A qualitative exploration of e-cigarette prevention advertisements' effectiveness among college students in China.

INTRODUCTION: The rapid growth of e-cigarette usage among youth and young people has emerged as a significant public health concern. It is imperative to initiate effective vaping prevention campaigns and undertake relevant research to address this pressing issue. This research seeks to identify effective video advertisements to deter young people from starting to use e-cigarettes. It aims to offer evidence-based insights and recommendations for creating communication materials and designing messages for youth e-cigarette prevention efforts. METHODS: College students aged 18-24 years (n=40) participated in focus groups within this qualitative study. After viewing four stimulus videos, participants discussed what they perceived as effective and ineffective video characteristics, as well as suggestions for future videos. RESULTS: Effective video characteristics included the use of real-life testimonials, displaying specific health hazards, revealing harmful chemical ingredients and the deceptive nature of flavors, and positively perceived effectiveness. Participants generally found that videos with strong visual impact and graphics were more engaging and that approaches using fear and emotion were more effective. Ineffective characteristics included complex and exaggerated information, lack of empathy and irrelevance, insufficiently specific information, extreme and death-themed content, industry messages, as well as preachy tones, animations, metaphors, dull formats, excessive length, and scenes of e-cigarette use. CONCLUSIONS: Developing anti-e-cigarette campaign materials for youth necessitates target audience-focused qualitative research. This helps in deeply exploring and identifying effective themes and messages, as well as video characteristics and details while avoiding ineffective or even misleading messages and themes from young people's perspectives outside the United States. Future development of e-cigarette prevention videos for Chinese college students may consider incorporating localized real-life testimonial cases to convey specific harms, including self-efficacy information, and utilizing fear and emotional appeals.

Towards safer robot-assisted surgery: A markerless augmented reality framework.

Robot-assisted surgery is rapidly developing in the medical field, and the integration of augmented reality shows the potential to improve the operation performance of surgeons by providing more visual information. In this paper, we proposed a markerless augmented reality framework to enhance safety by avoiding intra-operative bleeding, which is a high risk caused by collision between surgical instruments and delicate blood vessels (arteries or veins). Advanced stereo reconstruction and segmentation networks are compared to find the best combination to reconstruct the intra-operative blood vessel in 3D space for registration with the pre-operative model, and the minimum distance detection between the instruments and the blood vessel is implemented. A robot-assisted lymphadenectomy is emulated on the da Vinci Research Kit in a dry lab, and ten human subjects perform this operation to explore the usability of the proposed framework. The result shows that the augmented reality framework can help the users to avoid the dangerous collision between the instruments and the delicate blood vessel while not introducing an extra load. It provides a flexible framework that integrates augmented reality into the medical robotic platform to enhance safety during surgery.

Iron-Catalyzed Photoredox Alcohol α-C-H Alkylation and Tandem Intramolecular Cyclization: Facile Access to Multisubstituted 2,3-Dihydrofurans and γ-Butyrolactones.

Multisubstituted furans occupy a pivotal position within the realms of synthetic chemistry and pharmacological science due to their distinctive chemical configurations and inherent properties. We herein introduce a tandem difunctionalization protocol of alcohols for the efficient synthesis of multisubstituted 2,3-dihydrofurans and γ-butyrolactones through the combination of photocatalysis and iron catalysis under mild conditions. Photoredox alcohol α-C(sp3)-H activation and Pinner-type intramolecular cyclization are two key processes. This method features significant convenience, economic benefits, and environmental friendliness.

Metabolomics and network pharmacology reveal the mechanism of antithrombotic effect of Asperosaponin VI.

