Parameter optimization of vibration control system for adjacent building structures based on negative stiffness inerter damper.

Building structures are subjected to strong earthquakes, which result in lateral collisions between them. Such collisions often cause severe structural damage and exacerbate the seismic hazard risk of building structures during earthquake events. This paper discusses the application of vibration control devices based on negative stiffness inerter damper in single-story adjacent building structures. The dynamic equations of the vibration control system containing different types of negative stiffness inerter damper under seismic excitation are established as a unified model. The H2 norm theory and Monte Carlo pattern search method are used to optimize the design parameters to improve the vibration control performance of the system, and the dynamic characteristics of the system are investigated. The results demonstrate that attaching negative stiffness inerter damper to adjacent building structures can effectively improve the overall seismic capacity reserve of the building and reduce the risk of collision of adjacent building structures; improve the robustness and stability of the system, and better reduce the displacement response of the building structure under seismic excitation. In addition, the potential of NSID-based vibration control devices to convert seismic energy into usable electricity has been investigated.

Novel Isoalantolactone-Based Derivatives as Potent NLRP3 Inflammasome Inhibitors: Design, Synthesis, and Biological Characterization.

The NLRP3 inflammasome has been recognized as a promising therapeutic target in drug discovery for inflammatory diseases. Our initial research identified a natural sesquiterpene isoalantolactone (IAL) as the active scaffold targeting NLRP3 inflammasome. To improve its activity and metabolic stability, a total of 64 IAL derivatives were designed and synthesized. Among them, compound 49 emerged as the optimal lead, displaying the most potent inhibitory efficacy on nigericin-induced IL-1ß release in THP-1 cells, with an IC50 value of 0.29 µM, approximately 27-fold more potent than that of IAL (IC50: 7.86 µM), and exhibiting higher metabolic stability. Importantly, 49 remarkably improved DSS-induced ulcerative colitis in vivo. Mechanistically, we demonstrated that 49 covalently bound to cysteine 279 in the NACHT domain of NLRP3, thereby inhibiting the assembly and activation of NLRP3 inflammasome. These results provided compelling evidence to further advance the development of more potent NLRP3 inhibitors based on this scaffold.

NU6300 covalently reacts with cysteine-191 of gasdermin D to block its cleavage and palmitoylation.

Gasdermin D (GSDMD) serves as a vital mediator of inflammasome-driven pyroptosis. In our study, we have identified NU6300 as a specific GSDMD inhibitor that covalently interacts with cysteine-191 of GSDMD, effectively blocking its cleavage while not affecting earlier steps such as ASC oligomerization and caspase-1 processing in AIM2- and NLRC4-mediated inflammation. On the contrary, NU6300 robustly inhibits these earlier steps in NLRP3 inflammasome, confirming a unique feedback inhibition effect in the NLRP3-GSDMD pathway upon GSDMD targeting. Our study reveals a previously undefined mechanism of GSDMD inhibitors: NU6300 impairs the palmitoylation of both full-length and N-terminal GSDMD, impeding the membrane localization and oligomerization of N-terminal GSDMD. In vivo studies further demonstrate the efficacy of NU6300 in ameliorating dextran sodium sulfate-induced colitis and improving survival in lipopolysaccharide-induced sepsis. Overall, these findings highlight the potential of NU6300 as a promising lead compound for the treatment of inflammatory diseases.

Geochemical properties, heavy metals and soil microbial community during revegetation process in a production Pb-Zn tailings.

Lead-zinc (Pb-Zn) tailings pose a significant environmental threat from heavy metals (HMs) contamination. Revegetation is considered as a green path for HM remediation. However, the interplay between HM transport processes and soil microbial community in Pb-Zn tailings (especially those in production) remain unclear. This study investigated the spatial distribution of HMs as well as the crucial roles of the soil microbial community (i.e., structure, richness, and diversity) during a three-year revegetation of production Pb-Zn tailings in northern Guangdong province, China. Prolonged tailings stockpiling exacerbated Pb contamination, elevating concentrations (from 10.11 to 11.53 g/kg) in long-term weathering. However, revegetation effectively alleviated Pb, reducing its concentrations of 9.81 g/kg. Through 16 S rRNA gene amplicon sequencing, the dominant genera shifted from Weissella (44%) to Thiobacillus (17%) and then to Pseudomonas (comprising 44% of the sequences) during the revegetation process. The structural equation model suggested that Pseudomonas, with its potential to transform bioavailable Pb into a more stable form, emerged as a potential Pb remediator. This study provides essential evidence of HMs contamination and microbial community dynamics during Pb-Zn tailings revegetation, contributing to the development of sustainable microbial technologies for tailings management.

