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Hela cells or A549 cells stably expressing histone H2B-RFP were incubated with 10 μM of different PIPs for 24 h. Cells were then subjected to live-imaging using confocal microscopy. Scale bar, 10 μm.

(a) Hela cells or (b) A549 cells stably expressing histone H2B-RFP were incubated with 10 μM of PIP3. At different time points, cells were harvested, stained, and imaged. Scale bar, 50 μm. (c) Nuclear localization of PIP3 in A549 cells. Scale bar, 10 μm.

Live imaging of mitotic progression in PIP3 treated hTERT-RPE1 cells

(a and b) Plk1 mRNA levels (a) and Plk1 protein levels (b) in various cell lines. (c-e) Pearson correlation co-efficiency was calculated between Plk1 mRNA level, Plk1 protein expression level, and PIP3 sensitivity (represented by IC50 value).

(a and b) A549 cells were treated with different concentrations of PIP2 or PIP3. After 72 h of treatment, cells were incubated with 10 ng/ml TNF-α for additional 12 h, and then harvested for IL6 (a) and IL8 (b) qRT-PCR analysis.

(a) Comparison of the cellular uptake of PIP3 and Hoechst 33258. Hela cells were incubated with different concentrations of PIP3 or Hoechst 33258 for 24 hours. Fluorescent microscopy images were acquired and as shown. (b) PIP3 but not Hoechst 33258 shows Plk1 suppression ability. Hela cells were treated with different concentrations of PIP3 or Hoechst 33258 for 72 hours and then collected for western blotting analysis to examine the Plk1 expression. (c) Evaluation of PIP3 stability in vitro. Hela cells were treated with 10 μM PIP3 for 72 hours, then cells were collected and lysed. Released PIP3 was monitored by RP-HPLC analysis. PIP3 dissolved in water was served as control.

Live imaging of mitotic progression in PIP3 treated A549 cells

Live imaging of mitotic progression in control Hela cells.

Live imaging of mitotic progression in control A549 cells

Live imaging of mitotic progression in PIP3 treated Hela cells

(a) Representative images of mice from vehicle group and PIP3-treated group on the sacrifice day. Yellow arrows indicate tumor locations. (b) Images of isolated tumors from vehicle group or PIP3-treated group. (c) In vivo cellular localization of PIP3. Frozen sections of tumors from PIP3-treated group were imaged under microscopy to visualize the cellular uptake of PIP3 in vivo. The nuclei were stained by Topro3. Scale bar, 100 μm.

(a and b) The hTERT-RPE1 cells and HUVEC cells were synchronized, PIP3 treated, and analyzed as in Figure 4a and 4b. Plk1 inhibition efficiency examined by western blotting was shown in the top. (c and d) Percentages of mitotic cells at different phases were quantified in these treated cells (n.s, not significant; n=3). (e) Time-lapse microscopy of nontransformed cells with or without PIP3 treatment. hTERT-RPE1 cells and HUVEC cells stably expressing histone H2B-RFP were treated with 0.1% DMSO or 20 μM of PIP3 for 72 h and analyzed by time-lapse imaging. (f and g) The duration of total mitosis (f) and time spent in each sub-stage of mitosis (g) were further quantified (n.s, not significant; n{greater than or equal to}25).

Live imaging of mitotic progression in PIP3 treated HUVEC cells

Live imaging of mitotic progression in control HUVEC cells

Live imaging of mitotic progression in control hTERT-RPE1 cells

The serine/threonine kinase Polo-like kinase 1 (Plk1) plays a pivotal role in cell proliferation and has been validated as a promising anticancer drug target. However, very limited success has been achieved in clinical applications using existing Plk1 inhibitors, due to lack of sufficient specificity toward Plk1. To develop a novel Plk1 inhibitor with high selectivity and efficacy, we designed and synthesized a pyrrole-imidazole polyamide–Hoechst conjugate, PIP3, targeted to specific DNA sequence in the PLK1 promoter. PIP3 could specifically inhibit the cell cycle–regulated Plk1 expression and consequently retard tumor cell growth. Cancer cells treated with PIP3 exhibited severe mitotic defects and increased apoptosis, whereas normal cells were not affected by PIP3 treatment. Furthermore, subcutaneous injection of PIP3 into mice bearing human cancer xenografts induced significant tumor growth suppression with low host toxicity. Therefore, PIP3 exhibits the potential as an effective agent for targeted cancer therapy. Mol Cancer Ther; 17(5); 988–1002. ©2018 AACR.

