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The combination of permanent magnets and electrically excited windings creates an air gap magnetic field. The development of a hybrid magnetic circuit motor with an adjustable magnetic field is of great significance. This article introduces a hybrid magnetic circuit motor design that combines salient pole electromagnetic and permanent magnets. A tubular magnetic barrier has been designed to reduce inter-pole leakage and enhance the usage rate of permanent magnets in the hybrid magnetic circuit motor. The optimum eccentricity of the rotor has been accurately designed, resulting in an improved sinusoidal distribution of the air gap magnetic density waveform. An analysis of the static composite magnetic field under various excitation currents has been conducted, showcasing the capability of the hybrid magnetic circuit motor to stably adjust the air gap flux density level and output torque. A prototype has undergone comprehensive trial production and testing, conclusively confirming the machine’s superior output performance.

The armature reaction of the hybrid excitation starter generator (HESG) under load conditions will affect the distribution of the main magnetic field and the output performance. However, using the conventional field-circuit combination method to study the armature reaction has the problem of low accuracy and inaccurate influencing factors. Therefore, this paper proposed a graphical method to analyze the armature reaction and a new type of HESG with a combined-pole permanent magnet (PM) rotor and claw-pole electromagnetic rotor. The analytical formula of the voltage regulation rate under the armature reaction was derived using the graphical method. The main influencing parameters of the armature reaction magnetic field (ARMF) were analyzed, and the overall output performance was analyzed using finite element software. On this basis, comparison analyses before and after optimization and the prototype test were carried out. The results show that the direct-axis armature reaction reactance, quadrature-axis armature reaction reactance, and voltage regulation rate of the optimized HESG were significantly reduced, the output voltage range of the whole machine was wide, and the voltage regulation performance was good.

To solve the problems of the low power density of pure electric excitation generator and nonadjustable magnetic field of pure permanent magnet (PM) generator, a salient-pole hybrid excitation generator (HEG) was proposed in this paper. The designed generator realized coexcitation of two magnetic fields by changing the shape of the pole shoes and embedding the combined-pole PM steels. Compared with other HEGs, it had the advantages of high power density, less excitation loss, and small volume. The paper deduced the analytical expressions of the main magnetic field and armature reaction magnetic field of the HEG and analyzed the armature reaction magnetic circuit, the main influencing parameters, and the influence law of each parameter on the generator output performance to complete the parameter matching of the whole machine. The prototype was trial manufactured and tested with the optimized parameters. The results show that the designed HEG has a low voltage regulation rate, good no-load characteristics, and regulation characteristics. It can ensure the regulated output voltage under rated load conditions and meet the application requirement.

In this paper, a new hybrid excitation drive motor (HEDM) was proposed to solve the problem of an uncontrollable magnetic field of a permanent magnet motor. The rotor part of the motor was composed of a combined magnetic pole permanent magnet rotor and a brushless electric claw rotor, in which the combined magnetic pole permanent magnet rotor has a parallel magnetic circuit structure. According to the characteristics of the parallel rotor structure, the equivalent magnetic circuit model was established, and the no-load leakage flux coefficient of the claw pole rotor was calculated. The Taguchi method was used for objective optimization of the permanent magnet rotor structure. The distortion rate of no-load back electromotive force (EMF) was taken as the first optimization goal; the cogging torque and the average torque were taken as the second optimization goal; and the torque fluctuation coefficient was a constraint condition. The optimal parameter matching under the mixed horizontal matrix was obtained. The parameters of the claw pole were optimized by using the method of uniform variables, and the dimension parameters of the motor were obtained. Finite element analysis and prototype tests were carried out for the optimized motor structure. The rationality and feasibility of the new HEDM as a vehicle motor were verified, which provided a possibility for the application of the new energy vehicle drive motor field.

Aiming at the current problems of low excitation efficiency and poor reliability of single-rotor hybrid excitation generators, the large axial length of dual-rotor structure, and difficulty in magnetic field analysis, a new type of the dual-rotor hybrid excitation generator topology with high power density is proposed, with two rotors side-by-side coaxial, sharing a set of armature windings, and the magnetic fields do not interfere with each other, so the magnetic field analysis and optimization of the two rotors can be carried out separately. The magnetic density distribution of the new permanent magnet (PM) claw pole rotor is analyzed by the joint application of the equivalent magnetic circuit method and the equivalent magnetic network method, which ensures the simplicity of calculation and improves the calculation accuracy. The multi-objective optimization of the key structural parameters is carried out based on the Latin hypercube sampling–Pareto frontier solution method. The subdomain method is improved by segmented equivalence, the unique solution of the salient-pole rotor magnetic field is obtained, and the multi-objective optimization of the salient-pole rotor is used by the particle swarm algorithm. The trial prototype was experimental, and the results showed that the output characteristics of the optimized hybrid excitation generator were significantly improved, and the overall performance of the generator was improved.

