This paper presents a synthesis approach for the design of mechanically safe robots based on the concept of spatial isotropic force module (SIFM). In this concept, a number of torque limiters are ...included in the structure of the robot in order to limit the feasible forces at the end-effector. SIFMs are proposed in order to ensure that the feasible force space at the end-effector of the robot remains well conditioned for any configuration of the robot, thereby alleviating the configuration dependent transformation between articular torques and Cartesian forces. In this paper, possible architectures of SIFMs are proposed and the conditions required to ensure isotropy of the forces at the end-effector are derived. Then, a three-degree-of-freedom (3-dof) spatial robot including a SIFM is designed to demonstrate the effectiveness of the concept, and the forces that can be applied by the robot along its links are also analyzed as well as the power of potential collisions. Finally, a prototype of a SIFM is built, which is rather compact since the designed torque limiters do not have to be co-located with an actuated joint.
To investigate the antimicrobial activity of berberine and the mechanism by which it combats methicillin-resistant
(MRSA) strains isolated from patients with bloodstream infections.
Fifteen clinical ...MRSA isolates were collected, and their Multi-locus Sequence Types (MLST) were examined. The minimum inhibitory concentration (MIC) and combined antibacterial activity of berberine alone, and when combined with clindamycin and rifampicin separately, were determined. Additionally, two MRSA strains (ST239 and ST5) were selected to perform the time-killing assay and biofilm formation test. Cell wall alterations and cell membrane integrity were measured by confocal laser scanning microscopy (CLSM) and electron microscopy to assess the influence on cell morphology.
Our data showed berberine was effective against MRSA at MIC values varying from 256 to 64 mg*L
for different MLST types. Berberine alone, and when combined with clindamycin and rifampicin separately, displayed excellent antibacterial activity which reduced the bacterial counts by 2lgCFU*mL within 24h and significantly weakened biofilm formation compared with control strain. Additionally, bacterial cytological profiling indicates that berberine destroyed the structure of the cell walls, membrane integrity and further changed the cell morphology with concentration increased.
In our study, berberine has excellent anti-MRSA activities and has synergistic antibacterial property when combined with clindamycin and rifamycin separately, and the mechanism of activities involves the destruction of cell wall and membrane.
The role of JAM3 in different tumors is controversial. The epigenetic regulation and the mechanism of JAM3 remain to be elucidated in human esophageal cancer (EC).
Eleven EC cell lines, 49 cases of ...esophageal intraepithelial neoplasia (EIN) and 760 cases of primary EC samples were employed. Methylation-specific polymerase chain reaction, immunohistochemistry, MTT, western blot and xenograft mouse models were applied in this study.
The inverse association between RNA expression and promoter region methylation of JAM3 was found by analyzing 185 cases of EC samples extracted from the TCGA database (p < 0.05). JAM3 was highly expressed in KYSE450, KYSE520, TE1 and YES2 cells, low level expressed in KYSE70 cells and unexpressed in KYSE30, KYSE150, KYSE410, KYSE510, TE13 and BIC1 cells. JAM3 was unmethylated in KYSE450, KYSE520, TE1 and YES2 cells, partial methylated in KYSE70 cells and completely methylated in KYSE30, KYSE150, KYSE410, KYSE510, TE13 and BIC1 cells. The expression of JAM3 is correlated with methylation status. The levels of JAM3 were unchanged in KYSE450, KYSE520, TE1 and YES2 cells, increased in KYSE70 cells and restored expression in KYSE30, KYSE150, KYSE410, KYSE510, TE13 and BIC1 cells after 5-aza-2'-deoxycytidine treatment, suggesting that the expression of JAM3 is regulated by promoter region methylation. JAM3 was methylated in 26.5% (13/49) of EIN and 51.1% (388/760) of primary EC, and methylation of JAM3 was associated significantly with tumor differentiation and family history (all p < 0.05). Methylation of JAM3 is an independent prognostic factor of poor 5-year overall survival (p < 0.05). JAM3 suppresses cell proliferation, colony formation, migration and invasion and induces G1/S arrest and apoptosis in EC. Further study demonstrated that JAM3 suppressed EC cells and xenograft tumor growth by inhibiting Wnt/β-catenin signaling.
