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Sunitinib is the most commonly used first-line therapy for the treatment of advanced renal cell carcinoma (RCC), but intrinsic and extrinsic resistance to targeted therapies dramatically compromise the benefit of clinical outcome. Dissecting the underlying mechanisms and discovering reliable predictive biomarkers are urgently needed in clinic. Here, we discovered miR-885-5p was notably decreased after sunitinib treatment and associated with poor disease progression in clear cell renal cell carcinoma (ccRCC). In vitro and in vivo studies identified miR-885-5p inhibition contributed to sunitinib resistance. Mechanistically, sunitinib treatment reduced GATA1 expression, which in turn reduced its binding to MIR885 promoter and resulted in miR-885-5p downregulation in transcriptional level. In addition, PLIN3 was confirmed to be directly targeted by miR-885-5p and its upregulation significantly increased lipid droplets formation to decrease sunitinib sensitivity. Therefore, GATA1/miR-885-5p/ PLIN3 pathway may serve as a potential therapeutic strategy and a biomarker for sunitinib treatment in ccRCC.

Although chemical space is vast, there are many instances where chemical modifications make only insignificant changes in the current that passes through a molecule. This insensitivity comes, in part, from the energy mismatch between the molecular resonances and the Fermi level of the electrodes used. Here, we present a strategy to overcome this problem by employing two-dimensional transition-metal dichalcogenides as electrodes. The work function of the electrodes can be tuned across the entire molecular energy range (from the highest occupied molecular orbital to the lowest unoccupied molecular orbital) at a low bias with the appropriate choice of electrode material. We illustrate the effectiveness of this strategy by investigating the thermoelectric properties of the junctions with a model molecular system, as optimal thermoelectric performance requires a delicate balance between the electronic and the heat transport properties. By using van der Waals contacts between the binding groups and the electrod...

Background: Prostate cancer (PC) fearfully impacts men's health. We explored the efficacy and mechanism of circular RNA circZNF609 (circZNF609) on colony formation, viability, apoptosis, migration and invasion and in PC cells. Methods: Colony formation, CCK-8, flow cytometry, migration and invasion assay were respectively used to detect the functions of circZNF609 and microRNA (miR)-186-5p on cell colony ability, viability, apoptosis, migration and invasion. circZNF609 and miR-186-5p expression were changed by cell transfection and tested by RT-qPCR. Moreover, Cleaved-Caspase-3, Cleaved-Caspase-9, matrix metalloproteinase-9 (MMP-9), Vimentin and relate-proteins of cell pathways were examined through Western blot. Results: circZNF609 was highly expressed at PC tissues. circZNF609 declined cell colony ability, viability, migration and invasion and caused apoptosis. Furthermore, circZNF609 negatively regulated miR-186-5p, miR-186-5p inhibitor could reverse impacts of circZNF609. Finally, circZNF609 restrained the YAP1 and AMPK pathways by up-regulating miR-186-5p. Conclusion: Silencing circZNF609 restrained growth, migration and invasion of PC cells by up-regulating miR-186-5p via YAP1 and AMPK pathways. Highlights circZNF609 is highly expressed in PC tissues; circZNF609 restrains cell growth, migration and invasion; circZNF609 exerts its function by up-regulating miR-186-5p; circZNF609 exerts its function by YAP1 and AMPK signaling pathways.