The motor is an important component that affects the output performance of new energy vehicles (using new energy sources such as electric energy and hydrogen fuel energy to drive the motor and provide kinetic energy). Motors with high power and low noise can effectively improve the dynamic performance, passability and smoothness of new energy vehicles and bring a comfortable experience to driver and passengers. The magnetic field analytical model of the inner-mounted permanent magnet synchronous motor (IPMSM) is studied to improve its output quality. The motor is divided into four subdomains: the stator slot subdomain, the stator slot notch subdomain, the air-gap subdomain, and the permanent magnet (PM) subdomain. The general solution of the vector magnetic potential of each subdomain is solved, and the expression of magnetic flux density of each subdomain is derived. Meanwhile, the analytical model of the non-uniform air gap is established according to the uniform air-gap model. The model’s accuracy is verified by finite element analysis and prototype tests. The results show that the calculation results of the analytical model are effective. The model can be applied to predict the no-load back electromotive force (EMF) and cogging torque of the motor under different main air gaps. It also provides an effective and fast analysis method for the design and optimization of IPMSM for new energy vehicles.

Datong Basin is a Cenozoic fault basin located in the central part of the North China Block with strong tectonic activity. The unique geological environment of Datong Basin is believed to have good conditions for the formation of geothermal resources. Based on the research of the classification, genesis and geothermal geological characteristics of geothermal resources, the geological conditions, seismic activity, volcanic activity, geophysical exploration results, terrestrial heat flow and hot springs in Datong Basin are analyzed. The possibility of the occurrence of geothermal resources in Datong Basin is determined, and the genesis and occurrence mechanisms of geothermal resources in Datong Basin are judged. The results show that Datong Basin satisfies the geological geothermal conditions of the formation of geothermal resources and is of great research value. The formation of geothermal resources in the Datong Basin is affected by the uplift of the Qinghai–Tibet Plateau and the destruction of the North China Craton. The geothermal resources in Datong Basin are formed by the combination of modern volcanic activity and strong inner-plate tectonic activities. The geothermal system is a combination of convective hydrothermal systems and partial melt systems. At the same time, it is concluded that the key research areas for the occurrence of geothermal resources are mainly in the northeastern part of the basin. It is recommended to carry out detailed and comprehensive exploration of the northeastern part of Datong Basin.

The Regional Comprehensive Economic Partnership (RCEP) agreement is an important free trade agreement in the Asia Pacific region. The implementation of RCEP is greatly significant for ensuring the effective supply of agricultural products to member states. On the basis of the analysis of the agricultural product trade structure among China, Australia and New Zealand since 2000, we summarise in this article the potential consequences of tariff reduction for the agricultural products among the three countries under the RCEP framework. The Global Trade Analysis Project model has been used to analyse the effects of RCEP on the macroeconomic indicators, agricultural products trade and domestic agricultural output of the three countries. The research findings indicate that agricultural product trade among the three countries has grown rapidly since 2000. The results of the Global Trade Analysis Project simulations revealed that implementing RCEP will foster macroeconomic growth in the three countries. China's imports of beef and dairy products and wheat from Australia and New Zealand will substantially increase, and China's domestic production of this agricultural sector will decrease. Furthermore, India's potential participation in RCEP will further affect China's imports and exports of grain. These findings could guide the policymakers in the three countries in designing future agricultural production and trade strategies according to the different scenarios of international trade among the three countries and considering the potential of India joining.

