KinomeMETA: a web platform for kinome-wide polypharmacology profiling with meta-learning.

Kinase-targeted inhibitors hold promise for new therapeutic options, with multi-target inhibitors offering the potential for broader efficacy while minimizing polypharmacology risks. However, comprehensive experimental profiling of kinome-wide activity is expensive, and existing computational approaches often lack scalability or accuracy for understudied kinases. We introduce KinomeMETA, an artificial intelligence (AI)-powered web platform that significantly expands the predictive range with scalability for predicting the polypharmacological effects of small molecules across the kinome. By leveraging a novel meta-learning algorithm, KinomeMETA efficiently utilizes sparse activity data, enabling rapid generalization to new kinase tasks even with limited information. This significantly expands the repertoire of accurately predictable kinases to 661 wild-type and clinically-relevant mutant kinases, far exceeding existing methods. Additionally, KinomeMETA empowers users to customize models with their proprietary data for specific research needs. Case studies demonstrate its ability to discover new active compounds by quickly adapting to small dataset. Overall, KinomeMETA offers enhanced kinome virtual profiling capabilities and is positioned as a powerful tool for developing new kinase inhibitors and advancing kinase research. The KinomeMETA server is freely accessible without registration at https://kinomemeta.alphama.com.cn/.

Machine learning approaches to debris flow susceptibility analyses in the Yunnan section of the Nujiang River Basin.

Background: The Yunnan section of the Nujiang River (YNR) Basin in the alpine-valley area is one of the most critical areas of debris flow in China. Methods: We analyzed the applicability of three machine learning algorithms to model of susceptibility to debris flow-Random Forest (RF), the linear kernel support vector machine (Linear SVM), and the radial basis function support vector machine (RBFSVM)-and compared 20 factors to determine the dominant controlling in debris flow occurrence in the region. Results: We found that (1) RF outperformed RBFSVM and Linear SVM in terms of accuracy, (2) topographic conditions were prerequisites, and geology, precipitation, vegetation, and anthropogenic influence were critical to forming debris flows. Also, the relative elevation difference was the most prominent evaluation factor of debris flow susceptibility, and (3) susceptibility maps based on RF's debris flow susceptibility (DFS) showed that zones with very high susceptibility were distributed along the mainstream of the Nujiang River. These findings provide methodological guidance and reference for improvement of DFS assessment. It enriches the content of DFS studies in the alpine-valley areas.

The combined exposure of polystyrene microplastics and high-fat feeding affects the intestinal pathology damage and microbiome in zebrafish.

The pervasive utilization of plastics and their integration into ecosystems has resulted in significant environmental issues, particularly the pollution of microplastics (MPs). In aquaculture, high-fat feed (HFD) is frequently employed to enhance the energy intake and economic fish production. This study utilized zebrafish as a model organism to investigate the impact of concurrent exposure to HFD and MPs on fish intestinal pathology damage and intestinal microbiome. The experimental design involved the division of zebrafish into two groups: one receiving a normal diet (ND) and the other receiving HFD. The zebrafish were exposed to a control group, as well as polystyrene (PS) MPs of varying sizes (5 and 50 µm). Histopathological examination revealed that the combination of 5 µm MPs and HFD resulted in the most significant damage to the zebrafish intestinal tract. Furthermore, gut microbiome assays indicated that exposure to MPs and HFD altered the composition of the gut microbiome. This study demonstrates that in aquaculture, the issue of HFD must be considered alongside concerns about MPs contamination, as both factors appear to have a combined effect on the intestinal pathology damage and intestinal microbiome. The findings of this research offer valuable insights for the improvement of fish farming practices.

Cascade reaction triggered colorimetric array for identification of organophosphorus pesticides congeners.