Hela cells were treated with or without 10 μM PIP3 for 72 hours and then labeled by Propidium iodide and Annexin V-FITC for detecting early and late apoptotic signal.

Non-natural amino acids are increasingly used as building blocks in the development of peptide-based drugs, as they expand the available chemical space to tailor function, half-life and other key properties. However, while the chemical space of modified amino acids (mAAs) is potentially vast, experimental methods for measuring the developability properties of mAA-containing peptides are expensive and time consuming. To facilitate developability programs through computational methods, we present CamSol-PTM, a method that enables the fast and reliable sequence-based prediction of the solubility of mAA-containing peptides. From a computational screening of 50,000 mAA-containing variants of three peptides, we selected five different mAAs for a total number of 30 peptide variants for experimental validation. We demonstrate the accuracy of the predictions by comparing the calculated and experimental solubility values. Our results indicate that the computational screening of mAA-containing peptides can extend by over four orders of magnitude the ability to explore the solubility chemical space of peptides. This method is available as a web server athttps://www-cohsoftware.ch.cam.ac.uk/index.php/camsolptm.

Chronic non-specific low back pain (CNLBP) is one of the leading causes of disability worldwide. Acupoint embedding (ACE) is widely used in China for the treatment of chronic non-specific low back pain, but there are no rigorous randomized controlled trials (RCTs) to confirm the effectiveness and safety of ACE for chronic non-specific low back pain. In this study, we design a single-center, single-blind, prospective RCT, with the aim of evaluating the efficacy and safety of ACE for CNLBP. 82 participants with CNLBP will be randomized in a 1:1 ratio into an ACE group and a sham ACE group. Participants will receive either ACE treatment or sham ACE treatment at once every 2 weeks, for an 8-week period, and followed by 6 months of follow-up. The primary outcome will be the change in visual analog scale (VAS) scores before and after treatment. Secondary outcomes will include the Oswestry Disability Index (ODI), the Roland Morris Disability Questionnaire (RMDQ) and the Short Form 36-Health Survey (SF-36). Adverse events that occur during the course of the trial will be recorded. Data will be analyzed according to a predefined statistical analysis plan. This study was approved by the medical ethics committee of Guangzhou Panyu Hospital of Chinese Medicine (202230). Written informed consent from patients is required. This trial is registered in the Chinese Clinical Trial Registry (ChiCTR2200059245). Trial results will be published in a peer-reviewed academic journal.Clinical trial registrationhttps://www.chictr.org.cn, identifier ChiCTR2200059245.

Recommendation system serves as a conduit connecting users to an incredibly large, diverse and ever growing collection of contents. In practice, missing information on fresh (and tail) contents needs to be filled in order for them to be exposed and discovered by their audience. We here share our success stories in building a dedicated fresh content recommendation stack on a large commercial platform. To nominate fresh contents, we built a multi-funnel nomination system that combines (i) a two-tower model with strong generalization power for coverage, and (ii) a sequence model with near real-time update on user feedback for relevance. The multi-funnel setup effectively balances between coverage and relevance. An in-depth study uncovers the relationship between user activity level and their proximity toward fresh contents, which further motivates a contextual multi-funnel setup. Nominated fresh candidates are then scored and ranked by systems considering prediction uncertainty to further bootstrap content with less exposure. We evaluate the benefits of the dedicated fresh content recommendation stack, and the multi-funnel nomination system in particular, through user corpus co-diverted live experiments. We conduct multiple rounds of live experiments on a commercial platform serving billion of users demonstrating efficacy of our proposed methods., Comment: Accepted by KDD 2023

Additional file 1.