BACKGROUND Prostate cancer (PCa) is one of the commonest male urinary and reproductive system malignancies with high morbidity and mortality. circLMTK2 was reported as a tumor suppressor, therefore, we attempted to investigate the potential mechanism of circLMTK2 in PCa. METHODS qRT-PCR was employed to examine the expressions of circLMTK2 and miR-183. Afterwards, cell transfection was conducted for overexpressing circLMTK2 and miR-183 in LNCaP and PC3 cells, and silencing circLMTK2 in RWPE1 cells. Then, CCK-8 assay, BrdU, transwell assay, flow cytometry and western blot were respectively conducted to examine the variations of cell growth and metastasis, as well as apoptosis. The expressions of key proteins involved in Wnt/β-catenin and PI3K/AKT pathways were further investigated utilizing western blot. RESULTS circLMTK2 was lowly expressed in tumor tissues. circLMTK2 overexpression suppressed cell proliferation and metastasis, however promoted cell apoptosis in LNCaP and PC3 cells. circLMTK2 knockdown enhanced cell viability, proliferation, migration and invasion, while had no significant influences on apoptosis of RWPE1 cells. Further experiments verified that miR-183 up-regulation counteracted the influences triggered by circLMTK2 overexpression in LNCaP and PC3 cells. Besides, it markedly promoted the viability, proliferation, migration and invasion of LNCaP cells, however had no significant influence on cell apoptosis. Moreover, the inhibitory effects on Wnt/β-catenin and PI3K/AKT pathways evoked by circLMTK2 overexpression were diminished by miR-183 up-regulation in LNCaP and PC3 cells. CONCLUSION These outcomes illustrated that circLMTK2 overexpression exerts an anti-tumor effects through down-regulating the expression of miR-183.

The structure of an electrochemical interface is not determined by any external electrostatic field, but rather by external chemical potentials. This paper demonstrates that the electric double layer should be understood fundamentally as an internal electric field set up by the atomic structure to satisfy the thermodynamic constraints imposed by the environment. This is captured by the generalized computational hydrogen electrode model, which enables us to make efficient first-principles calculations of atomic scale properties of the electrochemical interface.

Ternary semiconductor nanowire arrays enable scalable fabrication of nano-optoelectronic devices with tunable bandgap. However, the lack of insight into the effects of the incorporation of Vy element results in lack of control on the growth of ternary III-V(1-y)Vy nanowires and hinders the development of high-performance nanowire devices based on such ternaries. Here, we report on the origins of Sb-induced effects affecting the morphology and crystal structure of self-catalyzed GaAsSb nanowire arrays. The nanowire growth by molecular beam epitaxy is changed both kinetically and thermodynamically by the introduction of Sb. An anomalous decrease of the axial growth rate with increased Sb2 flux is found to be due to both the indirect kinetic influence via the Ga adatom diffusion induced catalyst geometry evolution and the direct composition modulation. From the fundamental growth analyses and the crystal phase evolution mechanism proposed in this Letter, the phase transition/stability in catalyst-assisted ternary III-V-V nanowire growth can be well explained. Wavelength tunability with good homogeneity of the optical emission from the self-catalyzed GaAsSb nanowire arrays with high crystal phase purity is demonstrated by only adjusting the Sb2 flux.

The negative-AND (NAND) gate is universal for classical computation making it an important target for development. A seminal quantum computing algorithm by Farhi, Goldstone and Gutmann has demonstrated its realization by means of quantum scattering yielding a quantum algorithm that evaluates the output faster than any classical algorithm. Here, we derive the NAND outputs analytically from scattering theory using a tight-binding (TB) model and show the restrictions on the TB parameters in order to still maintain the NAND gate function. We map the quantum NAND tree onto a conjugated molecular system, and compare the NAND output with non-equilibrium Green's function (NEGF) transport calculations using density functional theory (DFT) and TB Hamiltonians for the electronic structure. Further, we extend our molecular platform to show other classical gates that can be realized for quantum computing by scattering on graphs., 17 pages, 6 figures, 1 table

