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Previous studies of transmembrane protein channels have employed noise analysis to examine their statistical current fluctuations. In general, these explorations determined a substrate-induced amplification in the Gaussian white noise of these systems at a low-frequency regime. This outcome implies a lack of slowly appearing fluctuations in the number and local mobility of diffusing charges in the presence of channel substrates. Such parameters are among the key factors in generating a low-frequency 1/ f noise. Here, we show that a protein-selective biological nanopore exhibits a substrate-induced amplification in the 1/ f noise. The modular composition of this biological nanopore includes a hydrophilic transmembrane protein pore fused to a water-soluble binding protein on its extramembranous side. In addition, this protein nanopore shows an open substate populated by a high-frequency current noise because of the flickering of an engineered polypeptide adaptor at the tip of the pore. However, the physical association of the protein ligand with the binding domain reversibly switches the protein nanopore from a high-frequency noise substate into a quiet substate. In the absence of the protein ligand, our nanopore shows a low-frequency white noise. Remarkably, in the presence of the protein ligand, an amplified low-frequency 1/ f noise was detected in a ligand concentration-dependent fashion. This finding suggests slowly occurring equilibrium fluctuations in the density and local mobility of charge carriers under these conditions. Furthermore, we report that the excess in 1/ f noise is generated by reversible switches between the noisy ligand-released substate and the quiet ligand-captured substate. Finally, quantitative aspects of the low-frequency 1/ f noise are in accord with theoretical predictions of the current noise analysis of protein channel-ligand interactions.

The small-polaron hopping model has been used for six decades to rationalize electronic charge transport in oxides. The model was developed for binary oxides, and, despite its significance, its accuracy has not been rigorously tested for higher-order oxides. Here, the small-polaron transport model is tested by using a spinel system with mixed cation oxidation states (Mn x Fe 3- x O 4 ). Using molecular-beam epitaxy (MBE), a series of single crystal Mn x Fe 3- x O 4 thin films with controlled stoichiometry, 0 ≤ x ≤ 2.3, and lattice strain are grown, and the cation site-occupation is determined through X-ray emission spectroscopy (XES). Density functional theory + U analysis shows that charge transport occurs only between like-cations (Fe/Fe or Mn/Mn). The site-occupation data and percolation models show that there are limited stoichiometric ranges for transport along Fe and Mn pathways. Furthermore, due to asymmetric hopping barriers and formation energies, the Mn O h 2 + polaron is energetically preferred to the Fe O h 2 + polaron, resulting in an asymmetric contribution of Mn/Mn pathways. All of these findings are not contained in the conventional small-polaron hopping model, highlighting its inadequacy. To correct the model, new parameters in the nearest-neighbor hopping equation are introduced to account for percolation, cross-hopping, and polaron-distribution, and it is found that a near-perfect correlation can be made between experiment and theory for the electronic conductivity., (© 2020 Wiley-VCH GmbH.)

Usually, materials with perfect structures possess excellent properties, but it is not always the case. Here, a new approach is reported to construct structural colored hydrogel films with excellent ultraviolet (UV) blocking performance for contact lenses. The theoretical simulation predicts that with perfect periodic structures, the hydrogel films can strongly reflect incident light in a narrow visible wavelength range and thus exhibit extraordinarily brilliant colors. However, such hydrogel films cannot effectively block UV light. By slightly breaking the structural periodicity (quasi-periodic structure), strong diffuse scattering or pseudoabsorption of light can occur for all of the wavelengths shorter than a structural characteristic length, leading to perfect UV blocking. According to the theoretical prediction, a structural colored hydrogel film with nearly periodic polystyrene sphere arrays in poly(hydroxyethyl methacrylate) hydrogel matrix is fabricated; this hydrogel film possesses brilliant colors and perfect UV blocking, and the core particle composition and size have been investigated in detail for the optimized properties of contact lenses. Meanwhile, the cell proliferation assay proves the cytocompatibility of the hydrogel for real application. Regarding its unique optical characteristics, the as-prepared structural colored hydrogel shows great promise in the fields of UV-protective equipment, medical device, soft robot, sensor, and so on.

