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Weeding and fertilization are important farming practices. Integrated weed management should protect or improve the biodiversity of farmland weed communities for a better ecological environment with not only increased crop yield, but also reduced use of herbicides. This study hypothesized that appropriate fertilization would benefit both crop growth and the biodiversity of farmland weed communities. To study the effects of different fertilizing patterns on the biodiversity of a farmland weed community and their adaptive mechanisms, indices of species diversity and responses of weed species and wheat were investigated in a 17-year field trial with a winter wheat-soybean rotation. This long term field trial includes six fertilizing treatments with different N, P and K application rates. The results indicated that wheat and the four prevalent weed species (Galium aparine, Vicia sativa, Veronica persica and Geranium carolinianum) showed different responses to fertilizer treatment in terms of density, plant height, shoot biomass, and nutrient accumulations. Each individual weed population exhibited its own adaptive mechanisms, such as increased internode length for growth advantages and increased light interception. The PK treatment had higher density, shoot biomass, Shannon-Wiener and Pielou Indices of weed community than N plus P fertilizer treatments. The N1/2PK treatment showed the same weed species number as the PK treatment. It also showed higher Shannon-Wiener and Pielou Indices of the weed community, although it had a lower wheat yield than the NPK treatment. The negative effects of the N1/2PK treatment on wheat yield could be balanced by the simultaneous positive effects on weed communities, which are intermediate in terms of the effects on wheat and weeds.

Highlights Polysaccharide-based microneedles are novel and emerging tools for ocular drug delivery and the research on the diagnosis and treatment of eye diseases is advancing at a fast pace. Microneedle devices constructed from polysaccharide molecules derived from ocular tissue have the potential to significantly enhance the efficiency of clinical treatments and improve patient compliance with therapeutic regimens. Guided by our vast clinical experience, this is the first review collates the cutting-edge scientific findings from the interdisciplinary field combining natural macromolecules and ophthalmology.

Abstract Fluctuations in gas emission or concentration at working face represent primary indicators of impending coal and gas outbursts, making them essential for monitoring processes. However, the direct use of original signals for predictive purposes may cause false warnings due to the inability to recognize valuable potential information. This can result in decreased prediction accuracy. Additionally, gas emission or concentration is affected by potential hazards such as sensor calibration, borehole spraying, and air duct damage, leading to complexity of their behavior and recognition process. This paper proposes an intelligent recognition method leveraging YOLOv8 neural network to discern coal and gas outburst precursors and potential hazards. By employing continuous wavelet transform (CWT) on the gas concentration signal processed by critical slowing down (CSD) method, a two-dimensional time–frequency representation is generated. This representation is then fed into YOLOv8 model to recognize the outburst precursor characteristics and potential hazards. The research results show that YOLOv8-based intelligent recognition adeptly identifies the relevant precursor characteristics and potential hazards, enhancing both coal mine safety protocols and the accuracy of early outburst warning mechanisms.

Abstract To address the design challenge of the rock-socketed piles posed by the void located below the pile tip, the physical laboratory model tests were designed and performed to simulate rock socketed piles using similar materials. The study investigates the behavior of the single pile under axial loading with the void located at varying distances from the pile tip. Through multi-level load tests, the variations of unit pile side friction, pile tip resistance, pile axial force and pile settlement are obtained for different positions of the void from the pile tip, as well as after grouting. Its comparison to the rock-socketed pile without void is performed as a reference to quantify the reduction in its bearing capacity. The results are presented in the form of graphs for different void positions and its grouting shows the influence on pile bearing capacity and emphasizes the importance of its detailed cautious investigation and introduction in the analysis. The 2D finite element modeling of the model pile-the void based on ABAQUS is performed to further investigate the influence of the void below pile tip on the bearing capacity of model pile, applying the Mohr Coulomb model as the constitutive model of rock mass behavior. The critical distance of the void below the pile tip is determined.

Abstract In nature, coenzyme-independent oxidases have evolved in selective catalysis using isolated substrate-binding pockets. Single-atom nanozymes (SAzymes), an emerging type of non-protein artificial enzymes, are promising to simulate enzyme active centers, but owing to the lack of recognition sites, realizing substrate specificity is a formidable task. Here we report a metal-ligand dual-site SAzyme (Ni-DAB) that exhibited selectivity in uric acid (UA) oxidation. Ni-DAB mimics the dual-site catalytic mechanism of urate oxidase, in which the Ni metal center and the C atom in the ligand serve as the specific UA and O2 binding sites, respectively, characterized by synchrotron soft X-ray absorption spectroscopy, in situ near ambient pressure X-ray photoelectron spectroscopy, and isotope labeling. The theoretical calculations reveal the high catalytic specificity is derived from not only the delicate interaction between UA and the Ni center but also the complementary oxygen reduction at the beta C site in the ligand. As a potential application, a Ni-DAB-based biofuel cell using human urine is constructed. This work unlocks an approach of enzyme-like isolated dual sites in boosting the selectivity of non-protein artificial enzymes.