Dipsaci Radix may possess antithrombotic properties, and one of its primary active ingredients is Asperosaponin VI. However, the antithrombotic effects and pharmacological mechanisms of Asperosaponin VI remain unclear. An in vivo experimental study has demonstrated the antithrombotic activity of Asperosaponin VI. Asperosaponin VI also exhibits anticoagulant properties. Asperosaponin VI significantly hindered collagen adrenergic-induced acute pulmonary thrombosis in mice and enhanced their survival rate. This hinders the formation of acute pulmonary embolisms induced by adenosine diphosphate (ADP) and decreases recovery time. A comprehensive strategy that combines metabolomics, network pharmacology, molecular docking, and experimental validation has the potential to reveal the antithrombotic mechanisms of Asperosaponin VI. Metabolomic evidence suggests that Asperosaponin VI may influence platelet aggregation and the production of anti-inflammatory metabolites through the regulation of pathways such as phenylalanine and arachidonic acid metabolism, thereby inhibiting thrombosis. Network pharmacology identified the pharmacological targets of Asperosaponin VI and indicated that it treats thrombi by partially regulating the signaling pathways related to inflammation and platelet aggregation. Asperosaponin VI showed strong binding affinity for F2, PTPRC, JUN, STAT3, SRC, AKT1. The antiplatelet aggregation activity of Asperosaponin VI was validated based on the metabolomic and network pharmacology results. Asperosaponin VI inhibits platelet aggregation induced by ADP, AA, and collagen. Therefore, Asperosaponin VI exerts antithrombotic effects through antiplatelet aggregation. Therefore, Asperosaponin VI is a promising antithrombotic agent.

Spatio-temporal layers based intra-operative stereo depth estimation network via hierarchical prediction and progressive training.

BACKGROUND AND OBJECTIVE: Safety of robotic surgery can be enhanced through augmented vision or artificial constraints to the robotl motion, and intra-operative depth estimation is the cornerstone of these applications because it provides precise position information of surgical scenes in 3D space. High-quality depth estimation of endoscopic scenes has been a valuable issue, and the development of deep learning provides more possibility and potential to address this issue. METHODS: In this paper, a deep learning-based approach is proposed to recover 3D information of intra-operative scenes. To this aim, a fully 3D encoder-decoder network integrating spatio-temporal layers is designed, and it adopts hierarchical prediction and progressive learning to enhance prediction accuracy and shorten training time. RESULTS: Our network gets the depth estimation accuracy of MAE 2.55±1.51 (mm) and RMSE 5.23±1.40 (mm) using 8 surgical videos with a resolution of 1280×1024, which performs better compared with six other state-of-the-art methods that were trained on the same data. CONCLUSIONS: Our network can implement a promising depth estimation performance in intra-operative scenes using stereo images, allowing the integration in robot-assisted surgery to enhance safety.

Plant hypersensitive induced reaction protein facilitates cell death induced by secreted xylanase associated with the pathogenicity of Sclerotinia sclerotiorum.

Necrotrophic fungal plant pathogens employ cell death-inducing proteins (CDIPs) to facilitate infection. However, the specific CDIPs and their mechanisms in pathogenic processes of Sclerotinia sclerotiorum, a necrotrophic pathogen that causes disease in many economically important crop species, have not yet been clearly defined. This study found that S. sclerotiorum secretes SsXyl2, a glycosyl hydrolase family 11 xylanase, at the late stage of hyphal infection. SsXyl2 targets the apoplast of host plants to induce cell death independent of xylanase activity. Targeted disruption of SsXyl2 leads to serious impairment of virulence, which can be recovered by a catalytically impaired SsXyl2 variant, thus supporting the critical role of cell death-inducing activity of SsXyl2 in establishing successful colonization of S. sclerotiorum. Remarkably, infection by S. sclerotiorum induces the accumulation of Nicotiana benthamiana hypersensitive-induced reaction protein 2 (NbHIR2). NbHIR2 interacts with SsXyl2 at the plasma membrane and promotes its localization to the cell membrane and cell death-inducing activity. Furthermore, gene-edited mutants of NbHIR2 displayed increased resistance to the wild-type strain of S. sclerotiorum, but not to the SsXyl2-deletion strain. Hence, SsXyl2 acts as a CDIP that manipulates host cell physiology by interacting with hypersensitive induced reaction protein to facilitate colonization by S. sclerotiorum. These findings provide valuable insights into the pathogenic mechanisms of CDIPs in necrotrophic pathogens and lead to a more promising approach for breeding resistant crops against S. sclerotiorum.

