Generalized interacting multiple model Kalman filtering algorithm for maneuvering target tracking under non-Gaussian noises.

The traditional interacting multiple model Kalman filtering algorithm (IMM-KF) can deal with the maneuvering target problem under Gaussian noise by soft switching among possible motion models. In practice, its performance is likely to degrade when handling non-Gaussian noise. We introduce the Gaussian mixture model (GMM) into the IMM-KF, and the GMM is utilized to model the non-Gaussian measurement noise as a mixture of multiple Gaussian probability densities with a certain probability. Then, a GIMM framework is proposed that enables accurate switching and fusion among multiple possible motion and noise models. And combined with Kalman filtering (KF), a GIMM-KF algorithm is proposed that enables accurate state estimation of maneuvering targets under non-Gaussian noise conditions. Subsequently, the provided simulations and experiments validate that the GIMM-KF algorithm outperforms existing methods in terms of accuracy, stability and robustness.

Extending Shelf-life of Two-step Method Precursor Solutions through Targeted Regulation for Highly Efficient and Reproducible Perovskite Solar Cells.

Precursor solution aging process can cause significant influence on the photovoltaic performance of perovskite solar cells (PVSCs). Notably, we first observe that the aging phenomenon is more severe in the precursor of two-step sequential method compared to that in one-step method due to that the protic solvent isopropanol facilitates amine-cation side reaction and iodide ions oxidation. Herein, we report a novel approach for selectively stabilizing both organic amine salt and lead iodide (PbI2) precursor solutions in two-step method. The introduction of benzene-1,3-dithiol into organic amine salt solution can mitigate amine-cation side reactions due to the formation of an acidic and reducing environment. Simultaneously, decamethylferrocene (FcMe10/FcMe+10) pair can act as a redox shuttle in PbI2 solution to concurrently oxidize Pb0 and reduce I2 in cyclic manner. Consequently, the PVSCs device fabricated from ameliorative precursor solutions demonstrates superior power conversion efficiency of 25.31%, retaining 95% of its efficiency after 21 days of solution aging. Moreover, the unencapsulated devices maintain 85% of primitive efficiency for 1500 h at maximum power point tracking under continuous illumination. This work establishes a fundamental guidance and scientific direction for the stabilization of two-step perovskite precursor solutions.

An enhanced snow ablation optimizer for UAV swarm path planning and engineering design problems.

The Snow Ablation Optimizer (SAO) is an advanced optimization algorithm. However, it suffers from slow convergence and a tendency to become trapped in local optima. To address these limitations, we propose an Enhanced Snow Ablation Optimization algorithm (ESAO). Initially, an adaptive T-distribution control strategy is employed to improve the algorithm's exploratory position adjustments, facilitating the identification of the global optimum. Furthermore, we introduce a Cauchy mutation strategy, endowing individuals with a robust capability to escape local extrema and steer the population towards more favorable directions. A leader-based boundary control strategy is also proposed to enhance the optimizer's search performance, significantly increasing the accuracy, speed, and stability of the algorithm in tackling complex problems. To validate the performance of ESAO, we utilize 29 CEC2017 benchmark functions for comparison against eight popular algorithms across various dimensions. Our algorithm ranked first in all comparisons, demonstrating ESAO's effectiveness. Additionally, to evaluate the practical applicability of the proposed method, we mathematically modeled the UAV swarm and solved the UAV swarm path planning problem using various competitor algorithms. Furthermore, we applied different competitor algorithms to two engineering design problems. The results demonstrate that ESAO performs the best. In general, ESAO outperforms its counterparts in terms of solution quality and stability, showcasing its superior application potential.

The role of circHmbox1(3,4) in ferroptosis-mediated cognitive impairments induced by manganese.

