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Lipid nanoparticles (LNPs) are widely used for nucleic acid delivery but face challenges like limited targeting and accelerated blood clearance (ABC) effect. We design three ionizable oligomers (IOs) that, with polylactide-polyethylene glycol (PLA-PEG), form a potential siRNA delivery system, named Ionizable Polymeric Micelles (IPMs). The siRNA encapsulated IPMs escape from lysosomes upon cellular uptake, and silence the target gene. A fibroblast activation protein inhibitor modified IPMs (FAPi-IPMs) show higher targeting for activated hepatic stellate cells (HSCs) compared to that for hepatocytes, silencing both HSP47 and HMGB1, reducing collagen secretion and liver inflammation, thereby treating fibrosis. Moreover, IPMs and FAPi-IPMs mitigate ABC effect and produce fewer PEG antibodies than LNPs, and show minimal apolipoprotein adsorption in vivo compared with LNPs, differentiating their targeting effects from LNPs. In conclusion, IPMs represent a nucleic acid delivery system with alternative targeting ability and reduced ABC effect. Authors develop a siRNA delivery system, named Ionizable Polymeric Micelles (IPMs) which employs a FAPi modification, enabling IPMs to target activated hepatic stellate cells, silencing target genes and treating liver fibrosis. [ABSTRACT FROM AUTHOR]

Intrahepatic accumulation dominates organ distribution for most nanomedicines. However, obscure intrahepatic fate largely hampers regulation on their in vivo performance. Herein, PEGylated liposomal doxorubicin is exploited to clarify the intrahepatic fate of both liposomes and the payload in male mice. Kupffer cells initiate and dominate intrahepatic capture of liposomal doxorubicin, following to deliver released doxorubicin to hepatocytes with zonated distribution along the lobule porto-central axis. Increasing Kupffer cells capture promotes doxorubicin accumulation in hepatocytes, revealing the Kupffer cells capture-payload release-hepatocytes accumulation scheme. In contrast, free doxorubicin is overlooked by Kupffer cells, instead quickly distributing into hepatocytes by directly crossing fenestrated liver sinusoid endothelium. Compared to free doxorubicin, liposomal doxorubicin exhibits sustained metabolism/excretion due to the extra capture-release process. This work unveils the pivotal role of Kupffer cells in intrahepatic traffic of PEGylated liposomal therapeutics, and quantitively describes the intrahepatic transport/distribution/elimination process, providing crucial information for guiding further development of nanomedicines. Here, authors looked at the roles of Kupffer cells in determining intrahepatic traffic of PEGylated liposomal doxorubicin, providing information for design and clinical applications of liposomal therapeutics. [ABSTRACT FROM AUTHOR]

Purpose: This article concentrates on the block-hierarchical structures of rock masses and investigates the dynamic problem and dispersion relation of pendulum-type waves caused by the low-frequency vibrations of rock blocks in blocky rock masses, and determines the effect of block-hierarchical structures. Methods: The blocky rock masses composed of granite blocks and rubber interlayers are simplified into the block–spring model and the wave motion model. Based on Bloch theorem and d'Alembert's principle, the dispersion relation and equations of motion of blocky rock masses with complex block-hierarchical structures are determined, respectively. Conclusion: With the increase of the rock size and geomechanical invariant, the initial frequency of the first attenuation zone gradually decreases, and only the low-frequency waves lower than that frequency can propagate in the blocky rock masses, which reveals the mechanism of low-frequency characteristics of pendulum-type waves theoretically. Research on the two models with different block-hierarchical structures indicates that the equivalent substitution of the two models is not universal and unconditional. The larger the stiffness ratio, or the higher the order of block-hierarchical structures, the smaller is the effect of ignoring the high-order hierarchical structures. Applications: The research will be of interest to a wide range of experts in the fields of stress wave propagation, earthquake engineering and rock bursts, as well as those working to reduce the engineering vibrations of underground structures and process monitored wave packet data for structures. [ABSTRACT FROM AUTHOR]

Rock mass is a typical inhomogeneous structure composed of hierarchically embedded rock blocks of different scales and separated by weaker interlayers. Due to weak mechanical properties of interlayers, the deformation of rock mass both in statics and dynamics is mainly concentrated in interlayers. Therefore, rock blocks as rigid bodies will experience translational and rotational motions, and the pendulum-type wave arises in rock mass. One-dimensional pendulum-type wave has been studied by many scholars, but two-dimensional pendulum-type wave has not been studied completely, especially the rotational motion of rock blocks should be considered. Therefore, the two-dimensional dynamic model of block-rock mass consisting of rectangular blocks separated by weaker interlayers is established based on accurate consideration of rotation effect. The applicability and reliability of this dynamic model are proved by comparing with experimental data. The propagation law and characteristics of pendulum-type wave in two-dimensional block-rock mass are investigated. Furthermore, the effect of these factors such as the viscous damping, geomechanical invariant and block size on the propagation of pendulum-type wave are determined. [ABSTRACT FROM AUTHOR]