Neutrophil extracellular traps (NETs) formed by neutrophils are netlike scaffolds that mainly contain DNA and a variety of granule proteins. Many stimuli can lead to the NET formation through independent molecular pathways. Clinically, the abundance of NETs is correlated with poor tumor prognosis. The biological actions of NETs are complex and diverse, including promoting tumor progression, awakening the dormant cancer cells, and resulting in immunosuppression in support of tumor growth and metastasis. Therefore, NET‐associated pathological processes provide an important clue for both diagnostic imaging and alternative therapies for many kinds of cancers. In recent years, scientists’ efforts have focused on developing novel imaging probes to visualize NETs and therapeutic strategies by degrading NETs or inhibiting its formation to block their pro‐tumoral functions. In this review, the development and evaluation of NETs‐targeted imaging and intervention progress for tumor therapy are focused on.

Abstract Electrochemical nitrate reduction to ammonia offers an attractive solution to environmental sustainability and clean energy production but suffers from the sluggish *NO hydrogenation with the spin–state transitions. Herein, we report that the manipulation of oxygen vacancies can contrive spin−polarized Fe1−Ti pairs on monolithic titanium electrode that exhibits an attractive NH3 yield rate of 272,000 μg h−1 mgFe −1 and a high NH3 Faradic efficiency of 95.2% at −0.4 V vs. RHE, far superior to the counterpart with spin−depressed Fe1−Ti pairs (51000 μg h–1 mgFe –1) and the mostly reported electrocatalysts. The unpaired spin electrons of Fe and Ti atoms can effectively interact with the key intermediates, facilitating the *NO hydrogenation. Coupling a flow−through electrolyzer with a membrane-based NH3 recovery unit, the simultaneous nitrate reduction and NH3 recovery was realized. This work offers a pioneering strategy for manipulating spin polarization of electrocatalysts within pair sites for nitrate wastewater treatment.

Abstract Traditional tumour‐dynamic therapy still inevitably faces the critical challenge of limited reactive oxygen species (ROS)‐generating efficiency due to tumour hypoxia, extreme pH condition for Fenton reaction, and unsustainable mono‐catalytic reaction. To fight against these issues, we skilfully develop a tumour‐microenvironment‐driven yolk‐shell nanoreactor to realize the high‐efficiency persistent dynamic therapy via cascade‐responsive dual cycling amplification of •SO4−/•OH radicals. The nanoreactor with an ultrahigh payload of free radical initiator is designed by encapsulating the Na2S2O8 nanocrystals into hollow tetra‐sulphide‐introduced mesoporous silica (HTSMS) and afterward enclosed by epigallocatechin gallate (EG)‐Fe(II) cross‐linking. Within the tumour microenvironment, the intracellular glutathione (GSH) can trigger the tetra‐sulphide cleavage of nanoreactors to explosively release Na+/S2O82−/Fe2+ and EG. Then a sequence of cascade reactions will be activated to efficiently generate •SO4− (Fe2+‐catalyzed S2O82− oxidation), proton (•SO4−‐catalyzed H2O decomposition), and •OH (proton‐intensified Fenton oxidation). Synchronously, the oxidation‐generated Fe3+ will be in turn recovered into Fe2+ by excessive EG to circularly amplify •SO4−/•OH radicals. The nanoreactors can also disrupt the intracellular osmolarity homeostasis by Na+ overload and weaken the ROS‐scavenging systems by GSH exhaustion to further amplify oxidative stress. Our yolk–shell nanoreactors can efficiently eradicate tumours via multiple oxidative stress amplification, which will provide a perspective to explore dynamic therapy.

Abstract Cytokine therapy, involving interleukin-15 (IL-15), is a promising strategy for cancer immunotherapy. However, clinical application has been limited due to severe toxicity and the relatively low immune response rate, caused by wide distribution of cytokine receptors, systemic immune activation and short half-life of IL-15. Here we show that a biomimetic nanovaccine, developed to co-deliver IL-15 and an antigen/major histocompatibility complex (MHC) selectively targets IL-15 to antigen-specific cytotoxic T lymphocytes (CTL), thereby reducing off-target toxicity. The biomimetic nanovaccine is composed of cytomembrane vesicles, derived from genetically engineered dendritic cells (DC), onto which IL-15/IL-15 receptor α (IL-15Rα), tumor-associated antigenic (TAA) peptide/MHC-I, and relevant costimulatory molecules are simultaneously anchored. We demonstrate that, in contrast to conventional IL-15 therapy, the biomimetic nanovaccine with multivalent IL-15 self-transpresentation (biNV-IL-15) prolonged blood circulation of the cytokine with an 8.2-fold longer half-life than free IL-15 and improved the therapeutic window. This dual targeting strategy allows for spatiotemporal manipulation of therapeutic T cells, elicits broad spectrum antigen-specific T cell responses, and promotes cures in multiple syngeneic tumor models with minimal systemic side effects.