JAM3 is frequently methylated in human EC, and the expression of JAM3 is regulated by promoter region methylation. JAM3 methylation is an early detection and prognostic marker of EC. JAM3 suppresses EC growth both in vitro and in vivo by inhibiting Wnt signaling.
Long noncoding RNAs (lncRNAs), which are noncoding RNAs (ncRNAs) with length more than 200 nucleotides (nt), have been demonstrated to be involved in various types of cancer. Consequently, it has ...been frequently discussed that lncRNAs with aberrant expression in cancer serve as potential diagnostic biomarkers and therapeutic targets. However, one major challenge of developing cancer biomarkers is tumor heterogeneity which means that tumor cells show different cellular morphology, metastatic potential as well as gene expression. In this study, a custom designed microarray platform covering both mRNAs and lncRNAs was applied to tumor tissues of gastric, colon, liver and lung. 316 and 157 differentially expressed (DE-) protein coding genes and lncRNAs common to these four types of cancer were identified respectively. Besides, the functional roles of common DE-lncRNAs were inferred based on their expression and genomic position correlation with mRNAs. Moreover, mRNAs and lncRNAs with tissue specificity were also identified, suggesting their particular roles with regard to specific biogenesis and functions of different organs. Based on the large-scale survey of mRNAs and lncRNAs in four types of cancer, this study may offer new biomarkers common or specific for various types of cancer.
Lipid–polymer hybrid nanoparticles (LPNs) have emerged as promising nanocarriers for oral delivery of poorly water-soluble drugs because they combine the advantages of polymeric and lipid-based ...nanoparticles. However, rational surface engineering of LPNs to reduce clearance in the gastrointestinal tract and improve bioavailability remains a challenge. Modification of LPNs with wheat germ agglutinin (WGA), a specific bioadhesive material, was hypothesised to increase site-specific adhesion and improve bioavailability. This study focused on the preparation and characterisation of WGA-modified LPNs (WGA-LPNs) for oral delivery of oridonin. WGA-LPNs were produced by incubating synthetic WGA-1,2-dioleoyl- sn-glycero -3-phosphoethanolamine with LPNs, which had been formed using nanoprecipitation. The WGA-LPNs had a particle size of 326.7 ± 5.2 nm and a zeta potential of −31.8 ± 1.04 mV. The core–shell structure and the WGA binding were confirmed by immune gold labelling electron microscopy. Approximately 80% of the drug was released from the nanoparticles within 24 h. WGA-LPNs showed efficient binding to both Caco-2 and HT29-MTX cells and underwent receptor-mediated endocytosis, as evidenced by cellular uptake and confocal imaging. In addition, coumarin 6-loaded WGA-LPNs showed enhanced uptake in the ligated intestinal loop model in vivo , probably due to improved bioadhesion to the villi. These results suggested that WGA-LNPs showed increased intestinal bioadhesion and cellular uptake and have the potential to improve the oral delivery of poorly water-soluble drugs.
Protease, serine, 3 (PRSS3), a member of the trypsin family of serine proteases, has been shown to be aberrantly expressed in several cancer types and to play important roles in tumor progression and ...metastasis. However, the expression and function of
PRSS3
gene in hepatocellular carcinoma (HCC) remain unclear. Here we found that PRSS3 expression was decreased in human HCC cell lines and HCC surgical specimens. This was associated with intragenic methylation of
PRSS3
gene. Treatment with DNA methyltransferase inhibitor 5-aza-2′-deoxycytidine and/or histone deacetylase inhibitor trichostatin A restored
PRSS3
expression in HCC cell lines. Ectopic overexpression of
PRSS3
gene in HCC cell lines significantly suppressed cell proliferation and colony formation and arrested cell cycle at G1/S phase, accompanied with downregulation of cyclin D1 (CCND1)/CDK4 and cyclin E1 (CCNE1)/CDK2 complexes. Moreover, PRSS3 overexpression in HCC cells inhibited HCC cell migration and invasion with downregulation of matrix metallopeptidase 2 (MMP2). Further study showed that PRSS3 overexpression diminished the phosphorylation of mitogen-activated protein kinase/extracellular-signal-regulated kinase signaling protein, mitogen-activated protein kinase kinase 1 (MEK1)/mitogen-activated protein kinase kinase 2 (MEK2) and extracellular-signal related kinase 1 (ERK1)/extracellular-signal related kinase 2 (ERK2), in HCC cells. In contrast, knockdown of
PRSS3
by small interfering RNA resulted in opposite effects on an HCC cell line SNU-387 which constitutively expresses PRSS3. These results demonstrate that downregulation of
PRSS3
by intragenic hypermethylation provides growth and metastasis advantage to HCC cells. The clinical relevance of PRSS3 to human HCC was shown by the intragenic methylation of
PRSS3
in HCC specimens and its association with poor tumor differentiation in patients with HCC. Thus,
PRSS3
is a potential prognostic biomarker and an epigenetic target for intervention of human HCC.