Exploring the Immunomodulatory Properties of Red Onion (Allium cepa L.) Skin: Isolation, Structural Elucidation, and Bioactivity Study of Novel Onion Chalcones Targeting the A2A Adenosine Receptor.

Onions are versatile and nutritious food widely used in various cuisines around the world. In our ongoing pursuit of bioactive substances with health benefits from red onion (Allium cepa L.) skin, a comprehensive chemical investigation was undertaken. Consequently, a total of 44 compounds, including three previously unidentified chalcones (1-3) were extracted from red onion skin. Of these isolates, chalcones 1-4 showed high affinity to A2A adenosine receptor (A2AAR), and chalcone 2 displayed the best binding affinity to A2AAR, with the IC50 value of 33.5 nM, good A2AAR selectivity against A1AR, A2BAR, and A3AR, and high potency in the cAMP functional assay (IC50 of 913.9 nM). Importantly, the IL-2 bioassay and the cell-mediated cytotoxicity assay demonstrated that chalcone 2 could boost T-cell activation. Furthermore, the binding mechanism of chalcone 2 with hA2AAR was elucidated by molecular docking. This work highlighted that the active chalcones in red onion might have the potential to be developed as A2AAR antagonists used in cancer immunotherapy.

High-speed information reconciliation with syndrome-based early termination for continuous-variable quantum key distribution.

Information reconciliation (IR) is an indispensable component in the post-processing stage of continuous-variable quantum key distribution (CV-QKD), which adopts error-correcting codes to address the asymmetry of secret keys. Currently, low-density parity-check (LDPC) decoding in IR is a post-processing bottleneck in high-speed CV-QKD systems since the upper bound on secret key rate is higher than the information throughput delivered by decoder. In this paper, we study the relationship between the syndrome variation pattern (SVP) in iterative decoding and reconciliation frame error rate. An early termination scheme based on SVP is proposed and applied to multidimensional reconciliation, which can increase information throughput by adaptively adjusting the iteration number of iterative decoding to real-time decoding status. Furthermore, we show that only the resulting syndrome of the highest-rate code part in Raptor-like LDPC codes needs to be calculated to verify whether the reconciliation is successful by studying the convergency of resulting syndrome, which can save a large fraction of computational resources for syndrome calculation. Simulation results show that information throughput of the proposed scheme can be improved by 617.1% compared to the existing scheme when the IR efficiency reaches 97.09%. The proposed scheme points out a new direction for breaking the post-processing bottleneck in high-speed CV-QKD systems.

Recent Progress and Prospects of Small Molecules for NLRP3 Inflammasome Inhibition.

NLRP3 inflammasome is a multiprotein complex involved in host immune response─which exerts various biological effects by mediating the maturation and secretion of IL-1ß and IL-18─and pyroptosis. However, its aberrant activation could cause amplification of inflammatory effects, thereby triggering a range of ailments, including Alzheimer's disease, Parkinson's disease, rheumatoid arthritis, gout, type 2 diabetes mellitus, and cancer. For the past few years, as an attractive anti-inflammatory target, NLRP3-targeting small-molecule inhibitors have been widely reported by both the academic and the industrial communities. In order to deeply understand the advancement of NLRP3 inflammasome inhibitors, we provide comprehensive insights and commentary on drugs currently under clinical investigation, as well as other NLRP3 inflammasome inhibitors from a chemical structure point of view, with an aim to provide new insights for the further development of clinical drugs for NLRP3 inflammasome-mediated diseases.

Discovery of Triazinone Derivatives as Novel, Specific, and Direct NLRP3 Inflammasome Inhibitors for the Treatment of DSS-Induced Ulcerative Colitis.