Effective exploration is believed to positively influence the long-term user experience on recommendation platforms. Determining its exact benefits, however, has been challenging. Regular A/B tests on exploration often measure neutral or even negative engagement metrics while failing to capture its long-term benefits. To address this, we present a systematic study to formally quantify the value of exploration by examining its effects on the content corpus, a key entity in the recommender system that directly affects user experiences. Specifically, we introduce new metrics and the associated experiment design to measure the benefit of exploration on the corpus change, and further connect the corpus change to the long-term user experience. Furthermore, we investigate the possibility of introducing the Neural Linear Bandit algorithm to build an exploration-based ranking system, and use it as the backbone algorithm for our case study. We conduct extensive live experiments on a large-scale commercial recommendation platform that serves billions of users to validate the new experiment designs, quantify the long-term values of exploration, and to verify the effectiveness of the adopted neural linear bandit algorithm for exploration., Comment: 19 pages

Considering the radial and tangential EM force waves that cause the stator core to vibrate and deform are the primary sources of EM vibration of a non-salient pole synchronous generator (NSPSG), this paper introduces a semi-analytical method of calculating the radial and tangential EM force waves, with the non-linearity of ferromagnetic material taken into account. The method includes the distributed magnetic circuit method (DMCM), the separation variable method (SVM) and the complex variable conformal transformation method (CVCTM). First of all, the radial air-gap flux density is obtained by using the DMCM to calculate the no-load magnetic circuit of the NSPSG and dealing with the non-linearity of ferromagnetic material by B-H curve. Then, the tangential air-gap flux density is calculated by the SVM and the complex relative air-gap permeance is calculated by the CVCTM to determine the effect of slotting. Finally, the radial and tangential EM force waves are obtained by Maxwell stress tensor method. The proposed semi-analytical method is verified through measuring vibration acceleration of the NSPSG

The induced radioactivity in accelerator components and decay characteristics of radioactive nuclei contained therein is critical for radiation safety of occupational workers as well as for the maintenance, repair, and decommissioning activities. The topic of induced radioactivity is widely reported and extensively explored in the literature by many researchers up to now. This mini-review would demonstrate the current state of the knowledge on induced radioactivity at particle accelerators. In this article, the concepts of activation-related studies and radionuclide generation in accelerator environments are reviewed. In addition, some studies on accelerator-induced radioactivity by Monte Carlo and experimental measurement methods are briefly described. The possible radiation protection problems caused by particle accelerator-induced radioactivity are briefly reviewed and analyzed. The produced radionuclides depend on the beam parameters such as particle type, energy, irradiation period, cooling time, and irradiated material. The Monte Carlo simulation method offers comparable advantages over empirical analysis method. A review of major studies in the field of induced radioactivity of particle accelerators confirmed that the extremely strong induced radioactivity generated at hot spots of accelerators means new challenges to radiation safety and deserves further investigation and discussion.

Peptides and peptide drug conjugates are emerging modalities to treat pulmonary diseases. Peptides are susceptible to proteolytic cleavage. Expression levels of specific proteases in the lung can be significantly increased in disease state and may lead to exaggerated peptide proteolysis. To support optimization of peptides for inhaled administration, we have recently reported a streamlined high-throughput LC-HRMS protocol to determine enzymatic protease stability of peptides. This method has now been complemented with profiling of peptide metabolic stability in two respiratory fluids, a lung supernatant (lung S9) and a bronchioalveolar lavage fluid (BALF) taken from rats. We have tested a set of 28 peptides with high structural diversity, analyzed the whole data set for formed metabolites, and identified the differences of cleavage pattern in the two test fluids. Comparison of our experimental results and literature-derived cleavage site estimates based on e.g. MEROPS show significant differences for a number of peptides. This indicates the need for an experimental workflow using both protease panels and testing of metabolic stability in lung fluid (BALF) to guide peptide optimization and selection of peptides for inhaled in vivo PK/PD studies in our drug discovery projects.

In this article, a fast circuit-field coupling method is proposed for the analysis of the skewed induction motor. Based on the multislice model, the equivalent circuit of the skewed induction motor is established. The distributed magnetic field method is used to calculate air-gap flux density and deal with the core saturation at each axial slice. Based on the coupling analysis of the equivalent circuit and magnetic field, a two-layer iterative process is used to calculate the magnetic field distribution and performance indexes of the skewed induction motor. By comparing with finite element analysis and experiment results, the proposed method is proved to be correct and effective. The proposed method is characterized by fast computation speed and good accuracy, so it is an ideal approach to analyze the skewed induction motor.