Key messages
• PRSS3
is downregulated by intragenic hypermethylation in HCC.
•
Epigenetic silencing of
PRSS3
facilitates growth, migration, and invasion of HCC.
• PRSS3
intragenic methylation has implication in diagnosis of HCC.
The aim of this study was to investigate the epigenetic regulation and underlying mechanism of NRIP3 in colorectal cancer (CRC).
Eight cell lines (SW480, SW620, DKO, LOVO, HT29, HCT116, DLD1, and ...RKO), 187 resected margin samples from colorectal cancer tissue, 146 cases with colorectal adenomatous polyps, and 308 colorectal cancer samples were used. Methylation-specific PCR, Western blotting, RNA interference assay, and a xenograft mouse model were used.
NRIP3 exhibited methylation in 2.7% (5/187) of resected margin samples from colorectal cancer tissue, 32.2% (47/146) of colorectal adenomatous polyps, and 50.6% (156/308) of CRC samples, and the expression of NRIP3 was regulated by promoter region methylation. The methylation of NRIP3 was found to be significantly associated with late onset (at age 50 years or older), poor tumor differentiation, lymph node metastasis, and poor 5-year overall survival in CRC (all P < 0.05). In addition, NRIP3 methylation was an independent poor prognostic marker ( P < 0.05). NRIP3 inhibited cell proliferation, colony formation, invasion, and migration, while induced G1/S arrest. NRIP3 suppressed CRC growth by inhibiting PI3K-AKT signaling both in vitro and in vivo . Methylation of NRIP3 sensitized CRC cells to combined PI3K and ATR/ATM inhibitors.
NRIP3 was frequently methylated in both colorectal adenomatous polyps and CRC. The methylation of NRIP3 may potentially serve as an early detection, late-onset, and poor prognostic marker in CRC. NRIP3 is a potential tumor suppressor. NRIP3 methylation is a potential synthetic lethal marker for combined PI3K and ATR/ATM inhibitors.
Synthetic lethality is a novel model for cancer therapy. To understand the function and mechanism of BEN domain-containing protein 4 (BEND4) in pancreatic cancer, eight cell lines and a total of 492 ...cases of pancreatic neoplasia samples were included in this study. Methylation-specific polymerase chain reaction, CRISPR/Cas9, immunoprecipitation assay, comet assay, and xenograft mouse model were used. BEND4 is a new member of the BEN domain family. The expression of BEND4 is regulated by promoter region methylation. It is methylated in 58.1% (176/303) of pancreatic ductal adenocarcinoma (PDAC), 33.3% (14/42) of intraductal papillary mucinous neoplasm, 31.0% (13/42) of pancreatic neuroendocrine tumor, 14.3% (3/21) of mucinous cystic neoplasm, 4.3% (2/47) of solid pseudopapillary neoplasm, and 2.7% (1/37) of serous cystic neoplasm. BEND4 methylation is significantly associated with late-onset PDAC (> 50 years, P < 0.01) and tumor differentiation (P < 0.0001), and methylation of BEND4 is an independent poor prognostic marker (P < 0.01) in PDAC. Furthermore, BEND4 plays tumor-suppressive roles in vitro and in vivo. Mechanistically, BEND4 involves non-homologous end joining signaling by interacting with Ku80 and promotes DNA damage repair. Loss of BEND4 increased the sensitivity of PDAC cells to ATM inhibitor. Collectively, the present study revealed an uncharacterized tumor suppressor BEND4 and indicated that methylation of BEND4 may serve as a potential synthetic lethal marker for ATM inhibitor in PDAC treatment.Synthetic lethality is a novel model for cancer therapy. To understand the function and mechanism of BEN domain-containing protein 4 (BEND4) in pancreatic cancer, eight cell lines and a total of 492 cases of pancreatic neoplasia samples were included in this study. Methylation-specific polymerase chain reaction, CRISPR/Cas9, immunoprecipitation assay, comet assay, and xenograft mouse model were used. BEND4 is a new member of the BEN domain family. The expression of BEND4 is regulated by promoter region methylation. It