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Chemotherapy remains the most common treatment for all types of breast cancer. Chemoresistance in tumors is still a major obstacle for treating late-stage breast cancer. In the process of acquiring resistance, tumor cells dynamically evolve to adapt to the challenge of anti-cancer drugs. Besides the upregulation of drug-pumps, signal pathways related to proliferation and survival undergo adaptive evolution. Thus, these drug-resistant cells are more conducive to proliferation, even in stressful conditions. Nevertheless, the detailed mechanism that drives cancer cells to sustain their proliferation ability is unclear. Herein, we reported that the upregulated C-MET signaling acts as a compensatory mechanism that sustains the proliferation of chemoresistant cells in which EGFR family signaling was attenuated. Both C-MET and EGFR family are essential for cell proliferation due to their activation of the STAT3 signaling. Different from other cell models in which C-MET interacts with and phosphorylates EGFR family members, our cell model showed no direct interaction between C-MET and EGFR family members. Therefore, C-MET and EGFR family signaling pathways function independently to sustain the proliferation of resistant cells. Moreover, chemoresistant cells have evolved a novel, STAT3-C-MET feed-forward loop that plays a vital role in sustaining cell proliferation. The activated STAT3 interacts with the MET gene promoter to upregulate its transcription. Most importantly, the combined inhibition of C-MET and EGFR family synergistically inhibits the proliferation of drug-resistant cells in vitro and in xenograft tumor models. This work provides a new strategy for treating drug-resistant breast cancer.

This paper theoretically investigates the evolutionary dynamics in the division of labor games performed on the cycle networks. Several typical updating processes based on the Moran process are considered here: Birth-Death (BD) updating process, Death-Birth (DB) updating process and the mixed DB-BD updating process. The exponential payoff-to-fitness mapping is adopted, and analytical results for fixation time and fixation probability under the condition of strong selection are provided. In addition, numerical values of several crucial quantities within the framework of different game scenarios, decided by the payoff matrix of the division of labor (DOL) games, are studied for comparison. The conclusion clearly shows that, even under different kinds of DOL games, the fixation times are closely associated with the specific update mechanism. This work provides a deeper look into the strategic interactions and network dynamics in the context of the DOL games based on self-organized task allocation.

Electroactive materials with high electrochemical activity, good rate capability and excellent cycling stability are urgently needed for hybrid supercapacitors, but achieving those performances at the same time is still a big challenge. Here, α phase nickel−cobalt−manganese hydroxide (NiCoMn−OH) with a flower-like structure is synthesized and used as the battery materials for hybrid supercapacitor. The NiCoMn−OH exhibits strong synergetic electrochemistry between the transition metals, which contributes better charge storage performances. The NiCoMn−OH shows a specific capacity of 757 C g−1 at 1 A g−1 and retains 369 C g−1 at very high specific current of 50 A g−1, which are both much higher than the corresponding bimetal and nomometal hydroxides. Therefore, both high electrochemical activity and rate capability have been achieved. The α phase NiCoMn−OH also exhibits a long-term cycling stability because the specific role of Co, maintaining 100% of the specific capacity after 1200 cycles. The hybrid supercapacitor based on NiCoMn−OH also shows high specific capacity of 219 C g−1 at 1 A g−1, high rate performance of 53% capacity retention when the specific current increases 25 times and ultralong cycling stability of 83% capacity retention after 12,000 cycles.