Anti-agglomerants (AAs), both natural and commercial, are currently being considered for gas hydrate risk management of petroleum pipelines in offshore operations. However, the molecular mechanisms of the interaction between the AAs and gas hydrate surfaces and the prevention of hydrate agglomeration remain critical and complex questions that need to be addressed to advance this technology. Here, we use molecular dynamics (MD) simulations to investigate the effect of model surfactant molecules (polynuclear aromatic carboxylic acids) on the agglomeration behaviour of gas hydrate particles and disruption of the capillary liquid bridge between hydrate particles. The results show that the anti-agglomeration pathway can be divided into two processes: the spontaneous adsorption effect of surfactant molecules onto the hydrate surface and the weakening effect of the intensity of the liquid bridge between attracted hydrate particles. The MD simulation results also indicate that the anti-agglomeration effectiveness of surfactants is determined by the intrinsic nature of their molecular functional groups. Additionally, we find that surfactant molecules can affect hydrate growth, which decreases hydrate particle size and correspondingly lower the risk of hydrate agglomeration. This study provides molecular-level insights into the anti-agglomeration mechanism of surfactant molecules, which can aid in the ultimate application of natural or commercial AAs with optimal anti-agglomeration properties., Competing Interests: The authors declare that they have no conflict of interest., (This journal is © The Royal Society of Chemistry.)

Metabolic reprogramming in cancer cells, vs. non-cancer cells, elevates levels of reactive oxygen species (ROS) leading to higher oxidative stress. The elevated ROS levels suggest a vulnerability to excess prooxidant loads leading to selective cell death, a therapeutically exploitable difference. Co-enzyme Q 10 (CoQ 10 ) an endogenous mitochondrial resident molecule, plays an important role in mitochondrial redox homeostasis, membrane integrity, and energy production. BPM31510 is a lipid-drug conjugate nanodispersion specifically formulated for delivery of supraphysiological concentrations of ubidecarenone (oxidized CoQ 10 ) to the cell and mitochondria, in both in vitro and in vivo model systems. In this study, we sought to investigate the therapeutic potential of ubidecarenone in the highly treatment-refractory glioblastoma. Rodent (C6) and human (U251) glioma cell lines, and non-tumor human astrocytes (HA) and rodent NIH3T3 fibroblast cell lines were utilized for experiments. Tumor cell lines exhibited a marked increase in sensitivity to ubidecarenone vs. non-tumor cell lines. Further, elevated mitochondrial superoxide production was noted in tumor cells vs. non-tumor cells hours before any changes in proliferation or the cell cycle could be detected. In vitro co-culture experiments show ubidecarenone differentially affecting tumor cells vs. non-tumor cells, resulting in an equilibrated culture. In vivo activity in a highly aggressive orthotopic C6 glioma model demonstrated a greater than 25% long-term survival rate. Based on these findings we conclude that high levels of ubidecarenone delivered using BPM31510 provide an effective therapeutic modality targeting cancer-specific modulation of redox mechanisms for anti-cancer effects.

Photothermal therapy (PTT) has been widely studied for tumor therapy. However, the clinical transformation of PTT has encountered significant challenges in tumor recurrence, because the uneven hyperthermia in tumor tissues can result in the survival of cancer cells in the lower temperature regions close to blood vessels (as the blood flow can dissipate the localized heat). It is therefore important for clinical treatments to retain the excellent therapeutic efficiency of PTT at relatively low temperatures. In this article, innocuous hollow mesoporous carbon spheres (HMCS) with a high photothermal conversion efficiency were obtained by a one-pot synthesis method. After modification with DSPE-PEG, the HMCS-PEG exhibited a superior stability in biomedia, which is beneficial for further biological applications. Interestingly, combined with hydrophobic gambogic acid (GA) which can downregulate heat shock protein 90 (HSP90), the HMCS-PEG-GA system showed a significant NIR-enhanced tumor therapeutic effect in vitro and in vivo under mild temperature conditions (∼43 °C), and the combination index (CI) value of HMCS-PEG-GA was found to be 0.72. Meanwhile, this nano-system possessed good photothermal imaging and photoacoustic imaging abilities. Guided by the photoacoustic imaging signal, HMCS-PEG-GA showed enormous potential for use in accurate tumor diagnosis and mild-temperature PPT treatment applications, which is very important for clinical transformation of this nano-system.