Abstract The immunologically “cold” microenvironment of triple negative breast cancer results in resistance to current immunotherapy. Here, we reveal the immunoadjuvant property of gas therapy with cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway activation to augment aggregation-induced emission (AIE)-active luminogen (AIEgen)-based photoimmunotherapy. A virus-mimicking hollow mesoporous tetrasulfide-doped organosilica is developed for co-encapsulation of AIEgen and manganese carbonyl to fabricate gas nanoadjuvant. As tetra-sulfide bonds are responsive to intratumoral glutathione, the gas nanoadjuvant achieves tumor-specific drug release, promotes photodynamic therapy, and produces hydrogen sulfide (H2S). Upon near-infrared laser irradiation, the AIEgen-mediated phototherapy triggers the burst of carbon monoxide (CO)/Mn2+. Both H2S and CO can destroy mitochondrial integrity to induce leakage of mitochondrial DNA into the cytoplasm, serving as gas immunoadjuvants to activate cGAS-STING pathway. Meanwhile, Mn2+ can sensitize cGAS to augment STING-mediated type I interferon production. Consequently, the gas nanoadjuvant potentiates photoimmunotherapy of poorly immunogenic breast tumors in female mice.

The rotary energy recovery device (RERD) plays an important role in reverse osmosis (RO) desalination; however, few investigations on the formation and influence of lateral force on the RERD rotor have been published. The transient characteristics of lateral force and its relationship with pressure distribution and fluctuation in the clearance were analyzed via computational fluid dynamics (CFD) simulation. The clearance pressure distribution and lateral force were quantified under different working conditions. The eccentricity of the rotor, resistance torque and decrease in the rotary speed due to the lateral force were simulated and they were found to change with flow rate and pressure of high-pressure outlet (PHO). A new rotary speed prediction method including the effect of PHO was developed. With the increasing flow rate or PHO, the stability of RERD declined. A design optimization direction was proposed. The variation trends of rotary speed, pressure in the clearance and its fluctuation were verified through experiment. This research provides an explanation why in practice the rotary speed decreases with increasing pressure. The conclusions obtained herein can be of great significance for future research on improving the stability and lifespan and reducing the maintenance consumption of RERD.

Gradient-descent-based digitized adjoint method offers a way to realize the high-efficiency inverse design of digital nanophotonic devices with diverse functions. However, the vanishing gradient problem encountered in the design of high-dimension devices may lead to significant inefficiencies, making it difficult to integrate novel functions on a single chip. Here, we propose a highly efficient digitized adjoint method for large-scale inverse design, called adaptive gradient-descent with momentum. It uses the first- and second-order momentum, instead of the gradient, to update the device pattern during adjoint optimization. To demonstrate the efficiency of the proposed method, we design a coarse wavelength division multiplexer and a three-mode power divider with design dimensions of 800 and 1360, respectively, which are approximately 2-4 times that of conventional digital nanophotonic devices. The simulation results show that, compared with the conventional gradient descent method, the momentum-assisted adjoint method has about 4-6 times higher efficiency and obtains better optimization performance, which provides a powerful tool for the inverse design of novel digital nanophotonic devices.

Enhancing the availability and reliability of dielectric ceramic energy storage devices is of great importance. In this work, (1-[Formula: see text])[Formula: see text]–[Formula: see text]Bi([Formula: see text])[Formula: see text] (NBT–[Formula: see text]BMH) lead-free ceramics were created utilizing a solid-state reaction technique. All NBT–[Formula: see text]BMH ceramics have a single perovskite structure. With increasing BMH doping, the grain size shrinks drastically, which greatly enhances the breakdown electric field (310 kV/cm at [Formula: see text] = 0.25). Additionally, the relaxation behaviors of NBT–[Formula: see text]BMH ceramics with high BMH content are more remarkable. Among all designed components, the NBT–0.25BMH ceramic exhibits the best energy storage performance with a high [Formula: see text] of 4.63 J/[Formula: see text] and an [Formula: see text] of 75.1% at 310 kV/cm. The NBT–0.25BMH ceramic has exceptional resistance to fluctuations in both frequency (5–500 Hz) and temperature (30–100[Formula: see text]C). Charge–discharge test shows that the NBT–0.25BMH ceramic has a quick discharge rate ([Formula: see text] 110 ns). With these properties, the NBT–0.25BMH ceramic may have applications in microdevices as well as in ultra-high power electronic systems.