Excessive environmental exposure to manganese (Mn) has been linked to cognitive impairments, circular RNAs (circRNAs) have been recognized for their roles in epigenetic regulation in various biological processes, including neurological pathogenesis. Previous studies found that ferroptosis, an iron ion-dependent programmed cell death, may be involved in cognitive impairments. However, specific mechanisms underlying the relationship among circRNA, ferroptosis, and neurotoxicity of Mn are not well-understood. In the current study, RNA sequencing was performed to profile RNA expression in Neuro-2a (N2a) cells that were treated with 300 µM Mn. The potential molecular mechanisms of circHmbox1(3,4) in Mn-induced cognitive impairments were investigated via various experiments, such as Western blot and intracerebroventricular injection in mice. We observed a significant decrease in the expression of circHmbox1(3,4) both in vitro and in vivo following Mn treatment. The results of Y maze test and Morris water maze test demonstrated an improvement in learning and memory abilities following circHmbox1(3,4) overexpression in Mn treated mice. Mn treatment may reduce circHmbox1(3,4) biogenesis through lowered expression of E2F1/QKI. Inhibiting circHmbox1(3,4) expression led to GPX4 protein degradation through protein ligation and ubiquitination. Overall, the current study showed that Mn exposure-induced cognitive dysfunction may be mediated through ferroptosis regulated by circHmbox1(3,4).

Activated Carbon Based on Recycled Epoxy Boards and Their Adsorption toward Methyl Orange.

With the swift progress of the electronics industry, discarded circuit boards have become an important source of non-degradable waste. In this work, discarded epoxy resin was collected as a precursor to prepare activated carbon (AC) through stepwise carbonization/activation methods. The rough carbon materials with a certain graphite and amorphous structure reveal the multiple oxygen-containing groups on their surface. In the process of studying the adsorption of methyl orange by activated carbon, it is found that the adsorption is in accordance with the quasi-secondary kinetic model, and equilibrium adsorption amounts can reach 41.051 mg/g. The adsorption isotherm of AC is more in line with the Langmuir model, and the saturation adsorption amount at three different temperatures is 23.137 mg/g, 30.358 mg/g, and 37.202 mg/g, respectively. The enthalpy (ΔH) is 17.30 KJ/mol in the adsorption process, which indicates that is a physical process with heat-absorbing capabilities. This work is of great significance with regard to the recycling of waste to reduce pollution and in terms of gaining economic benefits.

Gossypetin targets the liver-brain axis to alleviate pre-existing liver fibrosis and hippocampal neuroinflammation in mice.

Liver fibrosis occurs in response to chronic damage and inflammation to the liver. Leaving untreated, it can lead to decreased liver function and can eventually progress to cirrhosis, a more advanced and irreversible state of liver damage. Clinical investigations showed that chronic liver disease associated with neurological symptoms including anxiety, depression, and cognitive decline. However, few therapeutic options are available for treating liver and related brain pathologies simultaneously. In this study, we aim to find therapeutic candidates that target the liver-brain axis. Gossypetin, a flavonoid from sedum, shows promising capability in treating liver and brain pathologies in CCl4-induced mouse model. Short term of gossypetin administration is sufficient to ameliorate impaired liver function and pre-existing liver fibrosis, suppress MKK3/6-p38 MAPK and p53 activation, and abolish the activation of hepatic stellate cells and Kupffer cells. Although we observe no neuronal loss in the brain of mice with liver fibrosis, we do observe astrogliosis and microglial activation in certain brain regions, especially the hippocampus. Brief gossypetin administration also shows potential in alleviating neuroinflammation in these regions. These results suggest that gossypetin can target the liver-brain axis and be a promising candidate for treating chronic liver fibrosis patients with neurological symptoms.

Tumor Immune Infiltration and Clinical Impact of Specific BCG-Related Genes in Melanoma.