The electro-cautery lumen apposing metal stent (EC-LAMS) is a newly developed device that integrates the electro-cautery cyctotome with the one-step metal stent delivery and releasing system in recent years. LAMS was first designed to complete the drainage of pancreatic fluid collection under endoscopic ultrasound guidance, and the technological innovation of EC-LAMS has made more off-labeled indications of endoscopic intervention for gastrointestinal diseases realized, such as abdominal fluid drainage, bile duct, or gallbladder drainage through stomach or duodenum, gastrointestinal anastomosis, and the establishment of fistulous channel for further endoscopic operation when necessary. The unique feature of this metal stent is that it has the design of a saddle shape and a large lumen, and can almost connect the adjacent structures to minimize the risk of perforation and leakage. Compared with traditional LAMS, EC-LAMS, an advanced integrated device, can greatly simplify the endoscopic process, shorten the procedure time and reduce the technical difficulty, thus it can help endoscopists complete more complex endoscopic interventions. In this review, we discuss the state of art with regard to EC-LAMS and its endoscopic process, current indications, outcomes, adverse events, and future application prospects.

Inhalation of small molecule drugs has proven very efficacious for the treatment of respiratory diseases due to enhanced efficacy and a favourable therapeutic index compared with other dosing routes. It enables targeted delivery to the lung with rapid onset of therapeutic action, low systemic drug exposure, and thereby reduced systemic side effects. An increasing number of pharmaceutical companies and biotechs are investing in new modalities-for this review defined as therapeutic molecules with a molecular weight800Da and therefore beyond usual inhaled small molecule drug-like space. However, our experience with inhaled administration of PROTACs, peptides, oligonucleotides (antisense oligonucleotides, siRNAs, miRs and antagomirs), diverse protein scaffolds, antibodies and antibody fragments is still limited. Investigating the retention and metabolism of these types of molecules in lung tissue and fluid will contribute to understanding which are best suited for inhalation. Nonetheless, the first such therapeutic molecules have already reached the clinic. This review will provide information on the physiology of healthy and diseased lungs and their capacity for drug metabolism. It will outline the stability, aggregation and immunogenicity aspects of new modalities, as well as recap on formulation and delivery aspects. It concludes by summarising clinical trial outcomes with inhaled new modalities based on information available at the end of 2021.

Natural products are useful tools for biological mechanism research and drug discovery. Due to the excellent tumor cell growth inhibitory profile and sub-nanomolar potency, Coibamide A (CA), an N-methyl-stabilized depsipeptide isolated from marine cyanobacterium, has been considered as a promising lead compound for cancer treatment. However, the molecular anti-cancer mechanism of the action of CA remains unclear. Here, we showed that CA treatment induced caspase-independent cell death in breast cancer cells. CA treatment also led to severe lysosome defects, which was ascribed to the impaired glycosylation of lysosome membrane protein LAMP1 and LAMP2. As a consequence, the autophagosome-lysosome fusion was blocked upon CA treatment. In addition, we presented evidence that this autophagy defect partially contributed to the CA treatment-induced tumor cell death. Together, our work uncovers a novel mechanism underlying the anti-cancer action of CA, which will promote its further application for cancer therapy.

With the widespread use of resin infiltration, its properties have drawn increasing attention. The objective of this study was to investigate the effect of resin infiltration on the surface microhardness and roughness of enamel lesions after thermal cycling aging. Tooth blocks were made from extracted premolars and placed into a control group, resin-infiltrated group or demineralized group. Before and after the aging procedure, the surface microhardness and surface roughness was measured. Before the aging procedure, the surface microhardness of the control group, resin-infiltrated group and demineralized group was 302.14 (±9.77) HV, 146.62 (±8.22) HV, and 28.85 (±2.21) HV (p 0.001), respectively. After the aging procedure, the surface microhardness of the control group, resin-infiltrated group and demineralized group decreased by 9.42%, 16.59%, and 20.75% ( p 0.001), respectively. Before the aging procedure, the surface roughness of the control group, resin-infiltrated group and demineralized group was 0.29 (±0.04) μm, 0.32 (±0.04) μm, and 0.39 (±0.07) μm (p = 0.009), respectively. After the aging procedure, the surface roughness of the control group, resin-infiltrated group and demineralized group increased by 9.85%, 8.31%, and 17.37% (p = 0.634), respectively. Resin infiltration can improve the surface microhardness and surface roughness of demineralized teeth in an artificial enamel caries model. The treatment also shows good aging resistance after thermal cycling. The infiltrant resin provided a suitable material for early enamel caries.