In this study, electrically insulating polyolefin elastomer (POE)-based phase change materials (PCMs) comprising alumina (Al2O3) and graphene nanoplatelets (GNPs) are prepared using a conventional injection moulding technique, which exhibits promising applications for solar energy storage due to the reduced interfacial thermal resistance, excellent stability, and proficient photo-thermal conversion efficiency. A synergistic interplay between Al2O3 and GNPs is observed, which facilitates the establishment of thermally conductive pathways within the POE/paraffin wax (POE/PW) matrix. The in-plane thermal conductivity of POE/PW/GNPs 5 wt%/Al2O3 40 wt% composite reaches as high as 1.82 W m−1K−1, marking a remarkable increase of ≈269.5% when compared with that of its unfilled POE/PW counterpart. The composite exhibits exceptional heat dissipation capabilities, which is critical for thermal management applications in electronics. Moreover, POE/PW/GNPs/Al2O3 composites demonstrate outstanding electrical insulation, enhanced mechanical performance, and efficient solar energy conversion and transportation. Under 80 mW cm−2 NIR light irradiation, the temperature of the POE/PW/GNPs 5 wt%/Al2O3 40 wt% composite reaches approximately 65 °C, a notable 20 °C improvement when compared with the POE/PW blend. The pragmatic and uncomplicated preparation method, coupled with the stellar performance of the composites, opens a promising avenue and broader possibility for developing flexible PCMs for solar conversion and thermal storage applications.

This paper presents a general circuit and control design method for wireless power transfer (WPT) systems in DC microgrids to achieve optimal power transfer efficiency, while maintain accurate output voltage regulation. An auxiliary inductor is added at the transmitter resonator to form a current sink to ensure zero voltage switching (ZVS) of the primary-side full-bridge inverter with even extreme-light load conditions. Besides, an adaptive proportional-integral (PI) controller is adopted to track the output voltage references by regulating the phase shift angle of the phase shift control for the full-bridge inverter. The coefficients of the adaptive proportional-integral controller are determined by the inductor of the auxiliary inductor. Both simulation and experimental results have validated the effectiveness of the proposed circuit and control design in achieving optimal efficiency and output voltage regulation for wireless power transfer systems in DC microgrids with source and load variations.

Abstract Background Melanoma is the most serious type of skin cancer, and surgery is an effective method to treat melanoma. Unfortunately, local residual micro-infiltrated tumour cells and systemic circulating tumour cells (CTCs) are significant causes of treatment failure, leading to tumour recurrence and metastasis. Methods Small EVs were isolated from platelets by differential centrifugation, and doxorubicin-loaded small EVs (PexD) was prepared by mixing small EVs with doxorubicin (DOX). PexD and an anti-PD-L1 monoclonal antibody (aPD-L1) were co-encapsulated in fibrin gel. The synergistic antitumour efficacy of the gel containing PexD and aPD-L1 was assessed both in vitro and in vivo. Results Herein, we developed an in situ-formed bioresponsive gel combined with chemoimmunotherapeutic agents as a drug reservoir that could effectively inhibit both local tumour recurrence and tumour metastasis. In comparison with a DOX solution, PexD could better bind to tumour cells, induce more tumour immunogenic cell death (ICD) and promote a stronger antitumour immune response. PexD could enter the blood circulation through damaged blood vessels to track and eliminate CTCs. The concurrent release of aPD-L1 at the tumour site could impair the PD-1/PD-L1 pathway and restore the tumour-killing effect of cytotoxic T cells. This chemoimmunotherapeutic strategy triggered relatively strong T cell immune responses, significantly improving the tumour immune microenvironment. Conclusion Our findings indicated that the immunotherapeutic fibrin gel could “awaken” the host innate immune system to inhibit both local tumour recurrence post-surgery and metastatic potential, thus, it could serve as a promising approach to prevent tumour recurrence. Graphical Abstract

AimsTo observe the effects of intrathecal administration of motilin on pain behavior and expression of motilin (MTL)/motilin receptor (MTLR) in the spinal cord of a rat model of acute incisional pain.MethodsAn incisional pain model was established in rats using a unilateral plantar incision. The rats were also injected intrathecally with 1, 5, or 25 μg of motilin. The mechanical withdrawal threshold (MWT) and thermal withdrawal latency (TWL) were determined. MTL/MTLR expression in the spinal cord was detected by western blotting and immunofluorescence. The expression of MTL in the spinal cord, stomach, duodenum, and plasma was determined by enzyme-linked immunosorbent assay (ELISA).ResultsMotilin/motilin receptor were detected in the spinal cord. Spinal cord MTL/MTLR expression peaks at 2 h after modeling (P < 0.05) and start to decrease at 24 h (P < 0.05) to almost reach baseline levels at 72 h. The changes in gastric, duodenal, plasma, and spinal cord motilin levels correlated with MWT and TWL (all R2 > 0.82). The intrathecal injection of 1, 5, or 25 μg of motilin could increase the pain threshold of rats with incisional pain within 72 h in a dose-dependent manner.ConclusionThis study showed for the first time that MTL/MTLR are expressed in rats’ spinal dorsal horn. Acute pain increased MTL/MTLR expression in the spinal dorsal horn. Also, for the first time, this study showed that motilin intrathecal injection alleviates pain in rat models of acute incisional pain. These results suggest that MTL/MTLR could be a novel target for the management of acute pain.