Melanoma, caused by malignant melanocytes, is known for its invasiveness and poor prognosis. Therapies are often ineffective due to their heterogeneity and resistance. Bacillus Calmette-Guérin (BCG), primarily a tuberculosis vaccine, shows potential in treating melanoma by activating immune responses. In this study, data from The Cancer Genome Atlas and the NCBI GEO database were utilized to determine pivotal differentially expressed genes (DEGs) such as DSC2, CXCR1, BOK, and CSTB, which are significantly upregulated in BCG treated blood samples and are strongly associated with the prognosis of melanoma. We employ tools like edgeR and ggplot2 for functional and pathway analysis and develop a prognostic model using LASSO Cox regression analysis to predict patient survival. A notable finding is the correlation between BCG-related genes and immune cell infiltration in melanoma, highlighting the potential of these genes as both biomarkers and therapeutic targets. Additionally, the study examines genetic alterations in these genes and their impact on the disease. This study highlights the necessity of further exploring BCG-related genes for insights into melanoma pathogenesis and treatment enhancement, suggesting that BCG's role in immune activation could offer novel therapeutic avenues in cancer treatment.

Bioinspired Solar-Driven Osmosis for Stable High Flux Desalination.

The growing global water crisis necessitates sustainable desalination solutions. Conventional desalination technologies predominantly confront environmental issues such as high emissions from fossil-fuel-driven processes and challenges in managing brine disposal during the operational stages, emphasizing the need for renewable and environmentally friendly alternatives. This study introduces and assesses a bioinspired, solar-driven osmosis desalination device emulating the natural processes of mangroves with effective contaminant rejection and notable productivity. The bioinspired solar-driven osmosis (BISO) device, integrating osmosis membranes, microporous absorbent paper, and nanoporous ceramic membranes, was evaluated under different conditions. We conducted experiments in both controlled and outdoor settings, simulating seawater with a 3.5 wt % NaCl solution. With a water yield of 1.51 kg m-2 h-1 under standard solar conditions (one sun), the BISO system maintained excellent salt removal and accumulation resistance after up to 8 h of experiments and demonstrated great cavitation resistance even at 58.14 °C. The outdoor test recorded a peak rate of 1.22 kg m-2 h-1 and collected 16.5 mL in 8 h, showing its practical application potential. These results highlight the BISO device's capability to address water scarcity using a sustainable approach, combining bioinspired design with solar power, presenting a viable pathway in renewable-energy-driven desalination technology.

Amine-releasable Mediator In situ Repair Perovskites for Efficient and Stable Perovskite Solar Cells.

Residual lead iodide (PbI2) is deemed to a double-edged sword in perovskite film as small amounts of PbI2 are beneficial to the photovoltaic performance, but excessive will cause degradation of photovoltaic performance and stability. Herein, an in situ repair strategy has been developed by introducing amine-releasable mediator (methylammonium pyridine-2-carboxylic, MAPyA) to eliminate over-residual PbI2 and regulate the crystal quality of perovskite film. Notably, MAPyA can be partially decomposed into methylamine (MA) gas and pyridine-2-carboxylic (PyA) during high temperature annealing. The released MA can locally form liquid intermediate phase, facilitating the reconstruction of perovskite microcrystals and residual PbI2. Moreover, the leftover PyA is confirmed to effectively passivate the uncoordinated lead ions in final perovskite film. Based upon this, superior perovskite film with optimized crystal structure and holistic negligible PbI2 is acquired. The assembled device realizes outstanding efficiency of 24.06 %, and exhibits a remarkable operational stability that maintaining 87 % of its origin efficiency after continuous illumination for 1480 h. And the unencapsulated MAPyA-treated devices present significant uplift in humidity stability (maintaining ~93 % of the initial efficiency over 1500 h, 50-60 % relative humidity). Furthermore, the further optimization of this strategy with nanoimprint technology proves its superiority in the amplificative preparation for perovskite films.

Circular RNA circRest regulates manganese induced cell apoptosis by targeting the mmu-miR-6914-5p/Ephb3 axis.