A modern agriculture uses alternative pest control methods to boost productivity, leading to an accumulation of organophosphorus (OPPs) congeners. This necessitates an intuitive and quick way to identify OPPs congeners. A colorimetric sensor for detecting OPPs congeners using a double-enzyme cascade reaction has been successfully designed and constructed in this study. The OPPs regulate the color changes induced by manganese dioxide nanoflowers (MnO2 NFs) and specific alkaline phosphatases (ALP) during the etching of gold nanopyramids (Au NBPs). The ascorbic acid (AA) produced by ALP hydrolysis inhibits Au NBPs etching by MnO2 NFs oxidized 3, 3', 5, 5'-tetramethylbenzidine (TMB). By inhibiting ALP catalytic activity, OPPs prevent AA formation. In this process, Au NBPs will undergo further etching, resulting in various colors so they can be analyzed semi-quantitatively with the naked eye. It has been found that different types of OPPs inhibit enzymes differently and therefore result in varying degrees of etching of Au NBPs. Principal Component Analysis (PCA) is performed by smart devices that convert R, G, and B signals into digital signals. This colorimetric array tests various foods (tea, apple, and cabbage). Colorimetric visualization sensors combined with data analysis will be used in real-life product development.

Targeting pro-inflammatory T cells as a novel therapeutic approach to potentially resolve atherosclerosis in humans.

Atherosclerosis (AS), a leading cause of cardio-cerebrovascular disease worldwide, is driven by the accumulation of lipid contents and chronic inflammation. Traditional strategies primarily focus on lipid reduction to control AS progression, leaving residual inflammatory risks for major adverse cardiovascular events (MACEs). While anti-inflammatory therapies targeting innate immunity have reduced MACEs, many patients continue to face significant risks. Another key component in AS progression is adaptive immunity, but its potential role in preventing AS remains unclear. To investigate this, we conducted a retrospective cohort study on tumor patients with AS plaques. We found that anti-programmed cell death protein 1 (PD-1) monoclonal antibody (mAb) significantly reduces AS plaque size. With multi-omics single-cell analyses, we comprehensively characterized AS plaque-specific PD-1+ T cells, which are activated and pro-inflammatory. We demonstrated that anti-PD-1 mAb, when captured by myeloid-expressed Fc gamma receptors (FcγRs), interacts with PD-1 expressed on T cells. This interaction turns the anti-PD-1 mAb into a substitute PD-1 ligand, suppressing T-cell functions in the PD-1 ligands-deficient context of AS plaques. Further, we conducted a prospective cohort study on tumor patients treated with anti-PD-1 mAb with or without Fc-binding capability. Our analysis shows that anti-PD-1 mAb with Fc-binding capability effectively reduces AS plaque size, while anti-PD-1 mAb without Fc-binding capability does not. Our work suggests that T cell-targeting immunotherapy can be an effective strategy to resolve AS in humans.

Diagnostic significance and predictive efficiency of metabolic risk score for fertility-sparing treatment in patients with atypical endometrial hyperplasia and early endometrial carcinoma.

OBJECTIVE: This study aims to assess the impact of the metabolic risk score (MRS) on both the time to achieve complete remission (CR) of fertility-sparing treatments for atypical endometrial hyperplasia (AEH) and early EC patients. METHODS: Univariate and multivariate logistic analyses were employed to identify independent risk factors affecting the time to CR with patients at our center. These factors were subsequently incorporated into receiver operator characteristic curve analysis and decision curve analysis to assess the predictive accuracy of time to CR. Additionally, Kaplan-Meier analysis was utilized to determine the cumulative CR rate for patients. RESULTS: The 173 patients who achieved CR following fertility preservation treatment (FPT) were categorized into three subgroups based on their time to CR (<6, 6-9, >9 months). Body mass index (hazard ratio [HR]=0.20; 95% confidence interval [CI]=0.03, 0.38; p=0.026), MRS (HR=0.31; 95% CI=0.09, 0.52; p=0.005), insulin resistance (HR=1.83; 95% CI=0.05, 3.60; p=0.045), menstruation regularity (HR=3.77; 95% CI=1.91, 5.64; p=0.001), polycystic ovary syndrome (HR=-2.16; 95% CI=-4.03, -0.28; p=0.025), and histological type (HR=0.36; 95% CI=0.10, 0.62; p=0.005) were identified as risk factors for time to CR, with MRS being the independent risk factor (HR=0.29; 95% CI=0.02, 0.56; p=0.021). The inclusion of MRS significantly enhanced the predictive accuracy of time to CR (area under the curve [AUC]=0.789 for Model 1, AUC=0.862 for Model 2, p=0.032). Kaplan-Meier survival curves revealed significant differences in the cumulative CR rate among different risk groups. CONCLUSION: MRS emerges as a novel evaluation system that substantially enhances the predictive accuracy for the time to achieve CR in AEH and early EC patients seeking fertility preservation.