Multi-nodes dissemination of stable radio frequency with 10-17 instability over 2000 km optical fiber.

To meet the demand of flexible access for high-precision synchronization frequency, we demonstrate multi-node stable radio frequency (RF) dissemination over a long-distance optical fiber. Stable radio frequency signals can be extracted at any node along the optical fiber, not just at the endpoint. The differential mixing structure (DMS) is employed to avoid the frequency harmonic leakage and enhance the precision. The phase-locked loop (PLL) provides frequency reference for the DMS while improving the signal to noise ratio (SNR) of dissemination signal. We measure the frequency instability of multi-node stable frequency dissemination system (MFDS) at different locations along the 2,000 km optical fiber. The measured short-term instability with average time of 1 s are 1.90 × 10-14 @ 500 km, 2.81 × 10-14 @ 1,000 km, 3.46 × 10-14 @ 1,500 km, and 3.84 × 10-14 @ 2,000 km respectively. The long-term instability with average time of 10,000 s are basically the same at any position of the optical fiber, which is about (6.24 ± 0.05) × 10-17. The resulting instability is sufficient for the propagation of precision active hydrogen masers.

FRSR: Framework for real-time scene reconstruction in robot-assisted minimally invasive surgery.

3D reconstruction of the intra-operative scenes provides precise position information which is the foundation of various safety related applications in robot-assisted surgery, such as augmented reality. Herein, a framework integrated into a known surgical system is proposed to enhance the safety of robotic surgery. In this paper, we present a scene reconstruction framework to restore the 3D information of the surgical site in real time. In particular, a lightweight encoder-decoder network is designed to perform disparity estimation, which is the key component of the scene reconstruction framework. The stereo endoscope of da Vinci Research Kit (dVRK) is adopted to explore the feasibility of the proposed approach, and it provides the possibility for the migration to other Robot Operating System (ROS) based robot platforms due to the strong independence on hardware. The framework is evaluated using three different scenarios, including a public dataset (3018 pairs of endoscopic images), the scene from the dVRK endoscope in our lab as well as a self-made clinical dataset captured from an oncology hospital. Experimental results show that the proposed framework can reconstruct 3D surgical scenes in real time (25 FPS), and achieve high accuracy (2.69 ± 1.48 mm in MAE, 5.47 ± 1.34 mm in RMSE and 0.41 ± 0.23 in SRE, respectively). It demonstrates that our framework can reconstruct intra-operative scenes with high reliability of both accuracy and speed, and the validation of clinical data also shows its potential in surgery. This work enhances the state of art in 3D intra-operative scene reconstruction based on medical robot platforms. The clinical dataset has been released to promote the development of scene reconstruction in the medical image community.

Enantioselective Nickel-Catalyzed Hydrosilylation of 1,1-Disubstituted Allenes.

Here, we report the first example of Ni-catalyzed asymmetric hydrosilylation of 1,1-disubstituted allenes with high level of regioselectivities and enantioselectivities. The key to achieve this stereoselective hydrosilylation reaction was the development of the SPSiOL-derived bisphosphite ligands (SPSiPO). This protocol features broad substrate scope, excellent functional group, and heterocycle tolerance, thus provides a versatile method for the construction of enantioenriched tertiary allylsilanes in a straightforward and atom-economic manner. DFT calculations were performed to reveal the reaction mechanism and the origins of the enantioselectivity.

Encoding Deep Residual Features into Fisher Vector for Skin Lesion Classification.