Overexposure to manganese (Mn) can lead to neurotoxicity, the underlying mechanisms remain incompletely understood. Circular RNAs (circRNAs) have emerged as important regulators in various biological processes. It is plausible that circRNAs may be involved in the biological mechanisms underlying Mn caused neurotoxicity. Here, circRest was downregulated in Mn-exposed mouse neuroblastoma cells (N2a cells) by RNA sequencing and quantitative real-time PCR. When circRest was overexpressed, it led to an increase in cell viability and a decrease in apoptosis following Mn exposure. Conversely, silencing circRest resulted in opposite effects in N2a cells. Further investigation revealed that circRest acts as a mmu-miR-6914-5p sponge, and mmu-miR-6914-5p could bind and inhibit Ephb3, thereby promoting apoptosis in N2a cells. This was confirmed through RNA antisense purification and dual luciferase reporter assays. Additionally, the circRest/mmu-miR-6914-5p/Ephb3 axis may influence memory and learning in mice following Mn exposure. In conclusion, our study uncovers a novel mechanism by which circRest may attenuate Mn caused neurotoxicity via the mmu-miR-6914-5p/Ephb3 axis.

Synchronous Elimination of Excess Photoinstable PbI2 and Interfacial Band Mismatch for Efficient and Stable Perovskite Solar Cells.

Eliminating the undesired photoinstability of excess lead iodide (PbI2 ) in the perovskite film and reducing the energy mismatch between the perovskite layer and heterogeneous interfaces are urgent issues to be addressed in the preparation of perovskite solar cells (PVSCs) by two-step sequential deposition method. Here, the 1-ethyl-3-methylimidazolium tetrafluoroborate (EMIMBF4 ) is employed to convert superfluous PbI2 to more robust 1D EMIMPbI3 which can withstand lattice strain, while forming an interfacial dipole layer at the SnO2 /perovskite interface to reconfigure the interfacial energy band structure and accelerate the charge extraction. Consequently, the unencapsulated PVSCs device attains a champion efficiency of 24.28 % with one of the highest open-circuit voltage (1.19 V). Moreover, the unencapsulated devices showcase significantly improved thermal stability, enhanced environmental stability and remarkable operational stability accompanied by 85 % of primitive efficiency retained over 1500 h at maximum power point tracking under continuous illumination.

Manganese-induced neurological pyroptosis: Unveiling the mechanism through the ROS activaed Caspase-3/GSDME signaling pathway.

Manganese (Mn) is an essential micronutrient in maintaining homeostasis in the human body, while excessive Mn exposure can lead to neurological disorders. To investigate whether there is an association between elevated ROS and pyroptosis caused by Mn exposure using both in vitro and in vivo models. We exposed BV2 and N2a, which represent microglial cells and Neuroblastoma cells in the brain, respectively, to different concentrations of Mn for 24 h. Following Mn exposure, we assessed cell morphology, levels of lactate dehydrogenase, and cellular ROS levels. C57BL/6 male mice were exposed to 0-100 mg/kg MnCl2·4H2O for 12 weeks through gavage. The expression level of pyroptosis proteins including caspase3 and GSDME in the hippocampus was examined. We found that Mn exposure resulted in elevated levels of cellular ROS and protein expression of Caspase3 and GSDME in both N2a and BV2 cells. The pyroptosis levels were blunted by either inhibiting Caspase3 expression or ROS production. In the in vivo model, protein levels of Caspase3 and GSDME also increased dependent of Mn concentrations. These findings suggested that neuronal pyroptosis induced by Mn exposure may occur through the ROS-stimulated Caspase3-GSDME pathway. Moreover, utilizing inhibitors targeting Caspase3 or ROS may provide protection against Mn-induced toxicity.

Calligraphy of Nanoplasmonic Bioink-Based Multiplex Immunosensor for Precision Immune Monitoring and Modulation.