NLRP3 is an intracellular sensor protein that causes inflammasome formation and pyroptosis in response to a wide range of stimuli. Aberrant activation of NLRP3 inflammasome has been implicated in various chronic inflammatory diseases, making it a promising target for therapeutic intervention. In this work, a series of novel triazinone inhibitors of NLRP3 inflammasome were designed and synthesized. Compound L38 was identified for its excellent activity and acceptable metabolic stability among 41 compounds. Additionally, mechanism studies indicated that L38 inhibited NLRP3 inflammasome activation and pyroptosis by suppressing gasdermin D cleavage, ASC oligomerization, and NLRP3 inflammasome assembly while leaving mitochondrial ROS production, lysosome damage, and chloride/potassium efflux unaffected. Further investigation revealed that L38 could bind to the NACHT domain to exert inflammatory properties. Importantly, L38 exhibited positive therapeutic effects in DSS-induced ulcerative colitis mouse model. Taken together, this study presents a promising inhibitor of NLRP3 inflammasome deserving further investigation.

Design, Synthesis, and Biological Evaluation of Novel P2X7 Receptor Antagonists for the Treatment of Septic Acute Kidney Injury.

Sepsis-associated acute kidney injury (AKI) is a serious clinical problem, without effective drugs. Abnormal activation of the purinergic P2X7 receptor (P2X7R) in septic kidneys makes its antagonist a promising therapeutic approach. Herein, a series of novel P2X7R antagonists were designed, synthesized, and structurally optimized. Based on in vitro potency in human/mouse P2X7R using HEK293 cells, hepatic microsomal stability, and pharmacokinetic and preliminary in vivo assessments, compound 14a was identified by respective human and mouse P2X7R IC50 values of 64.7 and 10.1 nM, together with favorable pharmacokinetic properties. Importantly, 14a dose-dependently alleviated kidney dysfunction and pathological injury in both lipopolysaccharide (LPS)- and cecal ligation/perforation (CLP)-induced septic AKI mice with a good safety profile. Mechanistically, 14a could suppress NLRP3 inflammasome activation to inhibit the expression of cleaved caspase-1, gasdermin D, IL-1ß, and IL-18 in the injured kidneys of septic mice. Collectively, these results highlighted that P2X7R antagonist 14a exerted a therapeutic potential against septic AKI.

The day-night differences in cognitive and anxiety-like behaviors of mice after chronic sleep restriction.

Animal behavioral tests are often conducted during the day. However, rodents are nocturnal animals and are primarily active at night. The aim of this study was to determine whether there are diurnal changes in cognitive and anxiety-like performance of mice following chronic sleep restriction (SR). We also investigated whether this phenotypic difference is related to the diurnal variation of glymphatic clearance of metabolic wastes. Mice received 9-day SR by the use of the modified rotating rod method, followed by the open field, elevated plus maze, and Y-maze tests conducted during the day and at night, respectively. Brain ß-amyloid (Aß) and tau protein levels, the polarity of aquaporin4 (AQP4), a functional marker of the glymphatic system, and glymphatic transport ability were also analyzed. SR mice exhibited cognitive impairment and anxiety-like behaviors during the day, but not at night. AQP4 polarity and glymphatic transport ability were higher during the day, with lower Aß1-42 , Aß1-40 , and P-Tau levels in the frontal cortex. These day-night differences were totally disrupted after SR. These results reveal the diurnal changes in behavioral performance after chronic SR, which may be related to circadian control of AQP4-mediated glymphatic clearance of toxic macromolecules from the brain.

From lead to clinic: A review of the structural design of P2X7R antagonists.

P2X7R, which is a member of the purinergic P2 receptor family, is widely expressed in many immune cells, such as macrophages, lymphocytes, monocytes, and neutrophils. P2X7R is upregulated in response to proinflammatory stimulation, which is closely related to a variety of inflammatory diseases. The inhibition of P2X7 receptors has resulted in the elimination or reduction of symptoms in animal models of arthritis, depression, neuropathic pain, multiple sclerosis, and Alzheimer's disease. Therefore, the development of P2X7R antagonists is of great significance for the treatment of various inflammatory diseases. This review classifies the reported P2X7R antagonists according to their different cores, focuses on the structure-activity relationship (SAR) of the compounds, and analyzes some common substituents and strategies in the design of lead compounds, with the hope of providing valuable information for the development of new and efficient P2X7R antagonists.