Drug-resistant gram-negative bacteria have emerged as a global crisis. Therefore, novel antibiotics and novel anti-infection strategies are urgently needed. Current antibiotics remain unsatisfactory due to poor targeting efficiency and poor drug penetration through the bacterial cell wall. Thus, targeted delivery of antibiotics into gram-negative bacteria should be a promising approach. Moreover, gram-negative bacteria can release lipopolysaccharide (LPS) to induce inflammatory response and septic shock, further increasing the disease burden. Hence, it is also promising to neutralize LPS while delivering antibiotics. This study aims to develop a multifunctional bacteria-targeting liposome that could enhance the delivery of antibiotics and adsorb LPS.A polymyxin B (PMB)-modified liposomal system (P-Lipo) was developed as novel carrier of cinnamaldehyde (CA) by using a thin-film evaporation method. Liposome morphology, size, zeta potential, stability, entrapment efficiency, and in vitro release were systematically evaluated. The bacteria-targeting effect and LPS-neutralizing capacity of P-Lipo were evaluated both in vitro and in vivo. The antibacterial effect of CA-loaded P-Lipo was assessed in Escherichia coli (E. coli) O157:H7 and Pseudomonas aeruginosa (P. aeruginosa). Ultimately, the therapeutic effect of P-CA-Lipo was investigated in E. coli O157:H7-infected mice.P-Lipo was successfully synthesized and encapsulated with CA, which was well characterized. Both in vivo and in vitro experiments demonstrated that P-Lipo could efficiently target the E. coli after modification with PMB. Compared with free CA, CA-Lipo, and P-Lipo, P-CA-Lipo exhibited a significantly enhanced inhibitory effect on E. coli and P. aeruginosa. Further analysis demonstrated that P-CA-Lipo improved the bacterial uptake of CA and enhanced its antibacterial effect. It was also confirmed that P-Lipo could neutralize the LPS to avoid the inflammatory responses and inhibit the release of proinflammatory cytokines in both macrophages and mice. Finally, P-CA-Lipo inhibited E. coli-induced skin damage and death in mice and showed good biocompatibility.The P-Lipo could target E. coli by binding with LPS and enhancing the delivery and internalization of CA. In addition, P-Lipo could adsorb free LPS synergistically, thus promoting the infection management. We believe that this strategy can provide innovative insights into antibacterial agent delivery for the treatment of persistent and severe bacterial infections.

A widespread dense fog event associated with heavy air pollution occurred in the central and eastern regions of China from 30 December 2016 to 5 January 2017. The fog event was characterized by three distinct propagation processes on different spatial scales. This study investigated the propagation of fog and variations of pollutants during the fog event in order to better understand the mechanisms of fog. The cold high-pressure system moved southward, and the southerly wind on the western flank of the high-pressure system enhanced the temperature inversion, both of which were favorable for fog propagation. In addition, the invasion of the weak cold air and radiative cooling, and the different land-sea thermodynamic properties also contributed to the formation and propagation of the fog. Heavy pollution related to this severe fog was also investigated. The field experiment indicates that amounts of aerosol particles accounted for the enhancement of fog droplets through its role of being the condensation nuclei. As a result, the PM2.5 concentration decreased when the fog became strong. The strong temperature inversion and gas to particle phase conversion led to an increase of the PM2.5 concentration and a decrease of pollution gases (SO2, NO2) concentration during the mature stage.

Degradation of the antidepressant venlafaxine by an effective electrocatalytic process, boron-doped diamond (BDD) electrode, was study. The BDD electrode was selected as the anode, and the degradation efficiency of venlafaxine under different influencing factors was systematically investigated. The preliminary grasp of the degradation law of venlafaxine by anodic electro-degradation using BDD electrode was obtained. The experimental results showed that the electrochemical oxidation technology using BDD anode can effectively degrade venlafaxine and remove total organic carbon (TOC) from the solution, complete venlafaxine degradation and TOC elimination could be achieved within 30 and 120 min of BDD oxidation process, respectively, and it has good stability and reusability. Increasing the electrolyte concentration (≤0.1 mol/L) and current density (≤100 mA/cm2) within a certain range could accelerate the degradation of venlafaxine. HCO3– and PO43− could inhibit the degradation efficiency of venlafaxine through of competing for free radicals. It is interesting that the presence of Cl− significantly promoted the degradation efficiency of venlafaxine. The results of this study suggest that the Electro-degradation treatment may provide a promising way to treat venlafaxine contaminated water.