Background: Colorectal cancer (CRC), the most common cancer type, causes high morbidity and mortality. Patients who develop drug resistance to oxaliplatin-based regimens have short overall survival. Thus, identifying molecules involved in the development of oxaliplatin resistance is critical for designing therapeutic strategies.Methods: A proteomic screen was performed to reveal altered protein kinase phosphorylation in oxaliplatin-resistant (OR) CRC tumour spheroids. The function of CHK2 was characterised using several biochemical techniques and evident using in vitro cell and in vivo tumour models.Results: We revealed that the level of phospho-CHK2(Thr68) was elevated in OR CRC cells and in ~30% of tumour samples from patients with OR CRC. We demonstrated that oxaliplatin activated several phosphatidylinositol 3-kinase-related kinases (PIKKs) and CHK2 downstream effectors and enhanced CHK2/PARP1 interaction to facilitate DNA repair. A phosphorylation mimicking CHK2 mutant, CHK2T68D, but not a kinase-dead CHK2 mutant, CHK2D347A, promoted DNA repair, the CHK2/PARP1 interaction, and cell growth in the presence of oxaliplatin. Finally, we showed that a CHK2 inhibitor, BML-277, reduced protein poly(ADP-ribosyl)ation (PARylation), FANCD2 monoubiquitination, homologous recombination and OR CRC cell growth in vitro and in vivo.Conclusion: Our findings suggest that CHK2 activity is critical for modulating oxaliplatin response and that CHK2 is a potential therapeutic target for OR CRC. [ABSTRACT FROM AUTHOR]

Pendulum-type wave is a kind of sign-alternating wave with discontinuous and nonlinear characteristics found in deep rock mass, which is different from the traditional continuum elastic waves. The new dynamic engineering disasters such as rockbrusts and anomalously low friction phenomenon occur frequently in deep rock mass, and the study of pendulum-type wave is of great significance for explaining the mechanism and prevention of these engineering disasters. Aiming to the nonlinear deformation characteristics of deep rock mass, a nonlinear dynamic model of pendulum-type wave in block-rock mass is established by introducing hyperbolic elastic model, and the time-domain characteristics, frequency-domain characteristics, and the law of energy transfer are studied. Furthermore, the influence of initial geostress on pendulum-type wave propagation in nonlinear block-rock mass is studied. The research shows that the improved model can not only shows the nonlinear deformation of block-rock mass, but also limits the maximum compression deformation of cracks between rock blocks. Under the action of small impact loading and strong impact loading, the acceleration in nonlinear block-rock mass has completely different rules. With the increase of initial geostress, the displacement amplitude decreases in approximate exponential form. Therefore, we have made a prediction that in the ultra-high stress state, the pendulum-type wave phenomenon will not occur in block-rock mass, and the wave propagation is close to the longitudinal wave. This paper provides a fine reference for further study on pendulum-type wave propagation in block-rock mass under the conditions of nonlinear, strong impact, and high initial geostress. [ABSTRACT FROM AUTHOR]

Glioblastoma (GBM) is the most lethal type of primary brain tumor and is characterized by diffuse infiltrative growth. However, the mechanisms that control this phenotype remain largely unknown. Emerging evidence has demonstrated that the abnormal expression of microRNAs and their target genes are involved in the migration and invasion of glioma cells. In this study, we demonstrated that microRNA-720 (miR-720) was significantly upregulated in glioma tissues and cells. Functional experiments showed that overexpression of miR-720 promotes glioma migration and invasion, while downregulation of miR-720 inhibits glioma migration and invasion. Meanwhile, we found that threonyl-tRNA synthetase like-2 (TARSL2) was a direct and functional target of miR-720 in glioma. Reintroduction of TARSL2 into glioma cells repressed the invasion promoting function of miR-720, whereas downregulation of TARSL2 reversed the anti-invasion function of anti-miR-720. Furthermore, quantitative real-time polymerase chain reaction results showed that miR-720 was inversely correlated with TARSL2 expression in 40 GBM tissues. Finally, in vivo experiments showed that miR-720 promotes glioma growth and upregulates invasion-related genes in nude mice. Overall, our findings suggest increasing miR-720 enhances glioma migration and invasion through downregulation of TARSL2, which may provide novel insight into the treatment of glioma. [ABSTRACT FROM AUTHOR]