Coibamide A (1) is a highly N-methylated cyclodepsipeptide with low nanomolar antiproliferative activities against various cancer cell lines. In previous work, we discovered a simplified analogue, [MeAla3-MeAla6]-coibamide (1a), which exhibited the same inhibitory abilities as coibamide A. Herein, to reduce the whole-body toxicity and improve the solubility of 1a, two novel peptide-drug conjugates RGD-SS-CA (2) and RGD-VC-CA (3) were designed, synthesized, and evaluated. Composed of cyclodepsipeptide 1a, a tumor-homing RGD motif, and a conditionally labile linker, the conjugates are expected to release 1a tracelessly in specific tumor microenvironments. Compared with RGD-VC-CA (3), RGD-SS-CA (2) proved to be superior in in vitro drug release and cytotoxicity tests. Notably, intravenous injection of RGD-SS-CA (2) into mice-bearing human tumor xenografts induced significant tumor growth suppression with negligible toxicity. Therefore, as a novel prodrug of the coibamide A analogue, conjugate 2 has great potential for further exploration in cancer drug discovery.

The outbreak of COVID-19 by the end of 2019 has posed serious health threats to humanity and jeopardized the global economy. However, no effective drugs are available to treat COVID-19 currently and there is a great demand to fight against it. Here, we combined computational screening and an efficient cellular pseudotyped virus system, confirming that clinical HDAC inhibitors can efficiently prevent SARS-CoV-2 and potentially be used to fight against COVID-19.

A barrier function method based on the fmincon optimization function in MATLAB was used to determine the function to map a tunnel boundary to the unit circle in the complex plane, and a structural failure criterion of the mapping convergence was established based on the reliability theory of underground engineering. The joints were approximated as cracks around the tunnel, the anisotropy of the stress intensity factor due to the crack inclination and position changes was studied, and the modified scoring parameter of the layered joints around the tunnel for the rock geomechanics classification (RMR) was proposed and used at points around the tunnel. The calculation method for the supporting stress was required to balance the bias load. The results showed the following: (1) When taking the structural failure criterion as the convergence condition of the mapping function, the mapping function converged when the mapping accuracy was δ ≥ 31.74 % . (2) The crack with an inclination angle of β = 45 ° was the dominant structural plane of the jointed rock mass around the tunnel. The anisotropy of the stress intensity factor K II at the tip of the mode II crack indicated that the corresponding cracks at the various points around the tunnel had inconsistent influences on the tunnel. The position had the greatest influence, followed by the straight wall area, and then by the top and floor areas. (3) When the crack inclination β was equal to the inclination angle β 0 of the dominant joint plane, the secondary crack was parallel to the unloading surface of the corresponding tunnel. (4) The bias load formed by the layered joints around the tunnel reduced the stress threshold of the failure of the rib spalling.

A combined Computational Fluid Dynamics and Population Balance Model (CFD-PBM) was developed to study the flow hydrodynamics of the slurry bed. The CFD-PBM applied a modified drag force model by considering the reduced drag force between gas and liquid phases at the presence of particle. Results show that the CFD-PBM with the modified drag force model can reasonably predict the flow hydrodynamics compared with the experimental data. It was predicted that the increased particle loading can enhance bubble coalescence to form larger bubbles, which can flow faster and reduce the gas holdup in the slurry bed. In addition, simulation results indicate that the particle flow becomes more non-uniform with much faster upward flow in the center and downward flow near the wall with the increase of superficial velocity. Particle back-mixing can be enhanced at higher superficial gas velocity, which can be beneficial for the reaction system with limited decrease in catalyst particle's reaction activity and unbeneficial for the reaction system with almost fully deactivation of catalyst.

Non-relativistic quantum chromodynamics (NRQCD) factorization formulism is an important approach to investigate the production of the heavy quarkonium. In this paper, we study the production of the $Ω_{ccc}$ and $Ω_{bbb}$ at the $e^+e^-$ collider, using the NRQCD factorization formulism. We calculate the total and differential cross sections exactly of the processes, $e^+e^-\rightarrow γ^*/Z^*\rightarrow Ω_{ccc}\bar{c}\bar{c}\bar{c}$ and $e^+e^-\rightarrow γ^*/Z^*\rightarrow Ω_{bbb}\bar{b}\bar{b}\bar{b}$, in the leading order at the $e^+e^-$ colliders with different energies. The results show that it is hard to observe them at the $e^+e^-$ collider directly.