Permeability of coal seams is an important indicator for assessing the difficulty of gas seepage and extraction, and its accurate determination holds significant significance. In light of the existing issues with long testing cycles, unstable results, and imperfect models, this research focuses on developing a rapid and accurate method for determining coal seam permeability and the corresponding computational model. Based on the radial unsteady-state gas flow control equation within coal seams and the volume flow equation for gas under different pressure differentials within the coal seam, we have established an injection pressure drop calculation model that utilizes the entire pressure drop dataset for measuring coal seam permeability. The COMSOL numerical simulation software, equipped with the Darcy flow module, is employed to solve the model. To address variables affecting the pressure drop curve in field engineering design, a univariate analysis of the length of the pressure measuring gas chamber is conducted. According to simulation results, the gas chamber length for pressure measurement in boreholes can be designed as 2.0 meters. Field arrangements are made based on the numerical simulation results, and an underground repeated gas injection pressure drop test system is established. This system, in conjunction with coal seam gas occurrence conditions and tunnel conditions, facilitates the drilling of two cross-seam boreholes for each of the two test points. These boreholes are injected with compensatory gas twice, each time exceeding the coal seam gas pressure, to conduct in-situ permeability tests. The testing periods are approximately 6 days and 17 days for the first and second rounds, respectively, with the second round having higher injection pressures. Combined with theoretical derivation, it was verified that the Reynolds numbers of coal seam gas remained within the linear Darcy flow regime during the gas injection pressure drop process, and gas flow within the coal seam adheres to Darcy's law, thus satisfying the assumptions of the calculation model. When compared to traditional methods for calculating coal seam permeability, the results indicate that this method aligns closely with the radial flow rate method, effectively meeting the requirements of practical engineering applications. The testing results of the repeated gas injection pressure drop method are stable and reliable, offering the advantage of rapid determination.

The spatial mapping and prediction of groundwater quality (GWQ) is important for sustainable groundwater management, but several research gaps remain unexplored, including the inaccuracy of spatial interpolation, limited consideration of the geological environment and human activity effects, limitation to specific pollutants, and unsystematic indicator selection. This study utilized the entropy-weighted water quality index (EWQI), the LightGBM model, the pressure-state-response (PSR) framework and SHapley Additive exPlanations (SHAP) analysis to address the above research gaps. The normalized importance (NI) shows that NO3− (0.208), Mg2+ (0.143), SO42− (0.110), Cr6+ (0.109) and Na+ (0.095) should be prioritized as parameters for remediation, and the skewness EWQI distribution indicates that although most sampled locations have acceptable GWQ, a few areas suffer from severely poor GWQ. The PSR framework identifies 13 indicators from geological environments and human activities for the SMP of GWQ. Despite high AUROCs (0.9074, 0.8981, 0.8885, 0.9043) across four random training and testing sets, it was surprising that significant spatial uncertainty was observed, with Pearson correlation coefficients (PCCs) from 0.5365 to 0.8066. We addressed this issue by using the spatial-grid average probabilities of four maps. Additionally, population and nighttime light are key indicators, while net recharge, land use and cover (LULC), and the degree of urbanization have the lowest importance. SHAP analysis highlights both positive and negative impacts of human activities on GWQ, identifying point-source pollution as the main cause of the poor GWQ in the study area. Due to the limited research on this field, future studies should focus on six key aspects: multi-method GWQ assessment, quantitative relationships between indicators and GWQ, comparisons of various spatial mapping and prediction models, the application of the PSR framework for indicator selection, the development of methods to reduce spatial uncertainty, and the use of explainable machine learning techniques in groundwater management.

pH sensation is critical for survival of vertebrates. Here, authors found six vertebrate OTOP1 channels that were highly conserved and directly activated by extracellular alkali. Key mutations of OTOP1 reduced alkali affinity without affecting acid activation.

Taking advantage of carbonaceous composite materials in electrocatalysis or photocatalysis is a promising pathway for transforming biomass resources into sustainable energy‐conversion systems. Herein, a carbonaceous composite catalyst based on the monodispersed silver vanadate nanoparticles (Ag3VO4 NPs) modification of biomass‐derived porous carbon (named as AVO/PC) is proposed for ultrasensitive and electrochemical rapid detection of p‐nitrophenol (p‐NP) under acidic condition. The radish‐derived three‐dimensional porous carbonaceous aerogels as supporter subtly introduced in the carbonization process of alkaline activation remarkably promote the physicochemical properties of the biomass‐derived porous carbon (PC), which can provide a favorable internal surface to load Ag3VO4 NPs. Subsequently, this electrochemical behavior of AVO/PC‐modified glassy carbon electrode (AVO/PC/GCE) exhibits high sensitivity (4.95 mA mM−1 cm−2) and a varied linear detection range (1 μmol L−1 ≈ 1 mmol L−1), as well as reproducibility and stability for p‐NP. Besides, the as‐prepared AVO/PC demonstrates the enhanced photocatalytic degradation performance of rhodamine B (RhB), and the photocatalytic rate reaches to 94% in visible light irradiation. The findings should be useful for designing and constructing dual‐purpose carbonaceous composite materials with potential applications in environmental monitoring and contaminant treatment.

