for catalysis are excluded from the active site. Our results indicate that further regulation is necessary to rearrange the conformation of the active site of MRPP3 and trigger it, thus providing important information to understand the activation of MRPP123. [ABSTRACT FROM AUTHOR]