Plasmonic Multi-Layered Built-in Hotspots Nanogaps for Effectively Activating Analytes.

Multi-layered plasmonic nanostructures are able to highly promote the near-field confinement and effectively activate analytes, which are of predominate significance but are extremely challenging. Herein, the semi-open Au core@carved AuAg multi-shell superstructure nanoparticles (multi-Au@Ag-Au NPs, multi = mono, bi, tri, tetra, and penta) are reported with a high designability on electromagnetic field and capability of effectively capturing analytes. By controlling synthetic parameters such as the number of galvanic exchange and Ag growth, multi-Au@Ag-Au NPs are successfully obtained, with tunable layer numbers and asymmetric nanoholes. Due to collective plasmon oscillations of multi-layered built-in nanogaps, the electromagnetic field strength of a single penta-Au@Ag-Au entity reach 48841. More importantly, the penta-Au@Ag-Au NPs show a remarkable light-harvesting capability, which is adaptive to different Raman lasers, supporting high-diversity detection. Additionally, the structural specificity allows analytes to be sufficiently captured into interior hotspots, and further achieve highly sensitive detection with limit of detection down to 3.22 × 10-12  M. This study not only provides an effective pathway for integrating abundant hotspots and activating target molecules in single plasmonic superstructure, but stimulates advancements in SERS substrates for various applications.

Toxicity of Polystyrene Nanoplastics in the Liver and Intestine of Normal and High-Fat-Diet Juvenile Zebrafish.

Nanoplastics (NPs) are widely found and threaten environmental and biological safety, because they do not degrade completely. We aimed to preliminarily explore the toxicity of NPs in obese children, because childhood obesity is a growing global health concern. We used zebrafish as a vertebrate toxicological model to examine the hepatic lipid metabolism and gut microbiota in juvenile zebrafish exposed to 1000 µg/L polystyrene NPs and a high-fat diet (HFD) using Raman spectroscopy, pathological examination, transcriptome analysis, and 16S sequencing techniques. Our study showed that polystyrene NPs perturb the lipid metabolism and gut microbiota stability in zebrafish. Furthermore, the combined effects of polystyrene NPs and HFD resulted in gastrointestinal injury. Our study is one of the first to investigate the toxicity of polystyrene NPs to normal-diet and HFD juvenile zebrafish using confocal Raman spectroscopy. Our results show the importance of a healthy diet and a reduction in the use of plasticware. Environ Toxicol Chem 2024;43:147-158. © 2023 SETAC.

Post-crotonylation oxidation by a monooxygenase promotes acetyl-CoA synthetase degradation in Streptomyces roseosporus.

Protein post-translational modifications (PTMs) with various acyl groups play central roles in Streptomyces. But whether these acyl groups can be further modified, and the influences of these potential modifications on bacterial physiology have not been addressed. Here in Streptomyces roseosporus with rich crotonylation, a luciferase monooxygenase LimB is identified to elaborately regulate the crotonylation level, morphological development and antibiotic production by oxidation on the crotonyl groups of an acetyl-CoA synthetase Acs. This chemical modification on crotonylation leads to Acs degradation via the protease ClpP1/2 pathway and lowered intracellular crotonyl-CoA pool. Thus, we show that acyl groups after PTMs can be further modified, herein named post-PTM modification (PPM), and LimB is a PTM modifier to control the substrate protein turnover for cell development of Streptomyces. These findings expand our understanding of the complexity of chemical modifications on proteins for physiological regulation, and also suggest that PPM would be widespread.

Combined Surface-Enhanced Raman and Infrared Absorption Spectroscopies for Streamlined Chemical Detection of Polycyclic Aromatic Hydrocarbon-Derived Compounds.