Computer-aided skin lesion classification using dermoscopy is essential for early detection of melanoma, which is the most effective means to reduce the mortality rate. Although many deep learning models have been designed for this task, skin lesion classification remains challenging due to the small sample size, inter-class similarity, intra-class inconsistency, and class imbalance. In this paper, we propose a hybrid deep residual network and Fisher vector (ResNet-FV) algorithm for skin lesion classification, aiming to boost the performances of ResNet using the Fisher vector encoding scheme. The proposed algorithm has been evaluated on the 2018 Skin Lesion Analysis Towards Melanoma Detection Challenge (ISIC-skin 2018) dataset and achieved a balanced multi-class accuracy of 0.798, outperforming several existing solutions. Clinical relevance- We propose a computer-aided diagnosis algorithm called ResNet-FV which achieves superior performance when comparing to several existing solutions and hence has the potential to be applied to large-scale skin cancer screening.

Robot-assisted ex vivo neobladder reconstruction: preliminary results of surgical skill evaluation.

PURPOSE: Advanced developments in the medical field have gradually increased the public demand for surgical skill evaluation. However, this assessment always depends on the direct observation of experienced surgeons, which is time-consuming and variable. The introduction of robot-assisted surgery provides a new possibility for this evaluation paradigm. This paper aims at evaluating surgeon performance automatically with novel evaluation metrics based on different surgical data. METHODS: Urologists ([Formula: see text]) from a hospital were requested to perform a simplified neobladder reconstruction on an ex vivo setup twice with different camera modalities ([Formula: see text]) randomly. They were divided into novices and experts ([Formula: see text], respectively) according to their experience in robot-assisted surgeries. Different performance metrics ([Formula: see text]) are proposed to achieve the surgical skill evaluation, considering both instruments and endoscope. Also, nonparametric tests are adopted to check if there are significant differences when evaluating surgeons performance. RESULTS: When grouping according to four stages of neobladder reconstruction, statistically significant differences can be appreciated in phase 1 ([Formula: see text]) and phase 2 ([Formula: see text]) with normalized time-related metrics and camera movement-related metrics, respectively. On the other hand, considering experience grouping shows that both metrics are able to highlight statistically significant differences between novice and expert performances in the control protocol. It also shows that the camera-related performance of experts is significantly different ([Formula: see text]) when handling the endoscope manually and when it is automatic. CONCLUSION: Surgical skill evaluation, using the approach in this paper, can effectively measure surgical procedures of surgeons with different experience. Preliminary results demonstrate that different surgical data can be fully utilized to improve the reliability of surgical evaluation. It also demonstrates its versatility and potential in the quantitative assessment of various surgical operations.

Shift-channel attention and weighted-region loss function for liver and dense tumor segmentation.

PURPOSE: To assist physicians in the diagnosis and treatment planning of tumor, a robust and automatic liver and tumor segmentation method is highly demanded in the clinical practice. Recently, numerous researchers have improved the segmentation accuracy of liver and tumor by introducing multiscale contextual information and attention mechanism. However, this tends to introduce more training parameters and suffer from a heavier computational burden. In addition, the tumor has various sizes, shapes, locations, and numbers, which is the main reason for the poor accuracy of automatic segmentation. Although current loss functions can improve the learning ability of the model for hard samples to a certain extent, these loss functions are difficult to optimize the segmentation effect of small tumor regions when the large tumor regions in the sample are in the majority. METHODS: We propose a Liver and Tumor Segmentation Network (LiTS-Net) framework. First, the Shift-Channel Attention Module (S-CAM) is designed to model the feature interdependencies in adjacent channels and does not require additional training parameters. Second, the Weighted-Region (WR) loss function is proposed to emphasize the weight of small tumors in dense tumor regions and reduce the weight of easily segmented samples. Moreover, the Multiple 3D Inception Encoder Units (MEU) is adopted to capture the multiscale contextual information for better segmentation of liver and tumor. RESULTS: Efficacy of the LiTS-Net is demonstrated through the public dataset of MICCAI 2017 Liver Tumor Segmentation (LiTS) challenge, with Dice per case of 96.9 % ${\bf \%}$ and 75.1 % ${\bf \%}$ , respectively. For the 3D Image Reconstruction for Comparison of Algorithm and DataBase (3Dircadb), Dices are 96.47 % ${\bf \%}$ for the liver and 74.54 % ${\bf \%}$ for tumor segmentation. The proposed LiTS-Net outperforms existing state-of-the-art networks. CONCLUSIONS: We demonstrated the effectiveness of LiTS-Net and its core components for liver and tumor segmentation. The S-CAM is designed to model the feature interdependencies in the adjacent channels, which is characterized by no need to add additional training parameters. Meanwhile, we conduct an in-depth study of the feature shift proportion of adjacent channels to determine the optimal shift proportion. In addition, the WR loss function can implicitly learn the weights among regions without the need to manually specify the weights. In dense tumor segmentation tasks, WR aims to enhance the weights of small tumor regions and alleviate the problem that small tumor segmentation is difficult to optimize further when large tumor regions occupy the majority. Last but not least, our proposed method outperforms other state-of-the-art methods on both the LiTS dataset and the 3Dircadb dataset.