Properties and structural features of xNd2O3-(100-x)(20Fe2O3-60P2O5-20Na2O) (x = 0, 2, 4, 6 and 8 mol%) glasses have been investigated in detail by Differential Thermal Analysis (DTA), inductively coupled plasma mass spectrometry (ICP-MS), inductively coupled plasma optical emission spectroscopy (ICP-OES), Raman and Fourier Transform Infrared Spectroscopy (FTIR) respectively. The results show that the samples with x

Objective: To study the efficacy of Professor Zhiqiang Guo's unique sequential herbal therapy in the treatment of premature ovarian insufficiency (POI) of the kidney deficiency and liver constraint pattern. Methods: Ninety patients with POI who consulted with Professor Guo at Dongzimen Hospital, Beijing University of Chinese Medicine from January 2012 to December 2015 were enrolled. Treatment consisted of sequential therapy using traditional Chinese medicine formulae with the actions of nourishing the liver and kidney. Course of treatment was 3 consecutive menstrual cycles for each participant except for those who became pregnant during treatment. Baseline data including age, course of disease, past medical history, lifestyle, pregnancy outcome, menstrual status (cycle length, menstrual flow duration and volume), as well as gonadal hormone levels before and after treatment were recorded and analyzed. Results: During treatment, 18 (20.0%) participants became pregnant. Symptoms including scanty menstrual flow, irritability, low libido, insomnia and excessive dreaming at night, nightsweats, hot flashes, and depression were markedly alleviated. Changes in follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels at early follicular stage were observed (P = .009 and P = .002, respectively), and FSH/LH differed significantly pre- and posttreatment (P = .044). Conclusion: Professor Guo's sequential Chinese herbal therapy with the actions of nourishing the liver and kidney to treat POI can enhance ovarian function, promote pregnancy, and improve quality of life. Keywords: Premature ovarian insufficiency, Infertility, Traditional Chinese herbal medicinals, Sequential therapy, Nourish the liver and kidney

The puzzle of altruistic cooperation attracts many concerns of researchers in multiple subjects nowadays. In this work we establish punishment in the framework of a threshold multiple-player snowdrift game employed as the scenario for the cooperative dilemma problem. We show by analysis that given this assumption, punishing free riders can significantly influence the evolution dynamics, and the results are driven by the specific components of the punishing rule. Intriguingly larger thresholds of the game provide a more favorable scenario for the coexistence of the cooperators and defectors under a broad value range of parameters. Furthermore, we provide a two-layer network framework for describing the individual interactions, by extending the threshold snowdrift games to the double-layers networks. Here, cooperators are best supported on complex networks by applying the threshold, moreover, the interlinks between the two layers are conducive to reinforce the network reciprocity.

One phenomenon or social institution often observed in multi-agent interactions is the altruistic punishment, i.e. the punishment of unfair behavior by others at a personal cost. Inspired by the works focusing on punishment and the intricate mechanism behind it, we theoretically study the strategy evolution in the framework of two-strategy game models with the punishment on defectors, moreover, the cost of punishing will be evenly shared among the cooperators. Theoretical computations suggest that larger punishment on defectors or smaller punishment cost incurred by cooperators will enhance the fixation of altruistic cooperation in the population. Through the replicate dynamics, the group size of the randomly selected individuals from the sufficiently large population will notably affect the strategy evolution in populations nested within a dilemma. By theoretical modeling the concept of shared cost for punishment from one point of view, our findings underscore the importance of punishment with shared cost as a factor in real-life decisions in an evolutionary game context.