We have developed a dearomatization-rearomatization strategy for the modification of peptides/proteins through a thiol-Michael addition to the electrophilic cyclohexadienone intermediate that is generated in situ via the oxidation of tyrosine. This strategy enriches the conjugation toolbox and has great potential for applications in medicinal chemistry and chemical biology.

To observe the clinical therapeutic effect of the combination of electroacupuncture (EA) atA total of 58 patients after uterine curettage of incomplete abortion were randomized into an EA group and a western medication group, 29 cases in each one. In the western medication group, mifepristone tablets were administered orally, 2 tablets each time, once daily. In the EA group, on the base of the treatment as the western medication group, EA was applied toAfter treatment, the intrauterine residue area and CDFI blood flow signal positive rate were all reduced as compared with the values before treatment in patients of the two groups (The combined treatment of electroacupuncture at

The inhalation of peptides comes with the advantage of directly targeting the lung as tissue of interest. However, peptides are often rapidly metabolized in lung tissue through proteolytic cleavage. We have developed an assay workflow to obtain half-life and metabolite ID data for peptides incubated with four proteases abundant in lungs of asthma and COPD patients. The assay system has been validated using 28 structurally diverse linear and cyclic peptides with a molecular weight between 708 and 5808 Da. Experimental conditions for incubation, sample preparation, chromatography, data acquisition and analysis are compatible with the required throughput in early stage peptide projects. Together with co-crystal structures and Ala scans, we are using the described assay workflow to guide the first chemical modifications of peptide hits in early respiratory drug discovery projects.

Aurora kinase A (Aurora A) plays a critical role in regulating cell mitotic progression and has been considered as a promising drug target for cancer therapy. To develop a novel molecule targeting Aurora A with high selectivity and efficacy, we designed and synthesized a pyrrole-imidazole polyamide (PIP) Hoechst conjugate, PIP-Ht, targeting to a cell-cycle regulated DNA sequence locating at the promoter of human Aurora A gene (AURKA). PIP-Ht potently suppressed AURKA promoter activities, mRNA expression and protein level, induced tumor cell cycle delay and inhibited tumor cell proliferation in vitro. Furthermore, subcutaneous injection of PIP-Ht into mice bearing human cancer xenografts induced significant tumor growth suppression and cell apoptosis. Collectively, PIP-Ht exhibits the potential as an effective therapeutic candidate for the tumor treatment.

The blended teaching model integrates the dual experience of traditional classroom and online learning, helping teachers adopt appropriate teaching strategies and methods to apply to teaching practice, thereby improving the quality of teaching. Innovative application of blended teaching mode can help us solve many stubborn problems in current education. In recent years, the construction and application of smart learning environment has also gradually emerged in the field of education, becoming an inevitable direction for realizing the leap-forward development of education. The function of recording, monitoring and analyzing the learning process of the intelligent learning environment system; the function of perceiving the learning situation and the recognition of learner characteristics; the function of satisfying the learner's learning at any time, any place, and any way. Each function enables learners in the blended learning mode to obtain a comprehensive and personalized learning experience. This article briefly describes the connotation and functional characteristics of the smart learning environment and blended learning, analyzes the teaching link composition of the blended teaching mode, and based on the current problems in classroom teaching, combined with the characteristics of learners, conducts a smart learning environment-based the blended teaching model is designed and explained this model.

Radiation protection considerations related to radioactive ion beam facilities are discussed. Both the in-flight type and ISOL type are included in this paper. A description of the facility is first provided to better understand the problem. Then, two key components, the production target and beam dump are introduced for their impact on radiation safety. The study of prompt radiation field or shielding design is also presented for different facilities. In addition, the induced radioactivity in accelerator components is addressed for possible interventions and final decommissioning. Finally, the remote handling system in each facility is also reviewed, which is dedicated designed to conduct the maintenance of highly activated components. The aim of this work is to provide valuable experience for other under construction or planned accelerator facilities.