The aim of the present study was to investigate the effect and therapeutic potential of baicalin in breast cancer. Baicalin is used to treat inflammatory diseases. The effects of baicalin were assessed in breast cancer MCF-7 and MDA-MB‑231 cells, and human breast cancer xenograft mice. Cells were treated with 0, 20 or 30 µM baicalin for 48 h, while xenograft mice were treated with intraperitoneal injection of 0, 100 or 200 mg/kg baicalin for 30 days. The results demonstrated that treatment with baicalin dose-dependently suppressed breast cancer cell invasion, migration and proliferation, and also induced G1/S-phase cell cycle arrest in vitro and in vivo. Baicalin alleviated inflammation injury and inhibited the secretion of tumor necrosis factor (TNF)-α and interleukin (IL)-1β, thus suppressing nuclear factor (NF)-ĸB-p65 activation via inhibition of IĸB kinase. Investigation of the mechanism underlying baicalin activity indicated that it inhibited protein expression of NF-ĸB-p65, leading to NF-ĸB‑induced increased expression of CCND1, BCL2, BIRC2 and BIRC3, thus inhibiting cell proliferation, invasion and migration and suppressing anti-apoptotic factors in vitro and in vivo. In addition, baicalin did not affect non-tumorigenic normal breast epithelial cells. These results indicate that baicalin may exert therapeutic effects in breast cancer.

Using ab initio calculations we investigate the energy level alignment at the graphene/MoS2 heterostructure and the use of electron doping as a strategy to lower the Schottky barrier and achieve a low-resistance Ohmic contact. For the neutral heterostructure, density functional theory (DFT) with a generalized gradient approximation predicts a Schottky barrier height of 0.18 eV, whereas the G0W0 method increases this value to 0.60 eV. While the DFT band gap of MoS2 does not change when the heterostructure is formed, the G0W0 gap is reduced by 0.30 eV as a result of the enhanced screening by the graphene layer. In contrast to the case of metal substrates, where the band alignment is governed by Pauli repulsion-induced interface dipoles, the graphene/MoS2 heterostructure shows only a negligible interface dipole. As a consequence, the band alignment at the neutral heterostructure is not changed when the two layers are brought into contact. We systematically follow the band alignment as a function of doping co...

The microscopic origin of the p-type character of AuCl3 functionalized carbon nanotubes (CNTs) is investigated using first-principles self-interaction corrected density functional theory (DFT). Recent DFT calculations suggest that the p-type character of AuCl3 functionalized CNTs is due to the Cl atoms adsorbed on the CNTs. We test this hypothesis and show that adsorbed Cl atoms only lead to a p-type character for very specific concentrations and arrangements of the Cl atoms, which furthermore are not the lowest energy configurations. We therefore investigate alternative mechanisms and conclude that the p-type character is due to the adsorption of AuCl4 molecules. The unraveling of the exact nature of the p-doping adsorbates is a key step for further development of AuCl3 functionalized CNTs in water sensor applications.

Objective Results of in vitro and in vivo studies suggest that consumption of beer is less harmful for the liver than consumption of spirits. It also has been suggested that secondary plant compounds derived from hops such as xanthohumol or iso-α-acids may have beneficial effects on the development of liver diseases of various etiologies. The aim of this study was to determine whether iso-α-acids consumed in doses achieved by “normal” beer consumption have beneficial effects on health. Methods Female C57 Bl/6 J mice, pretreated for 4 d with an iso-α-acid–rich extract (∼30% iso-α-acids from hops, 0.75 mg/kg body weight), were fed one bolus of ethanol (6 g/kg body weight intragastric) or an iso-caloric maltodextrin solution. Markers of liver damage, toll-like receptor-4 signaling, and lipid peroxidation were determined. Furthermore, the effect of isohumulone on the lipopolysaccharide-dependent activation of J774 A.1 macrophages, used as a model of Kupffer cells, was determined. Results In the liver, acute ethanol administration led to a significant accumulation of fat (∼10-fold), which was accompanied by significantly higher inducible nitric oxide synthase protein level, elevated nitric oxide production, and increased plasminogen activator inhibitor 1 protein concentration when compared to controls. In mice pretreated with iso-α-acids, these effects of alcohol were markedly attenuated. Pretreatment of J774 A.1 macrophages with isohumulone significantly attenuated lipopolysaccharide-induced mRNA expression of inducible nitric oxide synthase and interleukin-6 as well as the release of nitric oxide. Conclusion Taken together, iso-α-acids markedly attenuated the development of acute alcohol-induced damage in mice.