Polycyclic aromatic hydrocarbons (PAHs) constitute a class of universally prevalent carcinogenic environmental contaminants. It is increasingly recognized, however, that PAHs derivatized with oxygen, sulfur, or nitrogen functional groups are frequently more dangerous than their unfunctionalized counterparts. This much larger family of chemicals─polycyclic aromatic compounds─PACs─is far less well characterized than PAHs. Using surface-enhanced Raman and IR Absorption spectroscopies (SERS + SEIRA) combined on a single substrate, along with density functional theoretical (DFT) calculations, we show that direct chemical detection and identification of PACs at sub-parts-per-billion concentration can be achieved. Focusing our studies on 9,10-anthraquinone, 5,12-tetracenequinone, 9-nitroanthracene, and 1-nitropyrene as model PAC contaminants, detection is made possible by incorporating a hydroxy-functionalized self-assembled monolayer that facilitates hydrogen bonding between analytes and the SERS + SEIRA substrate. 5,12-Tetracenequinone was detected at 0.3 ppb, and the limit of detection was determined to be 0.1 ppb using SEIRA alone. This approach is straightforwardly extendable to other families of analytes and will ultimately facilitate fieldable chemical detection of these dangerous yet largely overlooked environmental contaminants.

KinomeMETA: meta-learning enhanced kinome-wide polypharmacology profiling.

Kinase inhibitors are crucial in cancer treatment, but drug resistance and side effects hinder the development of effective drugs. To address these challenges, it is essential to analyze the polypharmacology of kinase inhibitor and identify compound with high selectivity profile. This study presents KinomeMETA, a framework for profiling the activity of small molecule kinase inhibitors across a panel of 661 kinases. By training a meta-learner based on a graph neural network and fine-tuning it to create kinase-specific learners, KinomeMETA outperforms benchmark multi-task models and other kinase profiling models. It provides higher accuracy for understudied kinases with limited known data and broader coverage of kinase types, including important mutant kinases. Case studies on the discovery of new scaffold inhibitors for membrane-associated tyrosine- and threonine-specific cdc2-inhibitory kinase and selective inhibitors for fibroblast growth factor receptors demonstrate the role of KinomeMETA in virtual screening and kinome-wide activity profiling. Overall, KinomeMETA has the potential to accelerate kinase drug discovery by more effectively exploring the kinase polypharmacology landscape.

d-tyrosine enhances disoctyl dimethyl ammonium chloride on alleviating SRB corrosion.

Microbiologically influenced corrosion (MIC) caused by sulfate reducing bacteria (SRB) is a serious challenge in many industries, but biofilm greatly decreases the toxicity of bactericides to cell inside. d-amino acids are potential enhancers for bactericides due to their excellent performance on biofilm inhibition. However, the mechanism of d-amino acid cooperating with bactericides for MIC inhibition is still unknown. In this study, d-tyrosine（D-Tyr）and disoctyl dimethyl ammonium chloride (DDAC) were selected as the typical d-amino acid and bactericide, respectively, to evaluate their synergetic inhibition on the corrosion caused by Desulfovibrio vulgaris. D-Tyr obviously enhanced the role of DDAC in inhibiting corrosion with high corrosion inhibition efficiency at 77.23 %. The attachment of EPS and live cells on the coupon surface decreased in the presence of D-Try, leading to more cells directly exposed to DDAC. Besides, D-Try decreased the amount of live cells on the surface and thus reduced the utilization of Fe by SRB and corrosion current. Moreover, dead cells settling to the coupon surface may form a protective lay to retard the contact between live SRB and Fe, leading to slow cathode reaction and less corrosion. Therefore, D-Tyr can reduce the coverage of biofilm, thereby reducing its protective effect on SRB and achieving better corrosion inhibition effect. This work provides a new strategy for improving bactericides and inhibiting MIC.

Corrigendum: Prognostic models for survival and consciousness in patients with primary brainstem hemorrhage.

[This corrects the article DOI: 10.3389/fneur.2023.1126585.].

Nanoscale CuO charge and morphology control Fusarium suppression and nutrient biofortification in field-grown tomato and watermelon.

Limited data exist on how surface charge and morphology impact the effectiveness of nanoscale copper oxide (CuO) as an agricultural amendment under field conditions. This study investigated the impact of these factors on tomatoes and watermelons following foliar treatment with CuO nanosheets (NS-) or nanospikes (NP+ and NP-) exhibiting positive or negative surface charge. Results showed plant species-dependent benefits. Notably, tomatoes infected with Fusarium oxysporum had significantly reduced disease progression when treated with NS-. Watermelons benefited similarly from NP+. Although disease suppression was significant and trends indicated increased yield, the yield effects weren't statistically significant. However, several nanoscale treatments significantly enhanced the fruit's nutritional value, and this nano-enabled biofortification was a function of particle charge and morphology. Negatively charged nanospikes significantly increased the Fe content of healthy watermelon and tomato (20-28 %) and Ca in healthy tomato (66 %), compared to their positively charged counterpart. Negatively charged nanospikes also outperformed negatively charged nanosheets, leading to significant increases in the content of S and Mg in infected watermelon (37-38 %), Fe in healthy watermelon (58 %), and Ca (42 %) in healthy tomato. These findings highlight the potential of tuning nanoscale CuO chemistry for disease suppression and enhanced food quality under field conditions.