This study demonstrates that the curvature of the cell membrane directly regulates the spatial distribution of Piezo1, a widely expressed mechanosensitive ion channel. Piezo1 may flatten upon activation and can mechanically inhibit membrane dynamics

Safe, efficacious, and deployable vaccines are urgently needed to control COVID-19 in the large-scale vaccination campaigns. We report here the preclinical studies of an approved protein subunit vaccine against COVID-19, ZF2001, which contains tandem-repeat dimeric receptor-binding domain (RBD) protein with alum-based adjuvant. We assessed vaccine immunogenicity and efficacy in both mice and non-human primates (NHPs). ZF2001 induced high levels of RBD-binding and SARS-CoV-2 neutralizing antibody in both mice and non-human primates, and elicited balanced TH1/TH2 cellular responses in NHPs. Two doses of ZF2001 protected Ad-hACE2-transduced mice against SARS-CoV-2 infection, as detected by reduced viral RNA and relieved lung injuries. In NHPs, vaccination of either 25 μg or 50 μg ZF2001 prevented infection with SARS-CoV-2 in lung, trachea, and bronchi, with milder lung lesions. No evidence of disease enhancement was observed in both animal models. ZF2001 has been approved for emergency use in China, Uzbekistan, Indonesia, and Columbia. The high safety, immunogenicity, and protection efficacy in both mice and NHPs found in this preclinical study was consistent with the results in human clinical trials.

Curcumin possesses a wide spectrum of liver cancer inhibition effects, yet it has chemical instability and poor metabolic properties as a drug candidate. To alleviate these problems, a series of new mono-carbonyl curcumin derivatives G1–G7 were designed, synthesized, and evaluated by in vitro and in vivo studies. Compound G2 was found to be the most potent derivative (IC50 = 15.39 μM) compared to curcumin (IC50 = 40.56 μM) by anti-proliferation assay. Subsequently, molecular docking, wound healing, transwell, JC-1 staining, and Western blotting experiments were performed, and it was found that compound G2 could suppress cell migration and induce cell apoptosis by inhibiting the phosphorylation of AKT and affecting the expression of apoptosis-related proteins. Moreover, the HepG2 cell xenograft model and H&E staining results confirmed that compound G2 was more effective than curcumin in inhibiting tumor growth. Hence, G2 is a promising leading compound with the potential to be developed as a chemotherapy agent for hepatocellular carcinoma.

Antibiotics can be a double-edged sword. The application of broad-spectrum antibiotics leads to the suppression of microorganisms in the human body without selective targeting, including numerous non-pathogenic microorganisms within the gut. As a result, dysbiosis of the gut microbiota can occur. The gut microbiota is a vast and intricate ecosystem that has been connected with various illnesses. Significantly, the gut and liver function in a closely coupled anatomical and physiological relationship referred to as the “gut-liver axis”. Consequently, metabolites stemming from the gut microbiota migrate via the portal vein to the liver, thereby influencing gene expression and proper physiological activity within the liver. This study aimed to investigate the dysbiosis of gut microbiota ecology and the disruption of gene expression resulting from oral antibiotics and their subsequent recovery. In the experiment, mice were tube-fed neomycin (0.5 mg/mL) and ampicillin (1 mg/mL) for 21 days (ABX group) to conduct 16s rRNA sequencing. By simultaneously analyzing public datasets PRJDB6615, which utilized the same antibiotics, it was found that nearly 50% of the total microbiota abundance was attributed to the f__Lactobacillaceae family. Additionally, datasets GSE154465 and GSE159761, using the same antibiotics, were used to screen for differentially expressed genes pre-and post-antibiotic treatment. Quantitative real-time PCR was employed to evaluate gene expression levels before and after antibiotic treatment. It was discovered that oral antibiotics significantly disrupted gene expression in the gut and liver, likely due to the dysregulation of the gut microbiota ecology. Fecal microbiota transplantation (FMT) was found to be an effective method for restoring gut microbiota dysbiosis. To further enhance the restoration of gut microbiota and gene expression, an antioxidant, vitamin C, was added to the FMT process to counteract the oxidative effect of antibiotics on microorganisms. The results showed that FMTs with vitamin C were more effective in restoring gut microbiota and gene expression to the level of the fecal transplant donor.