Objectives RNA interference (RNAi) has the potential to be developed into therapeutics for prostate cancer, but the lack of cellular targets limits its application. In the present study we attempt to develop a prostate cancer-specific RNAi system using the human prostate specific membrane antigen (PSMA) promoter/enhancer; furthermore, we analyzed its inhibitive effect on STAT3 expression. Methods The adenoviral vectors containing a small hairpin RNA (shRNA) to target exogenous reporters enhance green fluorescent protein (EGFP) and endogenous gene signal transducers and activators of transcription 3 (STAT3) were constructed. After prostate cancer and other cells were transfected, reverse transcription-polymerase chain reaction (RT-PCR), fluorescence microscopy, and Western blotting were used to measure EGFP expression. Inhibition of STAT3 was evaluated by Western blotting. Cell proliferation and viability were measured by using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay. Cell apoptosis was analyzed with double-staining of Annexin V and PI. Results Our study showed that with the PSMA promoter/enhancer directly driving shRNA transcription, expression of the exogenous reporters EGFP in prostate cancer cells, but not other cancer cells and normal cells, was specifically inhibited in vitro. The PSMA promoter/enhancer-driven shRNA also depressed the expression of STAT3 in only prostate cancer cells. Inhibition of STAT3 suppressed proliferation of PC-3 and LNCaP cells. Conclusions The present study describes an efficient RNAi system for gene silencing that is specific to prostate cancer cells using the PSMA promoter/enhancer. Suppression of STAT3 by using this system decreased proliferation and induced apoptosis of PC-3 and LNCaP cells. This system may be useful for RNAi therapy for prostate cancer.

Using a scanning tunnelling microscope break-junction technique, we produce 4,4'-bipyridine (44BP) single-molecule junctions with Ni and Au contacts. Electrochemical control is used to prevent Ni oxidation and to modulate the conductance of the devices via nonredox gating--the first time this has been shown using non-Au contacts. Remarkably the conductance and gain of the resulting Ni-44BP-Ni electrochemical transistors is significantly higher than analogous Au-based devices. Ab-initio calculations reveal that this behavior arises because charge transport is mediated by spin-polarized Ni d-electrons, which hybridize strongly with molecular orbitals to form a "spinterface". Our results highlight the important role of the contact material for single-molecule devices and show that it can be varied to provide control of charge and spin transport.

The formation and oxidation of the main discharge product in nonaqueous secondary Li−O2 batteries, that is, Li2O2, has been studied intensively, but less attention has been given to the formation of cathode−electrolyte interfaces, which can significantly influence the performance of the Li−O2 battery. Here we apply density functional theory with the Hubbard U correction (DFT+U) and nonequilibrium Green’s function (NEGF) methods to investigate the role of Li2O2@Li2CO3 interface layers on the ionic and electronic transport properties at the oxygen electrode. We show that, for example, lithium vacancies accumulate at the peroxide part of the interface during charge, reducing the coherent electron transport by two to three orders of magnitude compared with pristine Li2O2. During discharge, Li2O2@Li2CO3 interfaces may, however, provide an alternative in-plane channel for fast electron polaron hopping that could improve the electronic conductivity and ultimately increase the practical capacity in nonaqueous Li−O2 batteries.