Modulating the Reaction Configuration by Breaking the Structural Symmetry of Active Sites for Efficient Photocatalytic Reduction of Low-concentration CO2.

Photocatalytic conversion of low-concentration CO2 is considered as a promising way to simultaneously mitigate the environmental and energy issues. However, the weak CO2 adsorption and tough CO2 activation process seriously compromise the CO production, due to the chemical inertness of CO2 molecule and the formed fragile metal-C/O bond. Herein, we designed and fabricated oxygen vacancy contained Co3 O4 hollow nanoparticles on ordered macroporous N-doped carbon framework (Vo-HCo3 O4 /OMNC) towards photoreduction of low-concentration CO2 . In situ spectra and ab initio molecular dynamics simulations reveal that the constructed oxygen vacancy is able to break the local structural symmetry of Co-O-Co sites. The formation of asymmetric active site switches the CO2 configuration from a single-site linear model to a multiple-sites bending one with a highly stable configuration, enhancing the binding and structural polarization of CO2 molecules. As a result, Vo-HCo3 O4 /OMNC shows unprecedent activity in the photocatalytic conversion of low-concentration CO2 (10 % CO2 /Ar) under laboratory light source or even natural sunlight, affording a syngas yield of 337.8 or 95.2 mmol g-1 h-1 , respectively, with an apparent quantum yield up to 4.2 %.

IGF2BP3 drives gallbladder cancer progression by m6A-modified CLDN4 and inducing macrophage immunosuppressive polarization.

INTRODUCTION: N6-methyladenosine (m6A) is an emerging epigenetic modification, which plays a crucial role in the development of cancer. Nevertheless, the underlying mechanism of m6A-associated proteins and m6A modification in gallbladder cancer remains largely unknown. MATERIALS AND METHODS: The Gene Expression Omnibus database and tissue microarray were used to identify the key m6A-related gene in gallbladder cancer. The function and mechanism of IGF2BP3 were further investigated by knockdown and overexpression techniques in vitro and in vivo. RESULTS: We found that IGF2BP3 was elevated and correlated with poor prognosis in gallbladder cancer, which can be used as an independent prognostic factor for gallbladder cancer. IGF2BP3 accelerated the proliferation, invasion and migration of gallbladder cancer cells in vitro and in vivo. Mechanistically, IGF2BP3 interacted with and augmented the stability of CLDN4 mRNA by m6A modification. Enhancement of CLDN4 reversed the inhibitory effect of IGF2BP3 deficiency on gallbladder cancer. Furthermore, we demonstrated that IGF2BP3 promotes the activation of NF-κB signaling pathway by up-regulation of CLDN4. Overexpression of IGF2BP3 in gallbladder cancer cells obviously promoted the polarization of immunosuppressive phenotype in macrophages. Besides, Gallbladder cancer cells-derived IGF2BP3 up-regulated the levels of STAT3 in M2 macrophages, and promoted M2 polarization. CONCLUSIONS: We manifested IGF2BP3 promotes the aggressive phenotype of gallbladder cancer by stabilizing CLDN4 mRNA in an m6A-dependent manner and induces macrophage immunosuppressive polarization, which might offer a new theoretical basis for against gallbladder cancer.

Leveraging intracellular ALDH1A1 activity for selective cancer stem-like cell labeling and targeted treatment via in vivo click reaction.