Novel chemical-structure TPOR agonist, TMEA, promotes megakaryocytes differentiation and thrombopoiesis via mTOR and ERK signalings.

BACKGROUND: Non-peptide thrombopoietin receptor (TPOR) agonists are promising therapies for the mitigation and treatment of thrombocytopenia. However, only few agents are available as safe and effective for stimulating platelet production for thrombocytopenic patients in the clinic. PURPOSE: This study aimed to develop a novel small molecule TPOR agonist and investigate its underlying regulation of function in megakaryocytes (MKs) differentiation and thrombopoiesis. METHODS: A potential active compound that promotes MKs differentiation and thrombopoiesis was obtained by machine learning (ML). Meanwhile, the effect was verified in zebrafish model, HEL and Meg-01 cells. Next, the key regulatory target was identified by Drug Affinity Responsive Target Stabilization Assay (DARTS), Cellular Thermal Shift Assay (CETSA), and molecular simulation experiments. After that, RNA-sequencing (RNA-seq) was used to further confirm the associated pathways and evaluate the gene expression induced during MK differentiation. In vivo, irradiation (IR) mice, C57BL/6N-TPORem1cyagen (Tpor-/-) mice were constructed by CRISPR/Cas9 technology to examine the therapeutic effect of TMEA on thrombocytopenia. RESULTS: A natural chemical-structure small molecule TMEA was predicted to be a potential active compound based on ML. Obvious phenotypes of MKs differentiation were observed by TMEA induction in zebrafish model and TMEA could increase co-expression of CD41/CD42b, DNA content, and promote polyploidization and maturation of MKs in HEL and Meg-01 cells. Mechanically, TMEA could bind with TPOR protein and further regulate the PI3K/AKT/mTOR/P70S6K and MEK/ERK signal pathways. In vivo, TMEA evidently promoted platelet regeneration in mice with radiation-induced thrombocytopenia but had no effect on Tpor-/- and C57BL/6 (WT) mice. CONCLUSION: TMEA could serve as a novel TPOR agonist to promote MKs differentiation and thrombopoiesis via mTOR and ERK signaling and could potentially be created as a promising new drug to treat thrombocytopenia.

Identification of the target protein and molecular mechanism of honokiol in anti-inflammatory action.

BACKGROUND: Searching the targets of natural products is very important for drug discovery and elucidating the mechanism of drug action and disease. Honokiol (HK), as the major active component of Magnolia officinalis Rehder & E.H.Wilson, has been widely used in medicine and cosmetics. Among its bioactivities, its anti-inflammatory activity is particularly impressive. However, the target protein of HK in anti-inflammatory action and its regulatory mechanism are unclear. PURPOSE: Here, we identified the target protein and molecular mechanism of the anti- inflammatory action of HK. METHODS: First, an LPS-induced septic shock model and DSS-induced ulcerative colitis model were used to assess the anti-inflammatory efficacy of HK. Second, the drug affinity responsive target stability, proteomics analysis, thermal shift assays and cellular thermal shift assays were used to identify and validate the target of HK. Finally, western blot, ELISA, LDH immunofluorescence staining, shRNA and LC/MS for L-leucine analysis were performed to determine the mechanism of the anti-inflammatory action of HK. RESULTS: This study revealed that HK significantly alleviated LPS-induced septic shock and DSS-induced ulcerative colitis in vivo, suggesting that HK has significant anti-inflammatory activity. HK treatment dramatically reduced IL-1ß release and caspase-1 activation at different time points, showing that HK could inhibit both NLRP3 inflammasome priming and activation processes in cells. HK also suppressed adaptor apoptosis speck-like protein oligomerization. Mechanistically, SLC3A2 was identified as a direct target of HK in THP-1 cells. HK downregulated SLC3A2 expression by promoting its degradation via proteasome-mediated proteolysis. Further study demonstrated that HK triggered SLC3A2 to suppress NLRP3 inflammasome activation by significantly reducing the content of L-leucine transported into cells and lysosomes to block the mTORC1 pathway. CONCLUSIONS: Our work identified HK as a promising anti-inflammatory drug candidate through the SLC3A2/L-leucine/mTORC1/NLRP3 pathways.