BackgroundDiabetes mellitus, or hyperglycemia, is an independent risk factor for cognitive impairment. Here we systematically analyzed whether glycemic control could improve cognitive impairment in patients with diabetes mellitus (DM), hyperglycemia, or insulin resistance.MethodsThree databases (PubMed, EMBASE, and Cochrane Library) and ClinicalTrials.gov were searched for randomized controlled trials analyzing the relationship between glycemic control and cognitive function assessments, published from database inception to June 2022. Patients in experimental groups were treated with antidiabetic drugs, while control groups were treated with a placebo or alternative antidiabetic drugs. Data analysis was conducted using RevMan 5.3 and StataSE-64, and standardized mean difference (SMD) and 95% confidence intervals (CIs) were calculated.ResultsThirteen studies comprising 19,314 participants were included. Analysis revealed that glycemic control significantly attenuated the degree of decline in cognitive function assessment scores (SMD = 0.15; 95% CI 0.05, 0.26; p

Recent years have witnessed substantial potential in allying meta-optics with diverse waveguide platforms to enable exotic manipulation of guided light signals. This review cataloged recent advances on meta-waveguides for photonic integration.

Lack of expression and function of chloride ion-extruding transporter KCC2 in central neurons, a consequence of various forms of neural injury, is strongly suggested to contribute to chronic pain. Here the authors identify from a screen of cancer drugs a kinase-inhibitor, kenpaullone, as an enhancer of Kcc2/KCC2 gene expression and show that it (i) alleviates pain like behaviour in animal models, (ii) repairs neural-circuit disrupting elevated chloride in pain relay neurons in the dorsal spinal cord.

The heart switches its main metabolic substrate from glucose to fatty acids shortly after birth, which is one of reasons for the loss of heart regeneration capability in adult mammals. On the contrary, metabolic shifts from oxidative phosphorylation to glucose metabolism promote cardiomyocyte (CM) proliferation after heart injury. However, how glucose transportation in CMs is regulated during heart regeneration is still not fully understood. In this report, we found that the expression of Glut1 (slc2a1) was upregulated around the injury site of zebrafish heart, accompanied by an increase in glucose uptake at the injury area. Knockout of slc2a1a impaired zebrafish heart regeneration. Our previous study has demonstrated that the expression of Δ113p53 is activated after heart injury and Δ113p53+ CMs undergo proliferation to contribute to zebrafish heart regeneration. Next, we used the Δ113p53 promoter to generate the Tg(Δ113p53:cmyc) zebrafish transgenic line. Conditional overexpression of cmyc not only significantly promoted zebrafish CM proliferation and heart regeneration but also significantly enhanced glut1 expression at the injury site. Inhibiting Glut1 diminished the increase in CM proliferation in Tg(Δ113p53:cmyc) injured hearts of zebrafish. Therefore, our results suggest that the activation of cmyc promotes heart regeneration through upregulating the expression of glut1 to speed up glucose transportation.

Phototherapy has been intensively investigated as a non-invasive cancer treatment option. However, its clinical translation is still impeded by unsatisfactory therapeutic efficacy and severe phototoxicity. To achieve high therapeutic efficiency and high security, a nanoassembly of Forster Resonance Energy Transfer (FRET) photosensitizer pairs is developed on basis of dual-mode photosensitizer co-loading and photocaging strategy. For proof-of-concept, an erythrocyte-camouflaged FRET pair co-assembly of chlorine e6 (Ce6, FRET donor) and 1,1′-dioctadecyl-3,3,3′,3′-tetramethylindotricarbocyanine iodide (DiR, FRET acceptor) is investigated for breast cancer treatment. Notably, Ce6 in the nanoassemby is quenched by DiR and could be unlocked for photodynamic therapy (PDT) only when DiR is photobleached by 808-nm laser. As a result, Ce6-caused phototoxicity could be well controlled. Under cascaded laser irradiation (808–660 nm), tumor-localizing temperature rise following laser irradiation on DiR not only induces tumor cell apoptosis but also facilitates the tumor penetration of NPs, relieves tumor hypoxia, and promotes the PDT efficacy of Ce6. Such FRET pair-based nanoassembly provides a new strategy for developing multimodal phototherapy nanomedicines with high efficiency and good security.