Inhibition of overexpressed enzymes is among the most promising approaches for targeted cancer treatment. However, many cancer-expressed enzymes are "nonlethal," in that the inhibition of the enzymes' activity is insufficient to kill cancer cells. Conventional antibody-based therapeutics can mediate efficient treatment by targeting extracellular nonlethal targets but can hardly target intracellular enzymes. Herein, we report a cancer targeting and treatment strategy to utilize intracellular nonlethal enzymes through a combination of selective cancer stem-like cell (CSC) labeling and Click chemistry-mediated drug delivery. A de novo designed compound, AAMCHO [N-(3,4,6-triacetyl- N-azidoacetylmannosamine)-cis-2-ethyl-3-formylacrylamideglycoside], selectively labeled cancer CSCs in vitro and in vivo through enzymatic oxidation by intracellular aldehyde dehydrogenase 1A1. Notably, azide labeling is more efficient in identifying tumorigenic cell populations than endogenous markers such as CD44. A dibenzocyclooctyne (DBCO)-toxin conjugate, DBCO-MMAE (Monomethylauristatin E), could next target the labeled CSCs in vivo via bioorthogonal Click reaction to achieve excellent anticancer efficacy against a series of tumor models, including orthotopic xenograft, drug-resistant tumor, and lung metastasis with low toxicity. A 5/7 complete remission was observed after single-cycle treatment of an advanced triple-negative breast cancer xenograft (~500 mm3).

Sling Versus Abduction Brace Shoulder Immobilization After Arthroscopic Rotator Cuff Repair: A Systematic Review and Meta-analysis.

Background: The optimal immobilization position of the shoulder after rotator cuff repair is controversial. Purpose: To compare the clinical outcomes and incidence of retears after arthroscopic rotator cuff repair between patients who used an abduction brace versus a sling for postoperative shoulder immobilization. Study Design: Systematic review; Level of evidence, 1. Methods: This systematic review and meta-analysis was conducted using PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. We searched the PubMed, MEDLINE, and Embase electronic databases for randomized controlled trials (RCTs) that compared abduction brace and sling immobilization after arthroscopic rotator cuff repair using single-row, double-row, or suture-bridge fixation. Clinical scores, pain severity, and retear rates were compared between patients with abduction brace versus sling immobilization. Results: Of 1572 retrieved studies, 4 RCTs with a total of 224 patients (112 patients with abduction brace and 112 patients with sling) were included in the qualitative analysis, and 3 of the RCTs were included in the quantitative analysis (meta-analysis). There were no significant differences between the abduction brace and sling immobilization groups in the Constant-Murley score at 3 months (weighted mean difference [WMD], 0.26 [95% CI, -1.30 to 1.83]; P = .74; I 2 = 84%), 6 months (WMD, 1.91 [95% CI, -0.17 to 4.00]; P = .07; I 2 = 85%), and 12 months (WMD, 0.55 [95% CI, -1.37 to 2.47]; P = .57; I 2 = 0%); the visual analog scale score for pain at 1 week (WMD, 0.10 [95% CI, -0.20 to 0.41]; P = .51; I 2 = 0%), 3 weeks (WMD, -0.12 [95% CI, -0.34 to 1.00]; P = .29; I 2 = 0%), 6 weeks (WMD, -0.12 [95% CI, -0.30 to 0.06]; P = .20; I 2 = 0%), and 12 weeks (WMD, -0.13 [95% CI, -0.27 to 0.02]; P = .09; I 2 = 18%); or the retear rate at 3 months (risk ratio, 0.63 [95% CI, 0.09 to 4.23]; P = .64; Z = 0.47%) postoperatively. Conclusion: Our systematic review demonstrated a lack of significant differences between the abduction brace and sling immobilization groups regarding postoperative clinical scores, pain severity, and tendon healing.

Structure-Activity Relationship Study of 1H-Pyrrole-3-carbonitrile Derivatives as STING Receptor Agonists.

The use of small agonists to target stimulators of interferon genes (STING) has been demonstrated to be a promising strategy for the treatment of various cancers and infectious diseases. Herein, we discovered a series of 1H-pyrrole-3-carbonitrile derivatives as potential STING agonists. On this basis, the structure-activity relationship of this scaffold was studied by introducing various substituents on the aniline ring system. Representative compounds 7F, 7P, and 7R all displayed comparable activities to the reported STING agonist SR-717 in binding various hSTING alleles and induced reporter signal in human THP1 cell lines. Model compound 7F induced phosphorylation of TBK1, IRF3, p65, and STAT3 in a STING-dependent fashion and stimulated the expression of target genes IFNB1, CXCL10, and IL6 in a time-dependent manner in human THP1 cells. Our findings afforded a series of novel STING agonists with promising potential.