Immunomodulation therapies have attracted immense interest recently for the treatment of immune-related diseases, such as cancer and viral infections. This new wave of enthusiasm for immunomodulators, predominantly revolving around cytokines, has spurred emerging needs and opportunities for novel immune monitoring and diagnostic tools. Considering the highly dynamic immune status and limited window for therapeutic intervention, precise real-time detection of cytokines is critical to effectively monitor and manage the immune system and optimize the therapeutic outcome. The clinical success of such a rapid, sensitive, multiplex immunoanalytical platform further requires the system to have ease of integration and fabrication for sample sparing and large-scale production toward massive parallel analysis. In this article, we developed a nanoplasmonic bioink-based, label-free, multiplex immunosensor that can be readily "written" onto a glass substrate via one-step calligraphy patterning. This facile nanolithography technique allows programmable patterning of a minimum of 3 µL of nanoplasmonic bioink in 1 min and thus enables fabrication of a nanoplasmonic microarray immunosensor with 2 h simple incubation. The developed immunosensor was successfully applied for real-time, parallel detection of multiple cytokines (e.g., interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), and transforming growth factor-beta (TGF-ß)) in immunomodulated macrophage samples. This integrated platform synergistically incorporates the concepts of nanosynthesis, nanofabrication, and nanobiosensing, showing great potential in the scalable production of label-free multiplex immunosensing devices with superior analytical performance for clinical applications in immunodiagnostics and immunotherapy.

Association between creatinine to body weight ratio and all-cause mortality: a cohort study of NHANES.

Research on the relationship between the weight-adjusted skeletal muscle mass index and all-cause mortality is rare, and even rarer is the relationship between the creatinine/body weight (Cre/BW) ratio and all-cause mortality. Therefore, this study aimed to investigate the relationship between the Cre/BW ratio and mortality in individuals with normal renal function. This prospective study used data from the National Health and Nutrition Examination Survey (NHANES) database. A Cox hazard model was used to analyze the relationship between the Cre/BW ratio and mortality risk. In total, 45,459 participants were included, of which 49.97% were women, with an average age of 45.68 ± 18.08 years. The incidence of all-cause mortality was 10.9% among these participants during the median (interquartile range) follow-up of 9.6 (5.2, 14.2) years. After adjusting for all covariates, a U-shaped relationship was found between the Cre/BW ratio and all-cause mortality (P for nonlinearity <0.001), with the lowest risk observed at Cre/BW ratios (×100) between 0.821 and 0.987. In the threshold effect analysis, the Cre/BW ratio (×100) had a threshold value of 0.96. When the Cre/BW ratio (×100) was <0.96, all-cause mortality was negatively associated with the Cre/BW ratio (×100) (0.63 (0.41, 0.97)). In contrast, when the Cre/BW ratio (×100) was ≥0.96, the higher Cre/BW ratio was associated with a greater hazard ratio of all-cause mortality (1.67 (1.41, 1.97)). In conclusion, we report a U-shaped relationship between the Cre/BW ratio and all-cause mortality. Controlling the Cre/BW ratio within a certain range may reduce the risk of all-cause mortality.

Ectopic expression of Camellia oleifera Abel. gibberellin 20-oxidase gene increased plant height and promoted secondary cell walls deposition in Arabidopsis.