OLFM4 deficiency delays the progression of colitis to colorectal cancer by abrogating PMN-MDSCs recruitment.

Chronic inflammatory bowel disease (IBD) is strongly associated with the development of colitis-associated tumorigenesis (CAT). Despite recent advances in the understanding of polymorphonuclear myeloid-derived suppressor cell (PMN-MDSC) responses in cancer, the mechanisms of these cells during this process remain largely uncharacterized. Here, we discovered a glycoprotein, olfactomedin-4 (OLFM4), was highly expressed in PMN-MDSCs from colitis to colorectal cancer (CRC), and its expression level and PMN-MDSC population positively correlated with the progression of IBD to CRC. Moreover, mice lacking OLFM4 in myeloid cells showed poor recruitment of PMN-MDSCs, impaired intestinal homeostasis, and delayed development from IBD to CRC, and increased response to anti-PD1 therapy. The main mechanism of OLFM4-mediated PMN-MDSC activity involved the NF-κB/PTGS2 pathway, through the binding of LGALS3, a galactoside-binding protein expressed on PMN-MDSCs. Our results showed that the OLFM4/NF-κB/PTGS2 pathway promoted PMN-MDSC recruitment, which played an essential role in the maintenance of intestinal homeostasis, but showed resistance to anti-PD1 therapy in CRC.

Heat shock protein A12A activates migration of hepatocellular carcinoma cells in a monocarboxylate transporter 4-dependent manner.

Metastasis is responsible for most of the hepatocellular carcinoma (HCC)-associated death. However, its underlying mechanism has yet to be fully elucidated. Glycolysis-derived lactate has been shown to be a powerful regulator of cancer metastasis. Heat shock protein A12A (HSPA12A) encodes a novel member of HSP70 family. We have recently demonstrated that heat shock protein A12A (HSPA12A) inhibited renal cancer cell migration by suppressing lactate output and glycolytic activity, which were mediated by unstabilizing CD147 and promoting its degradation. By striking contrast, here we demonstrated that HSPA12A promoted migration of human HCC cells. Extracellular acidification, lactate export, and glycolytic activity in HCC cells were also promoted following HSPA12A overexpression. Further analysis revealed that HSPA12A interacted with MCT4 and increased its membrane localization, thereby promoting export of lactate generated from glycolysis; this led, ultimately, to HCC cell migration. Our results revealed the opposite effect of HSPA12A on migration of renal cancer cells and that of HCC cells. Of note, in contrast to the inhibitory effect on CD147 expression in renal cancer cells, we found that HSPA12A increased CD147 expression in HCC cells, indicating that the expression of CD147 might exist heterogeneity in different cancer cell types. Taken together, we identified HSPA12A as an activator of HCC migration, a role opposite to that of renal cancer cells. Inhibiting HSPA12A might be a potential therapeutic intervention for HCC metastasis.