In this work, flavonoids from the leaves of Chionanthus retusa were extracted using alcohol, and the extraction yield was optimized by single-factor and orthogonal experiments. Then, the extracted solution with flavonoids was purified via macroporous resin by elution with different concentrations of ethanol. The antioxidative activity of total flavonoid in purified extracted solution was evaluated by detecting its ability to scavenge DPPH free radicals. The results demonstrated that ethanol with a concentration of 60%, ultrasonic power of 140 W, liquid–solid ratio of 25:1 ml g−1, and water-bath temperature of 80°C were the optimal conditions for the extraction of total flavonoids from C. retusa leaf, achieving a yield of 121.28 mg g−1. After purification by macroporous resin using different concentrations of ethanol, the highest content of total flavonoids (88.51%) in the extracted solution can be obtained with the 50% ethanol eluant. The results of scavenging DPPH free radicals suggest that the purified flavonoids in the 50% ethanol eluant had the best antioxidant capacity over the flavonoids in other ethanol eluants. In addition, it is confirmed the antioxidant capacity of the extractives was associated with the content of total flavonoids and kinds of flavonoids. These results may provide a feasible pathway to make full use of total flavonoids from C. retusa leaf.

Animals have evolved sophisticated temperature-sensing systems and mechanisms to detect and respond to ambient temperature changes. As a relict species endemic to the Qinghai-Tibet Plateau, hot-spring snake (Thermophis baileyi) survived the dramatic changes in climate that occurred during plateau uplift and ice ages, providing an excellent opportunity to explore the evolution of temperature sensation in ectotherms. Based on distributional information and behavioral experiments, we found that T. baileyi prefer hot-spring habitats and respond more quickly to warmth than other two snakes, suggesting that T. baileyi may evolve an efficient thermal-sensing system. Using high-quality chromosome-level assembly and comparative genomic analysis, we identified cold acclimation genes experiencing convergent acceleration in high-altitude lineages. We also discovered significant evolutionary changes in thermosensation- and thermoregulation-related genes, including the transient receptor potential (TRP) channels. Among these genes, TRPA1 exhibited three species-specific amino acid replacements, which differed from those found in infrared imaging snakes, implying different temperature-sensing molecular strategies. Based on laser-heating experiments, the T. baileyi-specific mutations in TRPA1 resulted in an increase in heat-induced opening probability and thermal sensitivity of the ion channels under the same degree of temperature stimulation, which may help the organism respond to temperature changes more quickly. These results provide insight into the genetic mechanisms underpinning the evolution of temperature-sensing strategies in ectotherms as well as genetic evidence of temperature acclimation in this group.

Pain is the most common presenting physical symptom and a primary reason for seeking medical care, which chronically affects people's mental health and social life. CaV3.2 channel plays an essential role in the peripheral processing maintenance of pain states. This study was designed to identify novel drug candidates targeting the CaV3.2 channel. Whole-cell patch-clamp, cellular thermal shift assay, FlexStation, in vivo and in vitro CaV3.2 knock-down, site-directed mutagenesis, and double-mutant cycle analysis were employed to explore the pain-related receptors and ligand-receptor direct interaction. We found that toddaculin efficiently inhibits the CaV3.2 channel and significantly reduced the excitability of dorsal root ganglion neurons and pain behaviors. The Carbonyl group of coumarins directly interacts with the pore domain of CaV3.2 via van der Waals (VDW) force. Docking with binding pockets further led us to identify glycycoumarin, which exhibited more potent inhibition on the CaV3.2 channel and better analgesic activity than the parent compound. Toddaculin and its analog showed beneficial therapeutic effects in pain models. Toddaculin binding pocket on CaV3.2 might be a promising docking site for the design of drugs.

The skin secretion of tree frogs contains a vast array of bioactive chemicals for repelling predators, but their structural and functional diversity is not fully understood. Paxilline (PAX), a compound synthesized by Penicillium paxilli, has been known as a specific antagonist of large conductance Ca2+-activated K+ Channels (BKCa). Here, we report the presence of PAX in the secretions of tree frogs (Hyla japonica) and that this compound has a novel function of inhibiting the potassium channel subfamily K member 18 (KCNK18) channels of their predators. The PAX-induced KCNK18 inhibition is sufficient to evoke Ca2+ influx in charybdotoxin-insensitive DRG neurons of rats. By forming π-π stacking interactions, four phenylalanines located in the central pore of KCNK18 stabilize PAX to block the ion permeation. For PAX-mediated toxicity, our results from animal assays suggest that the inhibition of KCNK18 likely acts synergistically with that of BKCa to elicit tingling and buzzing sensations in predators or competitors. These results not only show the molecular mechanism of PAX-KCNK18 interaction, but also provide insights into the defensive effects of the enriched PAX.

Menthol in mints elicits a coolness sensation by selective activation of TRPM8 ion channel. Here authors dock menthol to TRPM8 and systematically validate their menthol binding models with thermodynamic mutant cycle analysis in functional tests, and shed light on TRPM8 activation by menthol at the atomic level.