There is an unmet clinical need to develop therapies to alleviate metastatic bone pain, frequently observed in patients with advanced cancers. Here, using mouse models of bone cancer pain, the authors show that STING agonists not only suppress bone cancer tumor burden, but also attenuate bone pain and reduce cancer-induced bone destruction.

Objective: Patients with cancer pain are highly dependent on morphine analgesia, but studies have shown a negative correlation between morphine demand and patient outcomes. The long-term use of morphine may result in abnormally elevated serum morphine-3-glucuronide (M3G) levels. Hence, the effects of M3G on tumor progression are worth studying. Methods: The effects of M3G on PD-L1 expressions in human non-small cell lung cancer (NSCLC) cell lines were first evaluated. Activation of TLR4 downstream pathways after M3G treatment was then determined by Western blot. The effects of M3G on human cytotoxic T lymphocytes (CTL) cytotoxicity and INF-γ release was also detected. Finally, the LLC murine lung adenocarcinoma cell line were used to establish a murine lung cancer model, and the effects of M3G on tumor growth and metastasis were determined. Results: M3G promoted the expressions of PD-L1 in the A549 and H1299 cell lines in a TLR4-dependent manner (P < 0.05). M3G activated the PI3K and the NFκB signaling pathways, and this effect was antagonized by a TLR4 pathway inhibitor. A PI3K pathway inhibitor reversed the M3G-mediated PD-L1 upregulation. M3G inhibited the cytotoxicity of CTL on A549 cells and decreased the level of INF-γ. Repeated M3G intraperitoneal injections promoted LLC tumor growth and lung metastasis through the upregulation of tumor expressed PD-L1 and the reduction of CTL in the tumor microenvironment. Conclusions: M3G specifically activated TLR4 in NSCLC cells and upregulated PD-L1 expression through the PI3K signaling pathway, thereby inhibiting CTL cytotoxicity and finally promoting tumor immune escape.

Histone phosphorylation is a ubiquitous post-translational modification. Here the authors present a programmable chromatin kinase, dCas9-dMSK1, that enables controlled histone phosphorylation and specific gene activation.

One of the major barriers in utilizing prodrug nanocarriers for cancer therapy is the slow release of parent drug in tumors. Tumor cells generally display the higher oxidative level than normal cells, and also displayed the heterogeneity in terms of redox homeostasis level. We previously found that the disulfide bond-linkage demonstrates surprising oxidation-sensitivity to form the hydrophilic sulfoxide and sulphone groups. Herein, we develop oxidation-strengthened prodrug nanosystem loaded with pyropheophorbide a (PPa) to achieve light-activatable cascade drug release and enhance therapeutic efficacy. The disulfide bond-driven prodrug nanosystems not only respond to the redox-heterogeneity in tumor, but also respond to the exogenous oxidant (singlet oxygen) elicited by photosensitizers. Once the prodrug nanoparticles (NPs) are activated under irradiation, they would undergo an oxidative self-strengthened process, resulting in a facilitated drug cascade release. The IC50 value of the PPa@PTX-S-S NPs without irradiation was 2-fold higher than those of NPs plus irradiation. In vivo, the PPa@PTX prodrug NPs display prolonged systemic circulation and increased accumulation in tumor site. The PPa@PTX-S-S NPs showed much higher efficiency than free PTX or the PPa@PTX-C-C NPs to suppress the growth of 4T1 tumors. Therefore, this novel oxidation-strengthened disulfide-bridged prodrug-nanosystem has a great potential in the enhanced efficacy of cancer synergetic photochemotherapy.

The dynamic evolution of particle size distributions (PSDs) during coagulation is of great importance in many atmospheric and engineering applications. To date, various numerical methods have been developed for solving the general dynamic equation under different scenarios. In this study, a radial basis function (RBF) method was proposed to solve particle coagulation evolution. This method uses a Gaussian function as the basis function to approximate the size distribution function. The original governing equation was then converted to ordinary differential equations (ODEs), along with numerical quadratures. The RBF method was compared with the analytical solutions and sectional method to validate its accuracy. The comparison results showed that the RBF method provided almost accurate predictions of the PSDs for different coagulation kernels. This method was also verified to be reliable in predicting the self-preserving distributions reached over long periods and for describing the temporal evolution of moments. For multimodal coagulation, the RBF method also accurately predicted the temporal evolution of a bimodal distribution owing to scavenging effects. Moreover, the computational times of the RBF method for these cases were usually of the order of seconds. Thus, the RBF method is verified as a reliable and efficient tool for predicting PSD evolution during coagulation.