MAIN CONCLUSION: Ectopic expression of Camellia oleifera Abel. gibberellin 20-oxidase 1 caused a taller phenotype, promoted secondary cell wall deposition, leaf enlargement, and early flowering, and reduced chlorophyll and anthocyanin accumulation and seed enlargement phenotype in Arabidopsis. Plant height and secondary cell wall (SCW) deposition are important plant traits. Gibberellins (GAs) play important roles in regulating plant height and SCWs deposition. Gibberellin 20-oxidase (GA20ox) is an important enzyme involved in GA biosynthesis. In the present study, we identified a GA synthesis gene in Camellia oleifera. The total length of the CoGA20ox1 gene sequence was 1146 bp, encoding 381 amino acids. Transgenic plants with CoGA20ox1 had a taller phenotype; a seed enlargement phenotype; promoted SCWs deposition, leaf enlargement, and early flowering; and reduced chlorophyll and anthocyanin accumulation. Genetic analysis showed that the mutant ga20ox1-3 Arabidopsis partially rescued the phenotype of CoGA20ox1 overexpression plants. The results showed that CoGA20ox1 participates in the growth and development of C. oleifera. The morphological changes in CoGA20ox1 overexpressed plants provide a theoretical basis for further exploration of GA biosynthesis and analysis of the molecular mechanism in C. oleifera.

RNA-Seq transcriptome analysis of renal tissue from spontaneously hypertensive rats revealed renal protective effects of dapagliflozin, an inhibitor of sodium-glucose cotransporter 2.

Hypertensive nephropathy (HTN) is a common complication of hypertension. Although various agents for treatment of hypertension exert significant effects, there is currently no effective treatment for hypertensive nephropathy. Sodium-glucose cotransporter 2 (SGLT2) inhibitors, such as dapagliflozin (DAPA), are a new class of hypoglycemic agents shown to improve the prognosis of patients with chronic kidney disease and diabetes mellitus. However, the mechanisms underlying the protective effects of DAPA remain unclear. RNA-sequencing (RNA-Seq)-based computational analysis was conducted to explore the transcriptomic changes to spontaneously hypertensive rats (SHRs) treated with DAPA for 8 weeks. Differentially expressed genes in SHRs were related to dysregulation of lipid metabolism, oxidation-reduction reaction, immunity and inflammation in HTN. Transcriptome analysis showed that 8 weeks of DAPA therapy exerted protective effects on the renal tissues of SHRs through the lysosomal, phagosomal, and autophagic pathways. VENN diagram analysis identified Zinc finger and BTB domain-containing 20 (Zbtb20) as the potential target of DAPA therapy. Consistent with the RNA-Seq findings, real-time quantitative PCR and immunohistochemical analyses revealed increased expression of Zbtb20 in the renal tissues of SHRs, whereas expression was decreased following 8 weeks of DAPA administration. The results of this study clarified the transcriptome signature of HTN and the beneficial effects of DAPA on renal tissues by alleviating dysregulation of metabolic processes and reducing inflammation.

Superhydrophobic Rotation-Chip for Computer-Vision Identification of Drug-Resistant Bacteria.

The transport, distribution, and mixing of microfluidics often require additional instruments, such as pumps and valves, which are not feasible when operated in point-of-care (POC) settings. Here, we present a simple microfluidic pathogen detection system known as Rotation-Chip that transfers the reagents between wells by manually rotating two concentric layers without using external instruments. The Rotation-Chip is fabricated by a simple computer numerical control (CNC) machining process and is capable of carrying out 60 multiplexed reactions with a simple 30 or 60° rotation. Leveraging superhydrophobic coating, a high fluid transport efficiency of 92.78% is achieved without observable leaking. Integrated with an intracellular fluorescence assay, an on-chip detection limit of 1.8 × 106 CFU/mL is achieved for ampicillin-resistant Escherichia coli (E. coli), which is similar to our off-chip results. We also develop a computer vision method to automatically distinguish positive and negative samples on the chip, showing 100% accuracy. Our Rotation-Chip is simple, low-cost, high-throughput, and can display test results with a single chip image, making it ideal for various multiplexing POC applications in resource-limited settings.

TyG-BMI and hypertension in Normoglycemia subjects in Japan: A cross-sectional study.