Several dehydroabietylamine derivatives containing heterocyclic moieties such as thiophene and pyrazine ring were successfully synthesized. The antiproliferative activities of these thiophene-based Schiff-bases, thiophene amides, and pyrazine amides were investigated in vitro against Hela (cervix), MCF-7 (breast), A549 (lung), HepG2 (liver), and HUVEC (umbilical vein) cells by MTT assay. The toxicity of L1−L10 (IC50 = 5.92− >100 μM) was lower than L0 (1.27 μM) and DOX (4.40 μM) in every case. Compound L1 had higher anti-HepG2 (0.66 μM), anti-MCF-7 (5.33 μM), and anti-A549 (2.11 μM) and compound L3 had higher anti-HepG2 (1.63 μM) and anti-MCF-7 (2.65 μM) activities. Both of these compounds were recognized with high efficiency in apoptosis induction in HepG2 cells and intercalated binding modes with DNA. Moreover, with average IC50 values of 0.66 and 5.98 μM, L1 was nine times more effective at suppressing cultured HepG2 cells viability than normal cells (SI = 9). The relative tumor proliferation rate (T/C) was 38.6%, the tumor inhibition rate was up to 61.2%, which indicated that L1 had no significant toxicity but high anti-HepG2 activity in vivo. Thus, it may be a potential antiproliferation drug with nontoxic side effects.

Ball milling technology is the classical technology to isolate representative lignin in the cell wall of biomass for further investigation. In this work, different ball milling times were carried out on hardwood (poplar sawdust), softwood (larch sawdust), and gramineous material (bamboo residues) to understand the optimum condition to isolate the representative milled wood lignin (MWL) in these different biomass species. Results showed that prolonging ball milling time from 3 to 7 h obviously increased the isolation yields of MWL in bamboo residues (from 39.2% to 53.9%) and poplar sawdust (from 15.5% to 35.6%), while only a slight increase was found for the MWL yield of larch sawdust (from 23.4% to 25.8%). Importantly, the lignin substructure of ß-O-4 in the MWL samples from different biomasses can be a little degraded with the increasing ball milling time, resulting in the prepared MWL with lower molecular weight and higher content of hydroxyl groups. Based on the isolation yield and structure features, milling time with 3 and 7 h were sufficient to isolate the representative lignin (with yield over 30%) in the cell wall of bamboo residues and poplar sawdust, respectively, while more than 7 h should be carried out to isolate the representative lignin in larch sawdust.

Abstract Platinum‐based compounds in chemotherapy such as oxaliplatin often induce peripheral neuropathy and neuropathic pain such as cold allodynia in patients. Transient Receptor Potential Melastatin 8 (TRPM8) ion channel is a nociceptor critically involved in such pathological processes. Direct blockade of TRPM8 exhibits significant analgesic effects but also incurs severe side effects such as hypothermia. To selectively target TRPM8 channels against cold allodynia, a cyclic peptide DeC‐1.2 is de novo designed with the optimized hot‐spot centric approach. DeC‐1.2 modality specifically inhibited the ligand activation of TRPM8 but not the cold activation as measured in single‐channel patch clamp recordings. It is further demonstrated that DeC‐1.2 abolishes cold allodynia in oxaliplatin treated mice without altering body temperature, indicating DeC‐1.2 has the potential for further development as a novel analgesic against oxaliplatin‐induced neuropathic pain.

Abstract Transient receptor potential vanilloid 1 (TRPV1) ion channel is a nociceptor critically involved in pain sensation. Direct blockade of TRPV1 exhibits significant analgesic effects but also incurs severe side effects such as hyperthermia, causing failures of TRPV1 inhibitors in clinical trials. In order to selectively target TRPV1 channels that are actively involved in pain‐sensing, peptidic positive allosteric modulators (PAMs) based on the high‐resolution structure of the TRPV1 intracellular ankyrin‐repeat like domain are de novo designed. The hotspot centric approach is optimized for protein design; its usage in Rosetta increases the success rate in protein binder design. It is demonstrated experimentally, with a combination of fluorescence resonance energy transfer (FRET) imaging, surface plasmon resonance, and patch‐clamp recording, that the designed PAMs bind to TRPV1 with nanomolar affinity and allosterically enhance its response to ligand activation as it is designed. It is further demonstrated that the designed PAM exhibits long‐lasting in vivo analgesic effects in rats without changing their body temperature, suggesting that they have potentials for developing into novel analgesics.