Activity and Safety of Tegafur, Gimeracil, and Oteracil Potassium for Nasopharyngeal Carcinoma: A Systematic Review and Meta-Analysis.

In clinical practice, tegafur, gimeracil, and oteracil potassium (S-1) therapy is commonly administered to treat nasopharyngeal carcinoma (NPC). However, its efficacy and safety remain controversial in both randomized controlled trials (RCTs) and non-RCTs. We aimed to evaluate the efficacy and safety of S-1 treatment for NPC. We searched PubMed, Ovid, EMBASE, the Cochrane Library, China National Knowledge Infrastructure, Wanfang Database, and VIP databases for RCTs of chemotherapy with or without S-1 for NPC, from 2001 to 2020. A meta-analysis was performed using RevMan5.3 and Stata15. Randomized controlled trials published in journals were included irrespective of blinding and language used. Patients were diagnosed with NPC through a clinicopathological examination; patients of all cancer stages and ages were included. Overall, 25 trials and 1858 patients were included. There were significant differences in the complete remission (OR = 2.42, 95% CI (1.88-3.10), P < 0.05) and overall response rate (OR = 2.68, 95% CI (2.08-3.45), P < 0.05) between the S-1 and non-S-1 groups. However, there was no significant difference in partial remission (OR = 1.10, 95% CI (0.87-1.39), P=0.42) and seven adverse reactions (leukopenia, thrombocytopenia, nausea and vomiting, diarrhea, dermatitis, oral mucositis, and anemia) between the S-1 and non-S-1 groups. Additionally, statistical analyses with six subgroups were performed. S-1 was found to be a satisfactory chemotherapeutic agent combined with radiotherapy, intravenous chemotherapy, or chemoradiotherapy for NPC. As an oral medicine, the adverse reactions of S-1, especially gastrointestinal reactions, can be tolerated by patients, thereby optimizing their quality of life. S-1 may be a better choice for the treatment of NPC. This trial is registered with CRD42019122041.

Safety application of muscle relaxants and the traditional low-frequency ventilation during the flexible or rigid bronchoscopy in patients with central airway obstruction: a retrospective observational study.

BACKGROUND: Bronchoscopy treatments of central airway obstruction (CAO) under general anesthesia are high-risky procedures, and posing a giant challenge to the anesthesiologists. We summarized and analyzed our clinical experience in patients with CAO undergoing flexible or rigid bronchoscopy, to estimate the safety of skeletal muscle relaxants application and the traditional Low-frequency ventilation. METHODS: Clinical data of 375 patients with CAO who underwent urgent endoscopic treatments in general anesthesia from January 2016 to October 2019 were retrospectively reviewed. The use ratio of skeletal muscle relaxants, dose of skeletal muscle relaxants used, the incidence of perioperative adverse events, adequacy of ventilation and gas exchange, post-operative recovery between rigid bronchoscopy and flexible bronchoscopy therapy, and risk factors for postoperative ICU admission were evaluated. RESULTS: Of the 375 patients with CAO, 204 patients were treated with flexible bronchoscopy and 171 patients were treated with rigid bronchoscopy. Muscle relaxants were used in 362 of 375 patients (including 313 cisatracurium, 45 rocuronium, 4 atracurium, and 13 unrecorded). The usage rate of muscle relaxants (96.5% in total) was very high in patients with CAO who underwent either flexible bronchoscopy (96.6%) or rigid bronchoscopy (96.5%) therapy. The dosage of skeletal muscle relaxants (Cisatracium) used was higher in rigid bronchoscopy compared with flexible bronchoscopy therapy (10.8 ± 3.8 VS 11.6 ± 3.6 mg, respectively, p < 0.05). No patient suffered the failure of ventilation, bronchospasm and intraoperative cough either in flexible or rigid bronchoscopy therapy. Hypoxemia was occurred in 13 patients (8 in flexible, 5 in rigid bronchoscopy) during the procedure, and reintubation after extubation happened in 2 patients with flexible bronchoscopy. Sufficient ventilation was successfully established using the traditional Low-frequency ventilation with no significant carbon dioxide accumulation and hypoxemia occurred both in flexible and rigid bronchoscopy group (p > 0.05). Three patients (1 in flexible and 2 in rigid) died, during the post-operative recovery, and the higher grade of American Society of Anesthesiologists (ASA) and obvious dyspnea or orthopnea were the independent risk factors for postoperative ICU admission. CONCLUSION: The muscle relaxants and low-frequency traditional ventilation can be safely used both in flexible and rigid bronchoscopy treatments in patients with CAO. These results may provide strong clinical evidence for optimizing the anesthesia management of bronchoscopy for these patients.