Real-time monitoring devices are popularly utilized in modern power grids. To ensure long-term operations of the monitoring systems under complex outdoor conditions, a reliable and stable power supply is essential. In this paper, a general analysis of domino wireless power transfer (WPT) systems with load-independent outputs is proposed to realize a constant power supply for the monitoring equipment. In addition, the methodology of analyzing the self-oscillating points of the proposed domino WPT systems is deduced. The availability and feasibility of the proposed analysis and control method are verified by both simulation and experiment results based on a four-coil WPT system.

Summary: The immune checkpoint inhibitor programmed cell death protein 1 (PD-1) plays a critical role in immune regulation. Recent studies have demonstrated functional PD-1 expression in peripheral sensory neurons, which contributes to neuronal excitability, pain, and opioid analgesia. Here we report neuronal expression and function of PD-1 in the central nervous system (CNS), including the spinal cord, thalamus, and cerebral cortex. Notably, GABA-induced currents in spinal dorsal horn neurons, thalamic neurons, and cortical neurons are suppressed by the PD-1-neutralizing immunotherapeutic Nivolumab in spinal cord slices, brain slices, and dissociated cortical neurons. Reductions in GABA-mediated currents in CNS neurons were also observed in Pd1−/− mice without changes in GABA receptor expression. Mechanistically, Nivolumab binds spinal cord neurons and elicits ERK phosphorylation to suppress GABA currents. Finally, both GABA-mediated analgesia and anesthesia are impaired by Pd1 deficiency. Our findings reveal PD-1 as a CNS-neuronal inhibitor that regulates GABAergic signaling and GABA-mediated behaviors.

Abstract Background SUV39H2 (suppressor of variegation 3-9 homolog 2), which introduces H3K9me3 to induce transcriptional repression, has been reported to play critical roles in heterochromatin maintenance, DNA repair, and recently, carcinogenesis. Dysregulation of SUV39H2 expression has been observed in several types of cancers. However, neither the genomic landscape nor the clinical significance of SUV39H2 in lung adenocarcinoma has been probed comprehensively. Methods In this research, we conducted bioinformatics analysis to primarily sort out potential genes with dysregulated expressions. After we identified SUV39H2, RNA-seq was performed for a high-throughput evaluation of altered gene expression and dysregulated pathways, followed by a series of validations via RT-qPCR and bioinformatics analyses. Finally, to assess the potential oncogenic role of SUV39H2, we employed the invasion assay and clone formation assay in vitro and tumorigenesis assays in mouse models in vivo. Results Through bioinformatics analyses, we found that SUV39H2 underwent a severe upregulation in the tumor tissue, which was also confirmed in the surgically removed tissues. Overexpression of SUV39H2 was mainly associated with its amplification and with shorter patient overall survival. Then, the RNA-seq demonstrated that TPM4, STOM, and OPTN might be affected by the loss of function of SUV39H2. Finally, in vitro and in vivo experiments with SUV39H2 knockdown all suggested a potential role of SUV39H2 in both carcinogenesis and metastasis. Conclusions SUV39H2 expression was elevated in lung adenocarcinoma. TPM4, OPTN, and STOM were potentially regulated by SUV39H2. SUV39H2 might be a potential oncogene in lung adenocarcinoma, mediating tumorigenesis and metastasis.

Endotoxin detection is an important step in drug characterization. Herein we found that a chemotherapeutic drug nanoformulation composed of irinotecan hydrochloride (CPT-11) and an amphiphilic molecule DSPE-mPEG2000 can interfere with the limulus amebocyte lysate assay (LAL). Furthermore, the rabbit pyrogen test (RPT) results indicated that at a relatively high dosage, the drug irinotecan hydrochloride can induce a hypothermia effect which may render the RPT results ambiguous in determination of the safety of the drug formulation.Our findings demonstrate limitations of endotoxin detection in micellar drugs, and call for the necessity of developing reliable endotoxin detection methods that can overcome the interference of nanomaterials in order to better ensure the drug safety of patients in future pharmaceutical drug development. Keywords: Irinotecan hydrochloride, Endotoxin detection, Micelle, DSPE-mPEG2000, Limulus amebocyte lysate assay, Rabbit pyrogen test