Background: Whether anesthesia methods affect the prognosis of tumor patients is controversial. With the aim of comparing the effects of general anesthesia (GA) and local anesthesia (LA) in primary hepatocellular carcinoma (HCC) patients presenting for elective thermal ablation (TA) surgeries, a multiple center retrospective cohort study was designed and implemented., Methods: Patients who received elective TA surgery under GA or LA from Jan. 2014 to Dec. 2016 and met the eligibility criteria were included. Survival analysis was used to identify the influence of anesthesia methods on recurrence-free survival (RFS) and overall survival (OS). Propensity score matching (PSM) was used to minimize the bias between the GA group and the LA group., Results: A total of 244 patients with GA and 245 with LA were eligible for analysis. After PSM, 178 patients remained in each group. In the matched groups, GA showed a significantly higher recurrence rate compared with LA by both the Kaplan-Meier survival analyses (P=0.011) and multivariable Cox regression analyses (P=0.002). The multivariable Cox regression model also revealed that GA had a hazard ratio (HR) of 1.746 (P=0.036) for death compared with the LA group., Conclusions: GA is associated with decreased RFS and OS after surgery compared with LA in HCC patients undergoing TA surgery. Prospective trials exploring the effects of different anesthetic methods on cancer outcome in these patients are warranted., Competing Interests: Conflicts of Interest: The authors have no conflicts of interest to declare., (2020 Annals of Translational Medicine. All rights reserved.)

Adrenergic receptors (ARs) have gained attention for their involvement in breast cancer (BC) progression. Dexmedetomidine, a selective α 2 -AR agonist, has been reported to increase the malignancy of BC cells in vitro or stimulate tumor growth in mice. However, clinical evidence is lacking. Clinical research in this area is important as dexmedetomidine is widely used in BC surgery patients. Here we allocated 24 women with primary BC to the dexmedetomidine group (who received a total dose of 2 μg kg -1 dexmedetomidine perioperatively) or to the control group (who received the same volume of normal saline). Venous blood was obtained from all patients immediately upon entering the operating room and 24 hours postoperatively. Serum was then exposed to MCF-7 cells at a concentration of 10% for 24 hours. Cell proliferation, migration, and invasion were analyzed using EdU, Transwell, and Matrigel methods, respectively. We found that postoperative serum from those who received dexmedetomidine was associated with significantly increased cell proliferation, migration, and invasion compared with preoperative serum when used to culture MCF-7 cells. The mean percentage change from post to preoperative values in these cell functions was significantly larger in the dexmedetomidine group than in the control group (proliferation, 30.44% vs 8.45%, P = .0024; migration, 15.90% vs 3.25%, P = .0015; invasion, 8.17% vs 2.13%, P = .04). In conclusion, these findings suggest that in patients undergoing surgery for primary BC, perioperative administration of dexmedetomidine might influence the serum milieu in a way that favors the malignancy of MCF-7 cells. Clinical trial registration: NCT03108937., (© 2019 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Liver cancer is a leading cause of cancer morbidity and mortality worldwide, especially in China. Sorafenib (SRF) is currently the most commonly used systemic agent against advanced hepatocellular carcinoma (HCC), which is the most common type of liver cancer. However, HCC patients have only limited benefit and suffer a serious side effect from SRF. Therefore, new approaches are urgently needed to improve the therapeutic effectiveness of SRF and reduce its side effect. In our current study, we developed a self-imaging and self-delivered nanodrug with SRF and indocyanine (ICG) to improve the therapeutic effect of sorafenib against HCC. With the π-π stacking effect between SRF and ICG, a one-step nanoprecipitation method was designed to obtain the SRF/ICG nanoparticles (SINP) via self-assembly. Pluronic F127 was used to shield the SINP to further improve the stability in an aqueous environment. The stability, photothermal effect, cell uptake, ROS production, cytotoxicity, tumor imaging, and tumor-targeting and tumor-killing efficacy of the SINP were evaluated in vitro and in vivo by using an HCC cell line Huh7 and its xenograft tumor model. We found that our designed SINP showed monodisperse stability and efficient photothermal effect both in vitro and in vivo. SINP could rapidly enter Huh7 cells and achieve potent cytotoxicity under near-infrared (NIR) laser irradiation partly by producing a great amount of reactive oxygen species (ROS). SINP had significantly improved stability and blood half-life, and could specifically target tumor via the enhanced permeability and retention (EPR) effect in vivo. In addition, SINP showed improved cytotoxicity in both subcutaneous and orthotopic HCC implantation models in vivo. Overall, this rationally designed sorafenib delivery system with a very high loading capacity (33%) has considerably improved antitumor efficiency in vitro and could completely eliminate subcutaneous tumors without any regrowth in vivo. In conclusion, our self-imaging and self-delivered nanodrug could improve the efficacy of SRF and might be a potential therapy for HCC patients.