HuR (human antigen R), an mRNA-binding protein responsible for poor prognosis in nearly all kinds of malignancies, is a potential anti-tumor target for drug development. While screening HuR inhibitors with a fluorescence polarization (FP) based high-throughput screening (HTS) system, the clinically used drug eltrombopag was identified. Activity of eltrombopag on molecular level was verified with FP, electrophoretic mobility shift assay (EMSA), simulation docking and surface plasmon resonance (SPR). Further, we showed that eltrombopag inhibited in vitro cell proliferation of multiple cancer cell lines and macrophages, and the in vivo anti-tumor activity was also demonstrated in a 4T1 tumor-bearing mouse model. The in vivo data showed that eltrombopag was efficient in reducing microvessels in tumor tissues. We then confirmed the HuR-dependent anti-angiogenesis effect of eltrombopag in 4T1 cells and RAW264.7 macrophages with qRT-PCR, HuR-overexpression and HuR-silencing assays, RNA stability assays, RNA immunoprecipitation and luciferase assays. Finally, we analyzed the in vitro anti-angiogenesis effect of eltrombopag on human umbilical vein endothelial cells (HUVECs) mediated by macrophages with cell scratch assay and in vitro Matrigel angiogenesis assay. With these data, we revealed the HuR-dependent anti-angiogenesis effect of eltrombopag in breast tumor, suggesting that the existing drug eltrombopag may be used as an anti-cancer drug., Graphical abstract This study elucidated the anti-tumor effect and new mechanism of the clinical drug eltrombopag, where eltrombopag exhibited anti-tumor angiogenesis effect through targeting HuR protein in cancer cells and macrophages. With these data, we emphasize the efficiency of HuR inhibitor for tumor angiogenesis inhibition.Image 1

Nickel-cobalt-manganese sulfide (NiCoMn-S) with a mesoporous structure was synthesized as the electroactive battery materials for hybrid supercapacitors. The synergy between transition metals of NiCoMn-S was investigated theoretically by performing density functional theory calculations and experimentally by comparing the charge storage properties of sulfides with different transition metals. It is found that the Mn composition can activate the 3d electrons of Co and enhance affinity of NiCo–S with electrolyte ions, leading to synergy between transition metals for enhanced electrochemical activity and rate performance. The Mn composition also increases the specific area for more electroactive sites and reduces the charge transfer resistance of sulfides. In addition, it is found that the Mn and Ni compositions can greatly enhance the charge storage activity of sulfide, and the Co composition greatly improves the rate performance. The strong synergy between Ni, Co and Mn results in enhanced specific capacity, high rate performance and excellent cycling stability. The NiCoMn-S exhibits a specific capacity of 661 C g−1 at 1 A g−1, which retains 440 C g−1 at 50 A g−1. More significantly, the NiCoMn-S demonstrates well matched performance with the capacitive RGO electrode, and the resulting hybrid supercapacitor (HSC) demonstrates both high power and high energy performances. The HSC exhibits a specific energy of 42.1 Wh kg−1 at a specific power of 750 W kg−1, and showing a specific energy of 13.2 Wh kg−1 at a specific power of 22.5 kW kg−1.

Fog collection has been considered as an effective and sustainable approach for relieving the water deficiency in arid regions. Despite great progresses on bioinspired superwetting surfaces towards fog collection, practical fog-collecting devices face challenges by omnidirectional collection and lower-evaporation storage simultaneously. Inspired by unidirectional liquid movement caused by asymmetric wettability on the holey lotus leaf, a self-revolving collector was developed to efficiently harvest the fog in a wind-driven manner, finally storing it lastingly at lower-evaporation rate. Such a collector provided a superhydrophobic external surface for capturing fogdrops, a diode-liquid micro-hole array for the spontaneous droplet movement, and a hydrophilic internal surface for fast droplet collection and long-term storage. The synergy of these structural features together with composition merits made the self-revolving collector show efficient fog collection and lower-evaporation storage. The fog-laden wind field around the collector as well as the relationship between the self-revolving speed and the fog-laden wind speed were explored theoretically. The corresponding model analyses further supported the 49% enhancement of fog collection rate when the collector whipped by 1 m/s fog-laden wind revolves at 18 rad/s. This work opens an avenue for designing a novel fog collector used in real environment and offers a strategy for optimizing the existing fog collectors towards high efficiency.