Multi-dimensional variables and feature parameter selection for aboveground biomass estimation of potato based on UAV multispectral imagery.

Aboveground biomass (AGB) is an essential assessment of plant development and guiding agricultural production management in the field. Therefore, efficient and accurate access to crop AGB information can provide a timely and precise yield estimation, which is strong evidence for securing food supply and trade. In this study, the spectral, texture, geometric, and frequency-domain variables were extracted through multispectral imagery of drones, and each variable importance for different dimensional parameter combinations was computed by three feature parameter selection methods. The selected variables from the different combinations were used to perform potato AGB estimation. The results showed that compared with no feature parameter selection, the accuracy and robustness of the AGB prediction models were significantly improved after parameter selection. The random forest based on out-of-bag (RF-OOB) method was proved to be the most effective feature selection method, and in combination with RF regression, the coefficient of determination (R2) of the AGB validation model could reach 0.90, with root mean square error (RMSE), mean absolute error (MAE), and normalized RMSE (nRMSE) of 71.68 g/m2, 51.27 g/m2, and 11.56%, respectively. Meanwhile, the regression models of the RF-OOB method provided a good solution to the problem that high AGB values were underestimated with the variables of four dimensions. Moreover, the precision of AGB estimates was improved as the dimensionality of parameters increased. This present work can contribute to a rapid, efficient, and non-destructive means of obtaining AGB information for crops as well as provide technical support for high-throughput plant phenotypes screening.

Multispectral remote sensing for accurate acquisition of rice phenotypes: Impacts of radiometric calibration and unmanned aerial vehicle flying altitudes.

As a promising method, unmanned aerial vehicle (UAV) multispectral remote sensing (RS) has been extensively studied in precision agriculture. However, there are numerous problems to be solved in the data acquisition and processing, which limit its application. In this study, the Micro-MCA12 camera was used to obtain images at different altitudes. The piecewise empirical line (PEL) method suitable for predicting the reflectance of different ground objects was proposed to accurately acquire the reflectance of multi-altitude images by comparing the performance of the conventional methods. Several commonly utilized vegetation indices (VIs) were computed to estimate the rice growth parameters and yield. Then the rice growth monitoring and yield prediction were implemented to verify and evaluate the effects of radiometric calibration methods (RCMs) and UAV flying altitudes (UAV-FAs). The results show that the variation trends of reflectance and VIs are significantly different due to the change in component proportion observed at different altitudes. Except for the milking stage, the reflectance and VIs in other periods fluctuated greatly in the first 100 m and remained stable thereafter. This phenomenon was determined by the field of view of the sensor and the characteristic of the ground object. The selection of an appropriate calibration method was essential as a result of the marked differences in the rice phenotypes estimation accuracy based on different RCMs. There were pronounced differences in the accuracy of rice growth monitoring and yield estimation based on the 50 and 100 m-based variables, and the altitudes above 100 m had no notable effect on the results. This study can provide a reference for the application of UAV RS technology in precision agriculture and the accurate acquisition of crop phenotypes.

New Highly Potent NLRP3 Inhibitors: Furanochalcone Velutone F Analogues.

The NLRP3 inflammasome has now emerged as one of the most appealing drug targets for many inflammation-related diseases. Velutone F, a natural NLPR3 inhibitor, identified in our previous study has been limited in application by its low in planta abundance, weak activity, and complicated synthetic routes. To address these needs, structural optimization of velutone F led to a series of novel NLRP3 inhibitors. Among them, compound 14c exerted remarkable inhibitory activity with an IC50 value in the nanomolar range (251.1 nM) and was approximately 5-fold more potent than velutone F. Moreover, the synthesis method of 14c was simple, easy to handle, and scalable. Compound 14c could suppress NLRP3 inflammasome activation by attenuating ASC speck formation. Most importantly, compound 14c reduced peritoneal neutrophil influx in mice and IL-1ß in the spleen in the MSU-induced peritonitis in LPS-primed mouse model. Taken together, compound 14c is a prospective lead compound in the discovery of NLRP3 inflammasome inhibitors.

Effect of Smoking on Lung Function Decline in a Retrospective Study of a Health Examination Population in Chinese Males.