In this work, a distinguished hydrothermal treatment succeeded in modifying aramid nanofibers (ANFs) with the help of mixed acid, and the hydrothermal-treated ANFs (hANFs) were regarded as a reinforcement agent to be introduced into styrene-butadiene rubber (SBR) via latex co-agglutination treatment. The enhanced comprehensive behaviour of SBR/hANFs composites induced by π-π stacking interaction between hANFs and polymer chains were investigated in details. With respect to virgin SBR, it was found that the temperature at maximum rate of degradation, tear strength and tensile strength of composites with adding 7 phr (parts per hundred rubber) hANFs significantly improved by 14 °C, 148 % and 215 %, respectively. The incorporation of hANFs also endowed SBR with greatly enhanced solvent resistance. [ABSTRACT FROM AUTHOR]

In this study, the plasmonic extinction spectra and local field distributions of three different gold nanoframe models with multi-breakages are simulated based on the discrete dipole approximation (DDA) method. By tuning the length of one breakage, there are two clearly separated surface plasmon resonance (SPR) peaks which show a clear blue shift as the broken length increases, and the local field enhancement factor reaches a maximum of 140.8 when the broken length is 2 nm. The changing of plasmonic field interaction and the increased restoring force may be used to explain the resonance blue shift. In these three models, the three-dimensional (3D) local electric field distributions confirm that the hot spot regions mainly concentrate on the interior broken surfaces when the incident electric field is polarized along the broken edge. Moreover, the gold nanoframe with three breakages can create the polarization orientation-independent built-in hot spots inside the broken surfaces. Therefore, the local field enhancement and hot spot regions may be controlled by adjusting the number of breakages and the orientation of polarized field. Consequently, these simulated results about the plasmonic optical properties in gold nanoframe provide a theoretical guidance for the design of polarization orientation-independent SERS substrate, which could create the built-in hot spots and improve the SERS activity. [ABSTRACT FROM AUTHOR]

Sensitive analysis of oligosaccharides by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) is significantly hampered by the low ionization efficiency of oligosaccharides. Derivatization affords a feasible way to enhance the MALDI intensities of oligosaccharides by introducing an easily ionized and/or hydrophobic tag to their reducing ends. However, tagging and subsequent desalting processes are quite time-consuming. Herein, we develop a rapid and sensitive approach for oligosaccharide derivatization by using 2-hydrazinopyrimidine (2-HPM). As a result of the presence of an electron-withdrawing N-heterocycle, 2-HPM can quantitatively derivatize oligosaccharides within 15 min and selectively facilitate their ionization. Additionally, 2-HPM acts as co-matrix to enhance the MALDI signal of oligosaccharides, and therefore the tedious enrichment and purification processes prior to MALDI analysis are avoided. This approach is applied to the analysis of various oligosaccharides released from glycopeptides, glycoprotein, and biological samples. After derivatization, a significant increase of MALDI intensities (greater than 10-fold) was observed for all the tested neutral and sialylated oligosaccharides. Moreover, the enhanced fragmentation of MS/MS brings much convenience to the structural elucidation of oligosaccharides. [ABSTRACT FROM AUTHOR]

N-Glycosylation is one of the most prevalent protein post-translational modifications and is involved in many biological processes, such as protein folding, cellular communications, and signaling. Alteration of N-glycosylation is closely related to the pathogenesis of diseases. Thus, the investigation of protein N-glycosylation is crucial for the diagnosis and treatment of disease. In this research, we applied diethylaminoethanol (DEAE) Sepharose solid-phase extraction microcolumns for N-glycopeptide enrichment. This method integrated the advantages of Click Maltose and zwitterionic HILIC (ZIC-HILIC) and showed a relatively higher specificity for N-glycosylated peptides. This strategy was then applied to tryptic digests of normal human serum, followed by deglycosylation using peptide-N-glycosidase F (PNGase F) in H O. Subsequent LC-MS/MS analysis allowed for the assignment of 219 N-glycosylation sites from 115 serum N-glycoproteins. This study provides an alternative approach for N-glycopeptide enrichment and the method employed is effective for large-scale N-glycosylation site identification. [ABSTRACT FROM AUTHOR]