There is increasing evidence suggesting that dysregulation of some microRNAs (miRNAs) may contribute to tumor progression and metastasis and have been proposed to be key regulators of diverse biological processes such as transcriptional regulation, cell growth and tumorigenesis. Previous studies have shown that miR-137 is dysregulated in some malignancies, but its role in bladder cancer is still unknown. In our study, we find that miR-137 is up-regulated in human bladder cancer tissues and cell lines. Moreover, the higher level of miR-137 was associated with pM or pTNM stage in clinical bladder cancer patients. Enforced expression of miR-137 in bladder cancer cells significantly enhanced their proliferation, migration and invasion. Bioinformatics analysis identified the tumor suppressor gene PAQR3 as a potential miR-137 target gene. Further studies indicated that miR-137 suppressed the expression of PAQR3 by binding to its 3'-untranslated region. Silencing of PAQR3 by small interfering RNAs phenocopied the effects of miR-137 overexpression, whereas restoration of PAQR3 in bladder cancer cells bladder cancer cells overexpressing miR-137, partially reversed the suppressive effects of miR-137. These findings indicate that miR-137 could be a potential oncogene in bladder cancer.

When an electron tunnels between two metal contacts it temporarily induces an image charge (IC) in the electrodes which acts back on the tunneling electron. It is usually assumed that the IC forms instantaneously such that a static model for the image potential applies. Here we investigate how the finite IC formation time affects charge transport through a molecule suspended between two electrodes. For a single level model, an analytical treatment shows that the conductance is suppressed by a factor $Z^2$ (compared to the static IC approximation) where $Z$ is the quasiparticle renormalization factor. We show that $Z$ can be expressed either in terms of the plasma frequency of the electrode or as the overlap between the ground states of the electrode with and without an electron on the molecule. First-principles GW calculations for benzene-diamine connected to gold electrodes show that the dynamical corrections can reduce the conductance by more than a factor of two., Comment: 5 pages, 3 figures

We investigate the electronic conductance and thermopower of a single-molecule junction consisting of bis-(4-aminophenyl) acetylene (B4APA) connected to gold electrodes. We use nonequilibrium Green's function methods in combination with density-functional theory (DFT) and the many-body $GW$ approximation. To simulate recent break junction experiments, we calculate the transport properties of the junction as it is pulled apart. For all junction configurations, DFT with a standard semilocal functional overestimates the conductance by almost an order of magnitude, while the thermopower is underestimated by up to a factor of 3, except for the most highly stretched junction configurations. In contrast, the $GW$ results for both conductance and thermopower are in excellent agreement with experiments for a wide range of electrode separations. We show that the $GW$ self-energy not only renormalizes the molecular energy levels but also the coupling strength. The latter is a consequence of the finite response time associated with the electronic screening in the metal electrodes.

We study the effect of functional groups (CH3*4, OCH3, CH3, Cl, CN, F*4) on the electronic transport properties of 1,4-benzenediamine molecular junctions using the non-equilibrium Green function method. Exchange and correlation effects are included at various levels of theory, namely density functional theory (DFT), energy level-corrected DFT (DFT+Σ), Hartree-Fock and the many-body GW approximation. All methods reproduce the expected trends for the energy of the frontier orbitals according to the electron donating or withdrawing character of the substituent group. However, only the GW method predicts the correct ordering of the conductance amongst the molecules. The absolute GW (DFT) conductance is within a factor of two (three) of the experimental values. Correcting the DFT orbital energies by a simple physically motivated scissors operator, Σ, can bring the DFT conductances close to experiments, but does not improve on the relative ordering. We ascribe this to a too strong pinning of the molecular energy levels to the metal Fermi level by DFT which suppresses the variation in orbital energy with functional group.