Background: Chemo-photothermal therapy has attracted intensive attention because of its low side effects and better therapeutic efficiency. Although many photothermal agents have been loaded with chemotherapeutic drugs for chemo-photothermal therapy, their applications are limited by complex synthetic protocols and long-term safety. Therefore, there is significant clinical value in the development of a simple system of biocompatible and biodegradable photothermal nanomaterials with high payloads of chemotherapeutic drugs for chemo-photothermal synergistic therapy., Materials and Methods: In this study, PEG-modified polydopamine nanoparticles with mesoporous structure (MPDA-PEG) were successfully obtained by an emulsion-induced interface assembly strategy. Subsequently, paclitaxel (PTX) dissolved in acetone was loaded into the mesoporous channels of MPDA-PEG nanoparticles by solution absorption method. A PTX-loaded MPDA-PEG (MPDA-PEG-PTX) nanoplatform for combination of photothermal therapy (PTT) and chemotherapy was developed., Results: The synthesized MPDA-PEG nanoparticles had a great photothermal effect under near-infrared (NIR) laser irradiation and exhibited an enhanced photothermal effect with the increase of particle size. Meanwhile, MPDA-PEG nanoparticles also had a high payload of PTX, and the PTX release could be greatly accelerated by elevated temperature from photothermal effect. In MTT cytotoxicity assay, A549 cells incubated with MPDA-PEG-PTX under NIR laser irradiation (PTT + chemotherapy group) exhibited better therapeutic effect than single chemotherapy (MPDA-PEG-PTX group) and PTT (MPDA-PEG + Laser group). The synergistic therapeutic effect of MPDA-PEG-PTX with NIR laser irradiation in vivo was further investigated under the guidance of photoacoustic imaging (PAI), tumors of nude mice treated with MPDA-PEG-PTX with NIR laser irradiation were completely eliminated with minimal side effect., Conclusion: The MPDA-PEG-PTX nanoplatform is a simple and effective platform which can completely inhibit tumor growth with minimal side effects under NIR irradiation, and it exhibits better therapeutic effect than single chemotherapy and PTT., Competing Interests: The authors report no conflicts of interest in this work., (© 2019 Zhang et al.)

Atomic force microscopy (AFM) indentation is widely used to determine mechanical parameters of various materials. However, AFM tip may lead to phase transition of the cold sample in the region of contact area. It is a long-standing challenge that low-temperature phase-change materials (e.g., ice and hydrate) are hardly characterized by AFM, especially for clathrate hydrates. Here, with theoretical analysis and numerical simulation, we investigated the temperature influence of AFM tip on the tetrahydrofuran (THF) hydrate stability. At first, a steady-state model of heat conduction was established between a v-shaped probe and THF hydrate sample. The temperature of the tip was estimated at different laser spot positions and laser intensities. Through numerical simulation, the heat loss by air convection is less than 1% of the total laser heat, and the influence of ambient air on the AFM probe temperature can be neglected. Meanwhile, the local temperature in the region of contact area was also calculated at the THF hydrate temperature of 0°C, -10°C, -20°C, and -30°C. We found out that the AFM tip causes the cold THF hydrate to melt. The thermal melting thickness decreases with the reduction of laser intensity and THF hydrate temperature. On the contrary, it is positively correlated with the thickness of liquid-like layer on THF hydrate surface and is also linearly increased with the contact radius. This indicates that the thermal melting continues as the press-in depth of the tip into THF hydrate increases. The local temperature rises when the tip touches the THF hydrate. It is easier for THF hydrate to be melted by an external pressure. In addition, the proposed model may be useful for guiding force tests on low-temperature phase-change materials by the AFM indentation., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2019 Li Peng et al.)

Background and Purpose: Tanshinol borneol ester (DBZ) is a novel synthetic compound derived from Dantonic ® , a botanical drug approved in 26 countries outside the United States for angina pectoris and currently undergoing FDA Phase III clinical trial. Here, we investigated the angiogenic effects of (S)-DBZ and (R)-DBZ isomers in vitro and in vivo., Experimental Approach: A network pharmacology approach was used to predict molecular targets of DBZ. The effects of DBZ isomers on proliferation, migration, and tube formation of human endothelial cells were assessed. For in vivo approaches, the transgenic Tg (vegfr2:GFP) zebrafish and C57BL/6 mouse Matrigel plug models were used. ELISA and western blots were used to quantitate the release and expression of relevant target molecules and signalling pathways., Key Results: DBZ produced a biphasic modulation on proliferation and migration of three types of human endothelial cells. Both DBZ isomers induced tube formation in Matrigel assay and a 12-day co-culture model in vitro. Moreover, DBZ promoted Matrigel neovascularization in mice and partially reversed the vascular disruption in zebrafish induced by PTK787. Mechanistically, DBZ enhanced the cellular levels of VEGF, VEGFR2, and MMP-9, as well as activating Akt and MAPK signalling in endothelial cells. Selective inhibition of PI3K and MEK significantly attenuated its angiogenic effects., Conclusions and Implications: These data reveal, for the first time, that DBZ promotes multiple key steps of angiogenesis, at least in part through Akt and MAPK signalling pathways, and suggest it may be potentially developed further for treating myocardial infarction and other cardiovascular diseases., (© 2019 The British Pharmacological Society.)