Curcumin is a polyphenolic natural product that has promising anticancer properties. However, its clinical utility is limited by its chemical instability and poor metabolic properties. In this paper, a series of new curcumin analogs were synthesized and found to be potent antiproliferative agents against the HepG2 cell line by MTT assay. In general, Group B with single ketone and group C with chalcone were markedly more cytotoxic than group A with diketone. Compound B5 was found as the most potent analog (IC50 = 11.33 μM) compared to curcumin (IC50 = 32.83 μM) and the mechanism of its cytotoxicity was investigated. The result of the wound healing assay indicated B5 strong potential to suppress HepG2 cell migration in a dose- and time-dependent manner. Subsequent assays (including JC-1 staining, Bcl-2, and caspase 3 protein levels by Western blotting) confirmed that B5 exposure induced apoptosis in HepG2 cells. Curcumin-induced comprehensive transcriptomes profile, Western blotting, molecular docking, and molecular dynamics analysis showed that the mechanism may relate to the regulation of cellular metabolic process and the expression of AKT protein. Taken together, we could conclude that curcumin and its analogs induced HepG2 cell proliferation, migration, and apoptosis via AKT signaling pathway and the mitochondrial death pathway. This study could lay the foundation for optimizing curcumin and provide valuable information for finding novel anti-HCC drugs.

The heat-sensitive ion channel TRPV1 is essential to temperature sensing in mammals and other animals. Here the authors find that the platypus form of TRPV1 does not desensitize, identify the mechanism underlying this property, and show that knock-in of this form of the receptor in mice leads to deficits in heat sensitivity.

Rutin (R), a representative flavonoid found in various biomasses, can be used to prepare different fluorescent sensors for environmental, biological and medical fields. In this work, the natural R in Sophora japonica was extracted and purified to prepare fluorescent-responding sensor systems intended to recognize copper ions with both strong selectivity as well as appropriate sensitivity. Results showed that neat R had no obvious fluorescent emission peak in PBS buffer solution. However, when R and (2-hydroxypropyl)-β-cyclodextrin (CD) were introduced within buffer solution, fluorescent emission intensity was significantly increased due to the resultant R-CD inclusion complex. In addition, the formed R-CD inclusion complex was shown to behave as the aforementioned fluorescent sensor for copper ions through a mechanism of quenched fluorescent emission intensity when R-CD became bound with copper ions. The binding constant value for R-CD with copper ions was 1.33 × 106, allowing for quantification of copper ions between the concentration range of 1.0 × 10–7–4.2 × 10–6mol⋅L–1. Furthermore, the minimum detection limit was found to be 3.5 × 10–8mol⋅L–1. This work showed the prepared R-CD inclusion complex was both highly selective and strongly sensitive toward copper ions, indicating that this system could be applied into various fields where copper ions are of concern.

Taiyuan city has experienced serious land subsidence since the 1950s, with the maximum accumulated subsidence of 2,960 mm and a total affected area of 585 km2 by 2003. Tectonic settlement was found to contribute about 1% and the major cause is over-exploitation of groundwater. The spatial–temporal relationship between the areal distribution of land subsidence and that of groundwater drawdown from 1956 to 2000 indicates that although land subsidence centers overall match groundwater depression cones, there are local deviations, and that although the time series curves are similar, land subsidence always lags behind groundwater level decline, with different lag time at different sites. The major findings of this work on the control of stratigraphic heterogeneity on the spatial pattern of land subsidence at Taiyuan include: (1) land subsidence centers shift from the corresponding groundwater depression cones to the sides with thicker accumulated clay layers; (2) under the same pumping rate, land subsidence at places with more clay interlayers and thinner individual interlayers is greater and the lag time shorter; and (3) land subsidence is closely related to the physical properties of clay soils. The Interbed Storage Package-1, a modular subroutine of MODFLOW was employed to simulate the areal distribution of individual layer compression. The modeling results show that compression of different clay layers has different contribution to land subsidence. Pumping groundwater from water-bearing zones close to the most compressible clay layers should therefore be carefully controlled. [ABSTRACT FROM AUTHOR]

In Shanyin, Shanxi province, China, As concentration in shallow groundwater exceeds guide concentrations, set internationally and nationally at 10-50 µg/L, and may reach 1932.0 µg/L, which has resulted in severe clinical symptoms of arsenic toxicity. In this article, chemical characteristics of groundwaters containing anomalous As and mechanisms of arsenic release to shallow groundwaters were studied. Groundwaters containing anomalous As in the study area were characterized by higher pH, higher concentration of phosphate, higher concentration of naphthenic acid, and lower concentrations of sulfate and nitrate. Microbial metabolism of sedimentary organic matter, which is present as high as 1.0% organic C, results in the lower concentrations of sulfate and nitrate. The reactions decrease Eh and produce CO[sub 2], which promotes the dissolution of carbonates and increases pH. The clay minerals and colloids including organic matters scavenging arsenic would release arsenic to groundwater in higher pH and lower Eh environment. In addition, the competitive absorption between As and anions (such as phosphate and fluoride) contributes to the release of As from kaolinite, montmorillonite, illite, and Fe oxyhydroxides. Naphthenic acid also promotes mobilization and translocation of As in groundwater systems. [ABSTRACT FROM AUTHOR]