Nickel cobalt (Ni–Co) molybdates with different stoichiometric nickel and cobalt ratios have been synthesized by a facile hydrothermal method. The hydrothermal method is robust enough to synthesis of Ni–Co molybdates with same crystal structure and similar nanorods morphology at different ratios of Ni and Co. The electrochemical performance of Ni–Co molybdates is measured as positive electroactive material in a three-electrode configuration, which demonstrates typical faradaic redox behaviors of Ni–Co molybdates that consistent with battery-type materials. Owing to the synergistic effect of Ni and Co ions, the electrochemical performance in terms of specific capacity, rate capability and cycling stability can be readily tuned by varying the Ni and Co content. In particular, the Ni0.67Co0.33MoO4 demonstrates the highest specific capacity of 441C g−1 at 1 A g−1, superior rate capability of 71% capacity retention after 50 times increase in current density. In addition, the Ni0.67Co0.33MoO4 is used to assemble hybrid supercapacitors with reduced graphene oxide, which shows high specific capacity (119C g−1 at 1 A g−1), high specific energy (25.6 Wh kg−1 at 775 W kg−1) and high specific power (7750 W kg−1 at 13.2 Wh kg−1).

Salvianolate has been widely used for the treatment of cerebrovascular diseases. However, the detailed molecular mechanism of how it alleviates cerebral ischaemia-reperfusion injury is not well understood. In the present study, we investigated the neuroprotective effects of salvianolate in acute cerebral infarction using the PC12 cell oxygen-glucose deprivation (OGD) model in vitro and the rat transient middle cerebral artery occlusion (MCAO) model in vivo. The results showed that the salvianolate significantly reduced the level of reactive oxygen species and inhibited the Caspase-3 signalling pathway in vitro; at the same time, in vivo experiments showed that salvianolate obviously reduced the infarct area (12.9%) and repaired cognitive function compared with the model group (28.28%). In conclusion, our data demonstrated that the salvianolate effectively alleviated cerebral ischaemia-reperfusion injury via suppressing the Caspase-3 signalling pathway.

Throughout more than ten years of observations, strong dense fog (SDF) (visibility

The sequences necessary for liver-specific expression of the apolipoprotein (apo) E gene have been shown to reside 3' to the gene, within the apoE/C-I/C-II gene cluster, but have not been precisely characterized. Utilizing a transient transfection reporter gene assay based on the apoC-II promoter, we have localized a liver-specific enhancer to its approximate limit dimension of 154 base pairs. This enhancer directed liver-specific expression of an apoE gene construction in transgenic mice. A DNaseI protection assay revealed two footprints over an inverted repeat of a known transcriptionally active motif, TGACCT. DNaseI-sensitive sites were present in three of six repeats of a motif (consensus GCAAACA) which has been postulated to represent the recognition sequence of a hepatic transcriptional activity, HNF-5. This region of DNA may function as a liver-specific enhancer for the entire apoE/C-I/C-II gene cluster.

Among selected study populations, myocardial perfusion scintigraphy (MPS) in patients with left bundle branch block (LBBB) has been reported to show a low specificity for the diagnosis of coronary disease. However, the stress electrocardiogram (ECG) is nondiagnostic in this setting. To place this method in its appropriate clinical context, we evaluated MPS in all 69 consecutive patients with LBBB studied with scintigraphy for clinical reasons during a 4-year period. Among 32 patients who underwent coronary angiography for clinical indications, per patient sensitivity, 96%; per vessel sensitivity, 84%, 50%, and 100% for left anterior descending (LAD), left circumflex (LCX), and right coronary artery (RCA) involvement, respectively; and per vessel specificity, 95% and 68% for LCX and RCA disease, respectively, were not significantly different from those previously published for the method in patients without LBBB. Although per patient specificity, 38%, and specificity, 39%, for LAD disease were low, the predictive value of a positive test remained relatively high (83%) owing to the small number of patients selected for angiography, in part based on scintigraphic findings, with normal coronary anatomy. In addition to a possible specific pathophysiologic cause related to LBBB, apparent perfusion abnormalities in the LAD distribution may relate to generic conditions that can make scintigraphic interpretation ambiguous, often in the anterior distribution, regardless of the clinical setting. Additionally, the apparent lack of scintigraphic specificity in the LAD distribution could relate in part to a selection bias toward catheterization of patients with induced scintigraphic abnormalities, especially in the LAD distribution.(ABSTRACT TRUNCATED AT 250 WORDS)