BACKGROUND: Insulin Resistance (IR) are associated with Hypertension (HTN). Triglyceride glucose-body mass index (TyG-BMI) is a readily available and clinically significant indicator of IR. This study aimed to investigate whether TyG-BMI is independently associated with HTN. METHODS: A total of 15,464 patients with normal blood glucose from 2004 to 2016 participated in this study. Participants were divided into four groups using the quartile method: TyG-BMI below 153.1, between 153.1 and 174.2, between 174.2 and 199.3, and over 199.3. The covariates included age, sex, BMI, WC, HDL-C, TC, TG, HbA1c, FPG, ALT, AST, GGT, SBP, DBP, smoking status, alcohol consumption, and exercise habits. RESULTS: The average age was 43.7 ± 8.9 years, and 45.4% were men. The prevalence of HTN was 6.2% (964/15464) of the population. TyG-BMI remained significantly associated with HTN after multivariate adjustment for TyG-BMI as a continuous variable (adjusted OR = 2.87, 95% CI: 1.90-4.34). Each 10-unit rise in TyG-BMI (continuous variable) was linked to a 31% increase in the prevalence of HTN (adjusted OR = 1.31, 95% CI: 1.25-1.37). In the subgroup analysis stratified by age, sex, waist circumference, and smoking status, the association between TyG-BMI and HTN were stable. CONCLUSION: In this study, TyG-BMI was highly correlated with HTN, but more experiments and different populations are needed to verify this.

Multifunctional Metal-Organic Frameworks Capsules Modulate Reactivity of Lead Iodide toward Efficient Perovskite Solar Cells with UV Resistance.

The two-step sequential deposition process is demonstrated as a reliable technology for the fabrication of efficient perovskite solar cells (PVSCs). However, the complete conversion of dense PbI2 to perovskite in planar PVSCs is tough without mesoporous titanium dioxide as support. Herein, multifunctional capsules consisting of zeolitic imidazolate framework-8 (ZIF-8) encapsulant and formamidinium iodide (FAI) are introduced between tin oxide (SnO2 ) and lead iodide (PbI2 ) layer. Intriguingly, the capsule dopant interlayer benefits the formation of porous PbI2 film due to the porous nanostructure of ZIF-8 that is favorable for the subsequent intercalation reaction. Furthermore, the constituent of the perovskite precursor in ZIF-8 pores can convert into the crystal nuclei of perovskite by reacting with PbI2 first, thereby promoting further perovskite crystallization. Significantly, the incorporation of ZIF-8 can enhance the resistance of perovskite against UV illumination due to down-conversion effect. Consequently, the modified device achieves a champion power conversion efficiency (PCE) of 24.08% and displays enhanced UV stability, which can sustain 83% of its original PCE under 365 nm UV illumination for 300 h. Moreover, the unencapsulated device maintains 90% of initial PCE after 1500 h storage in dark ambient conditions with a relative humidity range of 50%-70%.

Discovery of 2H-Indazole-3-carboxamide Derivatives as Novel Potent Prostanoid EP4 Receptor Antagonists for Colorectal Cancer Immunotherapy.

Nowadays, small-molecule drugs have become an indispensable part of tumor immunotherapy. Accumulating evidence has indicated that specifically blocking PGE2/EP4 signaling to induce robust antitumor immune response represents an attractive immunotherapy strategy. Herein, a 2H-indazole-3-carboxamide containing compound 1 was identified as a EP4 antagonist hit by screening our in-house small-molecule library. Systematic structure-activity relationship exploration leads to the discovery of compound 14, which displayed single-nanomolar EP4 antagonistic activity in a panel of cell functional assays, high subtype selectivity, and favorable drug-like profiles. Moreover, compound 14 profoundly inhibited the up-regulation of multiple immunosuppression-related genes in macrophages. Oral administration of compound 14, either as monotherapy or in combination with an anti-PD-1 antibody, significantly impaired tumor growth via enhancing cytotoxic CD8+ T cell-mediated antitumor immunity in a syngeneic colon cancer model. Thus, these results demonstrate the potential of compound 14 as a candidate for developing novel EP4 antagonists for tumor immunotherapy.