In this paper, the distributed magnetic circuit method (DMCM) is used to calculate the magnetic circuit of a nonsalient pole synchronous generator and deal with the saturation effect of the iron-core material. The conformal transformation method is adopted for calculating the air-gap relative permeance to determine the slot effects of both the stator and the rotor and obtain the spatial and temporal distribution of air-gap flux density and radial vibration force wave. The results of the analytical calculation are very consistent with those of the finite-element method (FEM) and the time (8.47 s) spent on the calculation by the DMCM is much less than the time by the FEM (40 min 45 s). Through measuring the no-load back electromotive force waveform of the generator and the vibration acceleration spectrum of the generator feet, the DMCM is proved to be correct and effective, which will provide the theoretical basis for the accurate design of a magnetic circuit of the generator and for the quantitative analysis of its electromagnetic vibration.

The present study aimed to investigate the role of semaphorin 4D (Sema4D) in bladder cancer cell proliferation and metastasis in vivo and in vitro. Effects of Sema4D modulation on cancer cell viability and clonogenic abilities were assessed by MTT assay and colony formation assay. Cell apoptosis, cell cycle analysis, transwell assays, and wound-healing assays were also assayed. A mouse model of bladder cancer was established to observe the tumorigenesis in vivo. Our data showed that Sema4D was 4-fold upregulated in clinical bladder cancer tissues relative to noncancerous ones and differentially expressed in bladder cancer cell lines. Knockdown of Sema4D in bladder cancer T24 and 5637 cells significantly decreased cell proliferation, clonogenic potential, and motility. On the contrary, overexpression of Sema4D in bladder cancer SV-HUC-1 cells significantly increased cell viability and motility. Concordantly, knockdown of Sema4D impaired while overexpression of Sema4D promoted bladder cancer cell growth rates in xenotransplanted mice. Cell cycle was arrested by modulation of Sema4D. Cell apoptotic rates and the mitochondrial membrane potentials were consistently increased upon knockdown of Sema4D in T24 cells and 5637 cells. Western blotting revealed that epithelial–mesenchymal transition was promoted by Sema4D. The PI3K/AKT pathway was activated upon Sema4D overexpression in SV-HUC-1 cells, while it was inactivated by knockdown of Sema4D in T24 cells. All these data suggest that Sema4D promotes cell proliferation and metastasis in bladder cancer in vivo and in vitro. The oncogenic behavior of Sema4D is achieved by activating the PI3K/AKT pathway.

An efficient copper-catalyzed synthesis of pyrazolo[5,1-a]isoquinolines from 2-gem-dipyrazolylvinylbromobenzenes under mild conditions has been developed. The reaction occurred in moderate to good yields and tolerated nitrile, ether, and halogen substituted 2-gem-dipyrazolylvinylbromobenzenes.

Azobenzene functionalized peptides are of great importance in photoresponsive biosystems and photopharmacology. Herein, we report an efficient approach to prepare azobenzene functionalized peptides through late-stage modification of tyrosine-containing peptides using a dearomatization-rearomatization strategy. This approach shows good chemoselectivity and site selectivity as well as sensitive group tolerance to various peptides. This method enriches the postsynthetic modification toolbox of peptides and has great potential to be applied in medicinal chemistry and chemical biology.

Renal cell carcinoma (RCC) is a type of urinary tumor with a high incidence and is often associated with tumor metastasis. Long non-coding RNA (lncRNA) regulates tumorigenesis, progression, and metastasis. However, the role and the predictive value of lncRNA in RCC progression and metastasis have not been elucidated. The purpose of this study was to evaluate the effect of a newly discovered lncRNA LOC648987 on RCC proliferation and metastasis. LOC648987 was identified by RT-PCR for high expression in human RCC tissues as well as in metastatic RCC tissues. In the cell experiments, we infected the RCC cell lines ACHN and 786-O cells with LOC648987-shRNA and its negative control (shNC). The results showed that the knockdown of LOC648987 inhibited the proliferation of ACHN and 786-O cells and colony formation. The cell cycle and the apoptosis progression of ACHN and 786-O cells were assessed using flow cytometry. The knockdown of LOC648987 significantly inhibited the progression of ACHN and 786-O cells from G0/G1 to S phase and promoted cell apoptosis. The metastasis promoting effects of LOC648987 on ACHN and 786-O cells were verified by transwell migration assays, which depended on vimentin and MMP-9 to regulate the epithelial–mesenchymal transition. Finally, the promotion of LOC648987 on RCC tumorigenesis was evaluated in BALb/c nude mice. These data confirmed that lncRNA LOC648987 promoted RCC cell proliferation and tumor metastasis and regulated the expression of EMT-related proteins in RCC cells.