Classic opioid receptors, mu (μ), delta (δ), and kappa (κ), have been reported to be expressed in non-small cell lung cancer (NSCLC) cell lines and tumor tissues and to play a role in tumor prognosis. However, the expression and role of the non-classic opioid receptor, nociceptin receptor (NOP) in cancer are unclear. Our hypothesis was that NOP was also highly expressed in NSCLC tumor tissues and this could be correlated with patients' prognostic characters. Expression of NOP was examined in archived cancer tissues from 129 enrolled NSCLC patients by immunohistochemistry and was further analyzed with the patients' outcomes. NOP expression in NSCLC cell lines was also detected. The dataset from Kaplan-Meier Plotter was used to explore the correlation between the levels of NOP mRNA in cancerous tissue and the prognosis of NSCLC patients. Cell functional assays were performed to detect the effect of NOP activation on tumor aggressive furthers. Results showed NOP expression was highly expressed in cancer tissues and human cancer cell lines. NOP expression was not associated with patients' opioid requirement but closely with some clinicopathological indicators which reflected the malignancy. Moreover, NOP staining level was the independent poor prognostic factor for NSCLC patients receiving lobectomy, which was further verified by determining the mRNA expression levels through the online dataset. In vitro experiments revealed that NOP activation promotes the proliferation and invasion of A549 cells via PI3K/Akt signaling pathway. We conclude that NOP is overexpressed in NSCLC and is inversely correlated with patient's postoperative survival.

Objective: Recent studies have suggested that metformin can penetrate the blood–brain barrier, protecting neurons via anti-inflammatory action and improvement of brain energy metabolism. In this study, we aim to investigate the effect of metformin on cognitive function in patients with abnormal glucose metabolism and non-dementia vascular cognitive impairment (NDVCI).Methods: One hundred patients with NDVCI and abnormal glucose metabolism were randomly allocated into two groups: metformin and donepezil (n = 50) or acarbose and donepezil (n = 50). The neuropsychological status, glucose metabolism, and common carotid arteries intima–media thickness (CCA-IMT) before and after a year of treatment, were measured and compared between the groups.Results: Ninety four patients completed all the assessment and follow-up. After a year of treatment, there was a decrease in Alzheimer’s disease Assessment Scale-Cognitive Subscale scores and the duration of the Trail Making Test in the metformin-donepezil group. Furthermore, these patients showed a significant increase in World Health Organization–University of California–Los Angeles Auditory Verbal Learning Test scores after treatment (all P < 0.05). However, there was no obvious improvement in cognitive function in the acarbose-donepezil group. We also observed a significant decrease in the level of fasting insulin and insulin resistance (IR) index in the metformin-donepezil group, with a lower CCA-IMT value than that in the acarbose-donepezil group after a year of treatment (P < 0.05).Conclusion: We conclude that metformin can improve cognitive function in patients with NDVCI and abnormal glucose metabolism, especially in terms of performance function. Improved cognitive function may be related to improvement of IR and the attenuated progression of IMT.Trial Registration:ChiCTR-IPR-17011855.

Myeloid-derived suppressor cells (MDSCs) are a heterogeneous group of myeloid cells that suppress T-cell activity in a tumor microenvironment. However, the suppressive function of MDSCs on B cells and its underlying mechanism remain unclear. Here, we show that in 4T1 breast cancer mice, a significantly increased number of MDSCs, in parallel with splenic B cells, are accumulated when compared to normal mice. In the presence of MDSCs, the surface molecules of B cells are remolded, with checkpoint-related molecules such as PD-1 and PD-L1 changing prominently. MDSCs also emerge as vital regulators in B-cell immune functions such as proliferation, apoptosis and the abilities to secrete antibodies and cytokines. Our study further identifies that MDSCs can transform normal B cells to a subtype of immuno- regulatory B cells (Bregs) which inhibit T-cell response. Furthermore, we identified a novel kind of Bregs with a specific phenotype PD-1−PD-L1+CD19+, which exert the greatest suppressive effects on T cells in comparison with the previously reported Bregs characterized as CD1d+CD5+CD19+, CD5+CD19+ and Interleukin (IL)-10-secreting B cells. Our results highlight that MDSCs regulate B-cell response and may serve as a therapeutic approach in anti-tumor treatment. Investigation of this new Breg subtype extends our understanding of regulation of T-cell response and sheds new light on anti-tumor immunity and immune therapy.

Currently, the effect of inflammation on tumorigenesis and progression has been widely noted. As a member of pattern recognition receptors, toll-like receptor 4 (TLR4) plays a pivotal role in tumor immune microenvironment and has been increasingly investigated. In the present study, we evaluated TLR4 expression and its association with programmed cell death ligand 1 (PD-L1) in non-small cell lung cancer (NSCLC) tissues and assessed the predicting value of TLR4 on postoperative outcome. A total of 126 NSCLC patients receiving complete pulmonary resection and systematic lymph node dissection between April 2008 and August 2014 were enrolled. All the patients had integrated clinicopathological records and follow-up data. TLR4 and PD-L1 expression on NSCLC samples were determined by immunohistochemistry, and serum soluble TLR4 (sTLR4) levels were measured by enzyme-linked immunosorbent assay. Results showed that TLR4 expression level in cancer tissue was significantly higher than that in para-cancer tissue. Elevated TLR4 expression was significantly associated with histological type (adenocarcinoma higher than squamous cell carcinoma, P = 0.041), increased clinical TNM stage (P