is methylated in 58.1% (176/303) of pancreatic ductal adenocarcinoma (PDAC), 33.3% (14/42) of intraductal papillary mucinous neoplasm, 31.0% (13/42) of pancreatic neuroendocrine tumor, 14.3% (3/21) of mucinous cystic neoplasm, 4.3% (2/47) of solid pseudopapillary neoplasm, and 2.7% (1/37) of serous cystic neoplasm. BEND4 methylation is significantly associated with late-onset PDAC (> 50 years, P < 0.01) and tumor differentiation (P < 0.0001), and methylation of BEND4 is an independent poor prognostic marker (P < 0.01) in PDAC. Furthermore, BEND4 plays tumor-suppressive roles in vitro and in vivo. Mechanistically, BEND4 involves non-homologous end joining signaling by interacting with Ku80 and promotes DNA damage repair. Loss of BEND4 increased the sensitivity of PDAC cells to ATM inhibitor. Collectively, the present study revealed an uncharacterized tumor suppressor BEND4 and indicated that methylation of BEND4 may serve as a potential synthetic lethal marker for ATM inhibitor in PDAC treatment.
Colorectal cancer (CRC) is among the leading causes of cancer-related death throughout the world. Aberrant expression of voltage-gated potassium ion channel molecule Kv1.3 has been reported in ...various cancers. To explore the expression and regulation of Kv1.3 in colorectal cancer, 7 colorectal cancer cell lines and 147 cases of primary colorectal cancer were involved in this study. Kv1.3 was expressed in LOVO and SW480 cells and loss of expression was found in RKO, DLD1, SW620, HCT116, and HT29 cells. Complete methylation was found in RKO, DLD1, SW620, HCT116, and HT29 cells, partial methylation was found in LOVO and SW480 cells. Loss of/reduced expression of Kv1.3 is correlated with methylation of its promoter region. The expression of Kv1.3 was restored in RKO, DLD1, SW620, HCT116, and HT29 cells, and increased in LOVO and SW480 cells after 5-aza-2'-deoxycytidine (DAC) treatment. The results suggest that the expression of Kv1.3 is regulated by the gene's promoter region methylation in human CRC cells. Kv1.3 was methylated in 76.19% (112/147) of primary human colorectal cancer. Methylation of Kv1.3 is associated with age, tumor differentiation, and poor 5-year survival. In conclusion, Kv1.3 is frequently methylated in human colorectal cancer and the expression of Kv1.3 is regulated by its promoter region methylation. Kv1.3 methylation may serve as diagnostic and prognostic markers in colorectal cancer.
Hybrid organic-inorganic perovskites have attracted intensive attention as the absorber layer in high-performance perovskite solar cells (PSCs). The interface between the electron transport layer and ...the perovskite layer in perovskite solar cells has a large effect on the device performance. Herein, we report a perovskite solar cell with a cell structure of ITO/ETL/(FAPbI
3
)
0.97
(MAPbBr
3
)
0.03
/spiro-OMeTAD/MoO
3
/Ag, where the poly(vinylpyrrolidone) (PVP)-doped SnO
2
film works as the electron transport layer. We observe that the perovskite film grown on PVP-SnO
2
shows more uniform crystalline grains than the control sample grown on the pure SnO
2
, and the electron mobility of the PVP-SnO
2
film is higher than that of the pure SnO
2
film; consequently, PVP-SnO
2
can efficiently extract electrons from the perovskite layer. As a result, the PSCs using the PVP-doped SnO
2
ETL showed an increased power conversion efficiency (PCE). The optimized device using the PVP-SnO
2
electron transport layer shows an improved PCE of 19.55%, while the PSC using the SnO
2
electron transport later shows a PCE of 17.50%. Furthermore, it is feasible to add PVP into the electron transport layer of SnO
2
to improve the performance of the planar perovskite solar cell device.
Hybrid organic-inorganic perovskites have attracted intensive attention as the absorber layer in high-performance perovskite solar cells (PSCs).
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