Wntless (Wls) transports Wnt molecules for secretion; however, the cellular mechanism underlying the initial assembly of Wnt secretory vesicles is still not fully defined. Here, we performed proteomic and mutagenic analyses of mammalian Wls, and report a mechanism for formation of early Wnt secretory vesicles on ER membrane. Wls forms a complex with SEC12 (also known as PREB), an ER membrane-localized guanine nucleotide-exchange factor (GEF) activator of the SAR1 (the SAR1A isoform) small GTPase. Compared to palmitoylation-deficient Wnt molecules, binding of mature Wnt to Wls increases Wls-SEC12 interaction and promotes association of Wls with SAR1, the key activator of the COPII machinery. Incorporation of Wls into this exporting ER compartment is affected by Wnt ligand binding and SEC12 binding to Wls, as well as the structural integrity and, potentially, the folding of the cytosolic tail of Wls. In contrast, Wls-SEC12 binding is stable, with the interacting interface biochemically mapped to cytosolic segments of individual proteins. Mutant Wls that fails to communicate with the COPII machinery cannot effectively support Wnt secretion. These data suggest that formation of early Wnt secretory vesicles is carefully regulated to ensure proper export of functional ligands., Competing Interests: Competing interestsThe authors declare no competing or financial interests., (© 2017. Published by The Company of Biologists Ltd.)

Purpose: The association between menopause and overactive bladder is controversial. The purpose of this study was to determine the association between menopausal symptoms and overactive bladder, and identify the risk factors for overactive bladder., Methods: A cross-sectional study was performed. The study included 403 women aged 36-76 years who visited the menopause clinic at Peking University First Hospital between September 2012 and December 2013. The overactive bladder symptom score and modified Kupperman index questionnaires were used. Differences were assessed using descriptive statistics to determine any association between the overactive bladder symptom score and modified Kupperman index score, and to evaluate the risk factors for overactive bladder., Results: A total of 304 women were finally enrolled. The prevalence of overactive bladder was 9.43%, and the modified Kupperman index score; number of sexual problems; and frequency of urinary tract infections, vertigo, melancholia, and mood swings were significantly higher in patients with overactive bladder than in the patients without overactive bladder (p < 0.05). Menopausal symptoms (modified Kupperman index score ≥ 15) (odds ratio: 1.049, 95% confidence interval: 1.006-1.095, p = 0.025) and a low frequency of sexual intercourse in the last 6 months (odds ratio: 2.580, 95% confidence interval: 1.228-5.422, p = 0.012) were identified as independent risk factors for overactive bladder. The frequency of sexual intercourse was found to decrease with an increase in the severity of overactive bladder (p = 0.004, linear-by-linear association = 0.001)., Conclusion: Menopausal symptoms may be closely associated with overactive bladder, and sexual activity may be associated with the severity of overactive bladder. Moreover, sexual problems, urinary tract infections, vertigo, melancholia, and mood swings may be associated with overactive bladder.

Mutations in the APC or β-catenin genes are well-established initiators of colorectal cancer, yet modifiers that facilitate the survival and progression of nascent tumor cells are not well defined. Using genetic and pharmacologic approaches in mouse colorectal cancer and human colorectal cancer xenograft models, we show that incipient intestinal tumor cells activate CDC42, an APC-interacting small GTPase, as a crucial step in malignant progression. In the mouse, Cdc42 ablation attenuated the tumorigenicity of mutant intestinal cells carrying single APC or β-catenin mutations. Similarly, human colorectal cancer with relatively higher levels of CDC42 activity was particularly sensitive to CDC42 blockade. Mechanistic studies suggested that Cdc42 may be activated at different levels, including at the level of transcriptional activation of the stem cell-enriched Rho family exchange factor Arhgef4. Our results indicate that early-stage mutant intestinal epithelial cells must recruit the pleiotropic functions of Cdc42 for malignant progression, suggesting its relevance as a biomarker and therapeutic target for selective colorectal cancer intervention., (©2014 American Association for Cancer Research.)