Objective: China has established a goal of reducing adult smoking prevalence from 27.7% to 20% by 2030. Understanding the possible ongoing impairment in lung function in smokers, is critically important to encourage the populations to change their smoking behavior. Methods: A total of 14,273 males joined the health examination at Huadong Sanatorium from Jan 2012 to Dec 2019 were included. In cross-sectional analysis, we used multiple linear regression to evaluate the association between baseline lung function and smoking status. Then, 3,558 males who received ≥2 spirometry exams were analyzed in longitudinal study. Annual lung function decline was compared using mixed linear models adjusted for confounders. Results: In cross-sectional analysis, compared with never-smokers, decreases of -133.56 mL (95% CI: -167.27, -99.85) and -51.44 mL (-69.62, -33.26) in FEV1, -1.48% (-1.94, -1.02) and -1.29% (-1.53, -1.04) in FEV1/FVC were observed in former and current smokers. In longitudinal analysis, significant declines were observed in FEV1 [5.04 (2.30, 7.78) mL] and FEV1/FVC [0.09 (0.05, 0.13) %] in current smokers but not observed in former smokers after adjustment. Participants with long duration of smoking cessation had decelerate lung function than short duration. The annual decline rate of current smokers with high smoking intensity (≥30 cigarettes per day) was 13.80 and 14.17 times greater than that of never-smokers in FEV1 and FVC. Thus, early smoking cessation can slow down lung function decline trend for current smokers. Conclusions: The harms of current smoking on lung function emphasize the necessity of smoking cessation, especially for those with comorbidities.

Remotely sensed estimation of total iron content in soil with harmonic analysis and BP neural network.

BACKGROUND: The estimation of total iron content at the regional scale is of much significance as iron deficiency has become a routine problem for many crops. METHODS: In this study, a novel method for estimating total iron content in soil (TICS) was proposed using harmonic analysis (HA) and back propagation (BP) neural network model. Several data preprocessing methods of first derivative (FD), wavelet packet transform (WPT), and HA were conducted to improve the correlation between the soil spectra and TICS. The principal component analysis (PCA) was exploited to obtained three kinds of characteristic variables (FD, WPT-FD, and WPT-FD-HA) for TICS estimation. Furthermore, the estimated accuracy of three BP models based on these variables was compared. RESULTS: The results showed that the BP models of different soil types based on WPT-FD-HA had better estimation accuracy, with the highest R2 value of 0.95, and the RMSE of 0.68 for the loessial soil. It was proved that the characteristic variable obtained by harmonic decomposition improved the validity of the input variables and the estimation accuracy of the TICS models. Meanwhile, it was identified that the WPT-FD-HA-BP model can not only estimate the total iron content of a single soil type with high accuracy but also demonstrate a good effect on the estimation of TICS of mixed soil. CONCLUSION: The HA method and BP neural network combined with WPT and FD have great potential in TICS estimation under the conditions of single soil and mixed soil. This method can be expected to be applied to the prediction of crop biochemical parameters.

TMEA, a Polyphenol in Sanguisorba officinalis, Promotes Thrombocytopoiesis by Upregulating PI3K/Akt Signaling.

Thrombocytopenia is closely linked with hemorrhagic diseases, for which induction of thrombopoiesis shows promise as an effective treatment. Polyphenols widely exist in plants and manifest antioxidation and antitumour activities. In this study, we investigated the thrombopoietic effect and mechanism of 3,3',4'-trimethylellagic acid (TMEA, a polyphenol in Sanguisorba officinalis L.) using in silico prediction and experimental validation. A KEGG analysis indicated that PI3K/Akt signalling functioned as a crucial pathway. Furthermore, the virtual molecular docking results showed high-affinity binding (a docking score of 6.65) between TMEA and mTOR, suggesting that TMEA might target the mTOR protein to modulate signalling activity. After isolation of TMEA, in vitro and in vivo validation revealed that this compound could promote megakaryocyte differentiation/maturation and platelet formation. In addition, it enhanced the phosphorylation of PI3K, Akt, mTOR, and P70S6K and increased the expression of GATA-1 and NF-E2, which confirmed the mechanism prediction. In conclusion, our findings are the first to demonstrate that TMEA may provide a novel therapeutic strategy that relies on the PI3K/Akt/mTOR pathway to facilitate megakaryocyte differentiation and platelet production.