Venomous animals have evolved with sophisticated bio-chemical strategies to arrest prey and defend themselves from natural predators. In recent years, peptide toxins from venomous animals have drawn considerable attention from researchers due to their surprising chemical, biochemical, and pharmacological diversity. Similar to other venomous animals, centipedes are one of the crucial venomous arthropods that have been used in traditional medicine for hundreds of years in China. Despite signifying pharmacological importance, very little is known about the active components of centipede venoms. More than 500 peptide sequences have been reported in centipede venomous glands by transcriptome analysis, but only a small number of peptide toxins from centipede has been functionally described. Like other venomous animals such as snakes, scorpions, and spiders, the venom of centipedes could be an excellent source of peptides for developing drugs for treatments as well as bio-insecticides for agrochemical applications. Although centipede venoms are yet to be adequately studied, the venom of centipedes as well as their components described to date, should be compiled to help further research. Therefore, based on previous reports, this review focusses on findings and possible therapeutic applications of centipede venoms as well as their components.

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Spicy foods elicit a pungent or hot and painful sensation that repels almost all mammals. Here, we observe that the tree shrew (Tupaia belangeri chinensis), which possesses a close relationship with primates and can directly and actively consume spicy plants. Our genomic and functional analyses reveal that a single point mutation in the tree shrew's transient receptor potential vanilloid type-1 (TRPV1) ion channel (tsV1) lowers its sensitivity to capsaicinoids, which enables the unique feeding behavior of tree shrews with regards to pungent plants. We show that strong selection for this residue in tsV1 might be driven by Piper boehmeriaefolium, a spicy plant that geographically overlaps with the tree shrew and produces Cap2, a capsaicin analog, in abundance. We propose that the mutation in tsV1 is a part of evolutionary adaptation that enables the tree shrew to tolerate pungency, thus widening the range of its diet for better survival.

The intense pain induced by scorpion sting is a frequent clinical manifestation. To date, there is no established protocol with significant efficacy to alleviate the pain induced by scorpion envenomation. One of the important reasons is that, little information on pain-inducing compound from scorpion venoms is available. Here, a pain-inducing peptide (BmP01) has been identified and characterized from the venoms of scorpion (Mesobuthus martensii). In an animal model, intraplantar injection of BmP01 in mouse hind paw showed significant acute pain in wild type (WT) mice but not in TRPV1 knock-out (TRPV1 KO) mice during 30 min recording. BmP01 evoked currents in WT dorsal root ganglion (DRG) neurons but had no effect on DRG neurons of TRPV1 KO mice. Furthermore, OPEN ACCESS Toxins 2015, 7 3672 BmP01 evoked currents on TRPV1-expressed HEK293T cells, but not on HEK293T cells without TRPV1. These results suggest that (1) BmP01 is one of the pain-inducing agents in scorpion venoms; and (2) BmP01 induces pain by acting on TRPV1. To our knowledge, this is the first report about a scorpion toxin that produces pain by targeting TRPV1. Identification of a pain-inducing compound may facilitate treating pain induced by scorpion envenomation.

It was recently discovered that Ssm Spooky Toxin (SsTx) with 53 residues serves as a key killer factor in red-headed centipede’s venom arsenal, due to its potent blockage of the widely expressed KCNQ channels to simultaneously and efficiently disrupt cardiovascular, respiratory, muscular, and nervous systems, suggesting that SsTx is a basic compound for centipedes’ defense and predation. Here, we show that SsTx also inhibits KV1.3 channel, which would amplify the broad-spectrum disruptive effect of blocking KV7 channels. Interestingly, residue R12 in SsTx extends into the selectivity filter to block KV7.4, however, residue K11 in SsTx replaces this ploy when toxin binds on KV1.3. Both SsTx and its mutant SsTx_R12A inhibit cytokines production in T cells without affecting the level of KV1.3 expression. The results further suggest that SsTx is a key molecule for defense and predation in the centipedes’ venoms and it evolves efficient strategy to disturb multiple physiological targets.