Water redispersion and cytotoxicity of reducing end-modified cellulose nanocrystals by grafting long-chain poly(ethylene oxide).

As an ageless "nano-element" in trees, plants and other cellulose-containing species, cellulose nanocrystal (CNC) has been widely used as a renewable building block in diverse applications. Traditional modification strategy of CNC is based on the reaction with its surface hydroxyl groups, suffering the change of its surface physiochemical properties. In this study, a regio-selective and local modification strategy was performed on the reducing end of CNC with the grafting of long-chain poly(ethylene oxide) (PEO) to produce the end-grafted nanocrystals (CNC-eg-PEO). Based on thiol-ene click reaction, the terminal allyl-PEO was covalently attached on the modified nanocrystal possessing the reactive thiol groups. With the preservation of surface chemistry, the redispsersion stability of CNC-eg-PEO was promoted, attributed to the dual effect of steric stabilization and electrostatic repulsion. Furthermore, the CNC-eg-PEO exhibited the low cytotoxicity to ATCC cell lines HFF and CAL-27, indicating its promising biomedical application.

Discovery of novel liver X receptor inverse agonists as lipogenesis inhibitors.

Based on the co-crystal structures of LXRß and its agonists (spiro [pyrrolidine-3,3'-oxindole] derivatives) discovered by us previously, we designed and synthesized a compound library to explore the agonistic activities. The library was screened with luciferase reporter assays, interestingly, it resulted in the discovery of 10 LXR inverse agonists besides 5 LXR agonists. To clarify the mechanism of the actions, we conducted molecular dynamics (MD) simulations on the LXR and inverse agonists complexes, and revealed that H3, H11 and H12 configurations are the key to turn on agonism or inverse agonism status for LXR. Binding tightly with H3, pushing H11 out and destabilizing H12 could form a bigger hydrophobic groove to accommodate NCOR1 to turn on LXR inverse agonism. The inverse agonist 10rr was further studied, and found as a lipogenesis inhibitor through down-regulating LXR target genes SREBP-1c, ACC, FAS and SCD-1, and demonstrated lipid-lowering effects in 3T3-L1 cells, HepG2 cells and mice with Triton WR-1339-induced hyperlipidemia. Therefore, we have proved that LXR inverse agonists can be promising agents for hyperlipidemia treatment.

Discovery of new LXRß agonists as glioblastoma inhibitors.

Discovery and optimization of selective liver X receptor ß (LXRß) agonists are challenging due to the high homology of LXRα and LXRß in the ligand-binding domain. There is only one different residue (Val versus Ile) at the ligand-binding pocket of LXRs. With machine learning methods, we identified pan LXR agonists with a novel scaffold (spiro[pyrrolidine-3,3'-oxindole]). Then, we figured out the mechanism of LXR isoform selectivity from co-crystal structures. Based on the mechanism and the new scaffold, LXRß selective agonists were designed and synthesized. This led to the discovery of LXRß agonists 4-7rr, 4-13 and 4-13rr with IC50 values ranging from 1.78 to 6.36 µM against glioblastoma in vitro. Treatment with 50 mg/kg/day of 4-13 for 15 days significantly reduced tumor growth using an in vivo xenograft glioblastoma model.