Single molecule devices are of great interest for what they reveal about fundamental aspects of electron transport and metal-molecule interactions. They represent the ultimate level of miniaturization in molecular electronics and are also of potential interest in sensor applications. We have used an electrochemical approach to realize a single molecule transistor based on 4,4′-bipyridine contacted by Ni. The top and bottom Ni contacts are an insulated Ni STM tip and an electrodeposited Ni film respectively, which are maintained free of oxide by being held in an aqueous electrolyte under potential control. The 4,4′-bipyridine molecules are initially present in the electrolyte and contacted using the STM break junction method. From numerous repeated experiments we build up a histogram of the measured conductance. This conductance depends strongly on the potential of tip and substrate relative to the reference electrode. This is a manifestation of electrostatic gating and shows that the device functions as a transistor. Remarkably, it shows a significantly higher gain than a similar transistor with Au electrodes. Calculations show that the current in the Ni-4,4′-bipyridine-Ni transistor is highly spin-polarized and therefore the device represents a true spin-based single molecule transistor.

Traffic flow prediction is one of the important components of ITS. However, satisfactory results of prediction cannot be obtained by classic mathematical methods. Fuzzy neural networks are extensively used in the prediction of traffic flow. In a fuzzy neural network, the optimization of each neuron and the connection weights between the layers is very critical. In this paper, an improved particle swarm optimization method is used to optimize the fuzzy neural network parameters. Simulation results show that this method can improve the efficiency of fuzzy neural network training and has good potential of generalization.

Using ANSYS finite element analysis software simulated and analyzed the integration shear weighing plate, found the reasonable areas of pasting strain gauge based on the laws of the beam's bending deformation shear stress, researched for offset loading measurement.

Background Stem cell therapy is a promising therapeutic strategy for stress urinary incontinence (SUI). However, its current efficacy is insufficient. Objective We designed a stem cell transplantation system that contains autologous adipose-derived stem cells (ADSC) and controlled-release nerve growth factor (NGF). We evaluated whether this system could enhance the therapeutic efficacy of ADSCs by periurethral coinjection in SUI rats. Design, setting, and participants We first tested for the presence of NGF receptors in rat ADSCs and observed the effect of NGF on ADSCs in vitro and in vivo. NGF was encapsulated within poly(lactic-co-glycolic acid—PLGA) microspheres (PLGA/NGF) to control its release. SUI was created in rats, and ADSCs were harvested, cultured from fat tissue, and retained for later transplantation. SUI rats then received different forms of periurethral injection therapy. Their urodynamic index was monitored. Eight weeks after injection, the SUI rats were sacrificed and their urethra removed for histologic evaluation. Intervention Forty SUI rats were allocated to five groups for receiving periurethral injection with phosphate-buffered saline (PBS), ADSC, ADSC+PLGA, ADSC+NGF, or ADSC+PLGA/NGF. Bladder capacities, abdominal leak point pressure (ALPP), and retrograde urethral perfusion pressure (RUPP) were reassessed at 2, 6, and 8 wk after injection. Measurements The rat SUI model was generated by bilateral pudendal nerve transection (PNT). Real-time polymerase chain reaction (RT-PCR) and western blotting detected the NGF receptor Ark-A. The regeneration of muscles and peripheral nerves was evaluated by Masson's trichrome and immunohistochemical staining. Results and limitations Results revealed the presence of the NGF receptor Trk-A on rat ADSCs. Short-term observations showed that NGF could improve ADSCs' viability in vitro and in vivo. ADSCs delivered intramuscularly into the urethra in combination with PLGA/NGF resulted in significant improvements in ALPP and RUPP as well as the amount of muscle and ganglia. There was a significant difference between the ADSC+PLGA/NGF group and other groups. Conclusions Periurethral coinjection of autologous ADSCs with controlled-release NGF may be a potential strategy for SUI treatment.

The dielectric properties show a typical ferroelectric relaxor behavior in CaCu3Ti4O12 ceramics with different grain sizes in the temperature range of 400–600K. The relaxation strength and the frequency dispersion increase with grain size decreasing, which can be due to the different stresses in grains with different sizes. These variations have been confirmed by the modified Curie-Weiss law. The results fitted well by the Volgel-Fulcher relationship and the variations in the slim current-voltage loops are correlated with the microstructures closely. It can be proposed that the grain size is one of the main factors of affecting the relaxor behavior.