The potential role of protein O-GlcNAcylation in cancer has been studied extensively, and the spread of cancer cells to regional lymph nodes is the first step in the dissemination of breast cancer. However, the correlation between O-GlcNAcylation and lymphatic metastasis in breast cancer remains elusive. In this study, we demonstrated that the overall O-GlcNAcylation as well as O-GlcNAc transferase (OGT) tends to decrease in response to the augmentation of lymph node metastasis (LNM) in invasive ductal breast carcinomas (IDCs). Although accumulating evidence indicates that individual O-GlcNAcylation may be important in the pathogenesis of breast cancer, O-GlcNAcylated proteins in IDCs are still largely unexplored. Herein, O-GlcNAcylated proteins of IDCs were chemo-enzymatically enriched and identified via liquid chromatography combined with tandem mass spectrometry. In total, 155 O-GlcNAcylated proteins were determined, of which 41 were only observed in LNM tissues, while 40 were unique in non-LNM samples. Gene ontology analysis showed that O-GlcNAc is primarily a nucleocytoplasmic post-translational modification, and most enriched functional terms were related to cancer development in both metastatic and non-metastatic IDCs. Moreover, several O-GlcNAcylated proteins involved in glycolysis and its accessory pathway were identified from LNM and non-LNM groups, respectively. These results indicate that the O-GlcNAcylation statuses of individual proteins were independent of the overall O-GlcNAcylation levels of metastatic and non-metastatic IDCs. Aberrant O-GlcNAc modification of these proteins might be associated with LNM progression. [ABSTRACT FROM AUTHOR]

In this study, a gold nanobox with 40 nm edge length has been transformed into nanoframe gradually by increasing the square-hole length in each {100} facet of the hexahedron. The local dielectric environment-dependent plasmon spectra and refractive index sensitivity of this face-holed single gold nanocage were investigated based on the discrete dipole approximation method. Both the redshift of the resonance peak position and the sensitivity factor increased near exponentially with increasing hole length, which could be attributed to the changing of hot regions of plasmonic field coupling. Moreover, the shift of their resonance peak position to the refractive index of environmental medium increased linearly, and the face-holed nanocage-based sensor shows an excellent sensitivity factor of 955.7 nm/RIU [figure of merit (FOM) = 3.58]. It was also noticed that the non-monotonic transform of the local field enhancement factor (|E/E0|) with a maximum of 80.9 is also extremely affected by the refractive index. The physical mechanism discussed herein may be that the polarized field in local dielectric environment becomes intense as the refractive index increases, resulting in an improvement of field enhancement factor on the corners. We therefore believe that the square-hole length of {100} facets could enhance the plasmonic optical sensitivity of nanocage-based nanoparticles. [ABSTRACT FROM AUTHOR]

H19 expression is elevated in many human tumors including glioblastomas, suggesting an oncogenic role for the long noncoding RNA; yet the upregulation of H19 in glioblastomas remains unclear. Here we report that hypoxia significantly stimulated H19 expression in glioblastoma cell lines, which was related to hypoxia-inducible factors 1α (Hif-1α). Hif-1α promoted H19 expression in U87 and U251 cells. Meanwhile PTEN is an advantageous factor to affect H19 expression, through attenuating Hif-1α stability. Hif-1α also positively correlates with H19 in human glioblastoma samples depending on PTEN status. ChIP and luciferase reporter assays showed that Hif-1α induced H19 transcription through directly binding to the H19 promoter. Furthermore, Hif-1α upregulated specific protein 1 (SP1) expression in glioblastomas cells in vitro and in vivo, and SP1 also strongly interacted with the H19 promoter to promote H19 expression under hypoxia. We also showed that H19 acts as a molecular sponge that binds miR-181d, relieving inhibition of β-catenin expression. Therefore, H19 participates in hypoxia-driven migration and invasion in glioblastoma cells. In summary, our results uncover the mechanisms that stimulate H19 expression under hypoxia to promote malignant effects in glioblastomas and suggest H19 might be a promising therapeutic target. [ABSTRACT FROM AUTHOR]

The root-knot nematode Meloidogyne incognita causes severe damage to continuously cropping vegetables. The control of this nematode relies heavily on organophosphate nematicides in China. Here, we described resistance to the organophosphate nematicide fosthiazate in a greenhouse-collected resistant population (RP) and a laboratory susceptible population (SP) of M. incognita. Fosthiazate was 2.74-fold less toxic to nematodes from RP than that from SP. Quantitative real-time PCR revealed that the acetylcholinesterase2 (ace2) transcription level in the RP was significantly higher than that in the SP. Eighteen nonsynonymous amino acid differences in ace2 were observed between the cDNA fragments of the RP and SP. The acetylcholinesterase (AChE) protein activity in the RP was significantly reduced compared with that in the SP. After knocking down the ace2 gene, the ace2 transcription level was significantly decreased, but no negative impact on the infection of juveniles was observed. The 50% lethal concentration of the RNAi RP population decreased 40%, but the inhibition rate of fosthiazate against AChE activity was significantly increased in RP population. Thus, the increased fosthiazate insensitivity in the M. incognita resistant population was strongly associated with mutations in ace2. These results provide valuable insights into the resistance mechanism of root-knot nematode to organophosphate nematicides. [ABSTRACT FROM AUTHOR]