Surface-based multimodal protein-ligand binding affinity prediction.

MOTIVATION: In the field of drug discovery, accurately and effectively predicting the binding affinity between proteins and ligands is crucial for drug screening and optimization. However, current research primarily utilizes representations based on sequence or structure to predict protein-ligand binding affinity, with relatively less study on protein surface information, which is crucial for protein-ligand interactions. Moreover, when dealing with multimodal information of proteins, traditional approaches typically concatenate features from different modalities in a straightforward manner without considering the heterogeneity among them, which results in an inability to effectively exploit the complementary between modalities. RESULTS: We introduce a novel multimodal feature extraction (MFE) framework that, for the first time, incorporates information from protein surfaces, 3D structures, and sequences, and uses cross-attention mechanism for feature alignment between different modalities. Experimental results show that our method achieves state-of-the-art performance in predicting protein-ligand binding affinity. Furthermore, we conduct ablation studies that demonstrate the effectiveness and necessity of protein surface information and multimodal feature alignment within the framework. AVAILABILITY AND IMPLEMENTATION: The source code and data are available at https://github.com/Sultans0fSwing/MFE.

Discovery of Novel 1-Phenylpiperidine Urea-Containing Derivatives Inhibiting ß-Catenin/BCL9 Interaction and Exerting Antitumor Efficacy through the Activation of Antigen Presentation of cDC1 Cells.

Aberrant activation of the Wnt/ß-catenin signaling is associated with tumor development, and blocking ß-catenin/BCL9 is a novel strategy for oncogenic Wnt/ß-catenin signaling. Herein, we presented two novel ß-catenin variations and exposed conformational dynamics in several ß-catenin crystal structures at the BCL9 binding site. Furthermore, we identified a class of novel urea-containing compounds targeting ß-catenin/BCL9 interaction. Notably, the binding modalities of inhibitors were greatly affected by the conformational dynamics of ß-catenin. Among them, 28 had a strong affinity for ß-catenin (Kd = 82 nM), the most potent inhibitor reported. In addition, 13 and 35 not only activate T cells but also promote the antigen presentation of cDC1, showing robust antitumor efficacy in the CT26 model. Collectively, our study demonstrated a series of potent small-molecule inhibitors targeting ß-catenin/BCL9, which can enhance antigen presentation and activate cDC1 cells, delivering a potential strategy for boosting innate and adaptive immunity to overcome immunotherapy resistance.

Assembled pH-Responsive Gastric Drug Delivery Systems Based on 3D-Printed Shells.

Gastric acid secretion is closely associated with the development and treatment of chronic gastritis, gastric ulcers, and reflux esophagitis. However, gastric acid secretion is affected by complex physiological and pathological factors, and real-time detection and control are complicated and expensive. A gastric delivery system for antacids and therapeutics in response to low pH in the stomach holds promise for smart and personalized treatment of stomach diseases. In this study, pH-responsive modular units were used to assemble various modular devices for self-regulation of pH and drug delivery to the stomach. The modular unit with a release window of 50 mm2 could respond to pH and self-regulate within 10 min, which is related to its downward floatation and internal gas production. The assembled devices could stably float downward in the medium and detach sequentially at specific times. The assembled devices loaded with antacids exhibited smart pH self-regulation under complex physiological and pathological conditions. In addition, the assembled devices loaded with antacids and acid suppressors could multi-pulse or prolong drug release after rapid neutralization of gastric acid. Compared with traditional coating technology, 3D printing can print the shell layer by layer, flexibly adjust the internal and external structure and composition, and assemble it into a multi-level drug release system. Compared with traditional coating, 3D-printed shells have the advantage of the flexible adjustment of internal and external structure and composition, and are easy to assemble into a complex drug delivery system. This provides a universal and flexible strategy for the personalized treatment of diseases with abnormal gastric acid secretion, especially for delivering acid-unstable drugs.

MoleMCL: a multi-level contrastive learning framework for molecular pre-training.

MOTIVATION: Molecular representation learning plays an indispensable role in crucial tasks such as property prediction and drug design. Despite the notable achievements of molecular pre-training models, current methods often fail to capture both the structural and feature semantics of molecular graphs. Moreover, while graph contrastive learning has unveiled new prospects, existing augmentation techniques often struggle to retain their core semantics. To overcome these limitations, we propose a gradient-compensated encoder parameter perturbation approach, ensuring efficient and stable feature augmentation. By merging enhancement strategies grounded in attribute masking and parameter perturbation, we introduce MoleMCL, a new MOLEcular pre-training model based on multi-level contrastive learning. RESULTS: Experimental results demonstrate that MoleMCL adeptly dissects the structure and feature semantics of molecular graphs, surpassing current state-of-the-art models in molecular prediction tasks, paving a novel avenue for molecular modeling. AVAILABILITY AND IMPLEMENTATION: The code and data underlying this work are available in GitHub at https://github.com/BioSequenceAnalysis/MoleMCL.

A bowl-shaped phosphangulene-protected cubic Cu58 nanocluster.

A bowl-shaped phosphangulene-protected cubic Cu58 nanocluster has been synthesized. The structure was determined by X-ray crystallography and further analyzed by multiple techniques. The phosphangulenes not only enable ligand substitutions with triphenylphosphines in a cluster-to-cluster transformation way, but also facilitate inter-cluster interactions with fullerenes. These interactions further influence the entirety's photocurrent response and ability to liberate hydrogen when stimulated by light.

Polariton Microfluidics for Nonreciprocal Dragging and Reconfigurable Shaping of Polaritons.

Dielectric environment engineering is an efficient and general approach to manipulating polaritons. Liquids serving as the surrounding media of polaritons have been used to shift polariton dispersions and tailor polariton wavefronts. However, those liquid-based methods have so far been limited to their static states, not fully unleashing the promise offered by the mobility of liquids. Here, we propose a microfluidic strategy for polariton manipulation by merging polaritonics with microfluidics. The diffusion of fluids causes gradient refractive indices over microchannels, which breaks the symmetry of polariton dispersions and realizes the microfluidic analogue to nonreciprocal polariton dragging. Based on polariton microfluidics, we also designed a set of on-chip polaritonic elements to actively shape polaritons, including planar lenses, off-axis lenses, Janus lenses, bends, and splitters. Our strategy expands the toolkit for the manipulation of polaritons at the subwavelength scale and possesses potential in the fields of polariton biochemistry and molecular sensing.

Design, synthesis, and biological evaluation of novel 8-substituted quercetin derivatives targeting the ß­catenin/B-cell lymphoma 9 interaction.

The ß-catenin/B-cell lymphoma 9 (BCL9) protein-protein interaction (PPI) is a potential target for aberrantly active Wnt/ß-catenin signaling which actively participates in initiating and progressing of many cancers. Herein, we discovered novel 8-substituted quercetin derivatives with potential inhibitory activities targeting ß-catenin/BCL9 PPI. Among all the derivatives, compound B4 displayed the most promising PPI inhibitory activity with an IC50 value of 2.25 µM in a competitive fluorescence polarization assay and a KD value of 1.44 µM for the ß-catenin protein. Furthermore, B4 selectively inhibited the growth of colorectal cancer (CRC) cells, suppressed the transactivation of Wnt signaling, and downregulated the expression of oncogenic Wnt target gene. Especially, B4 showed potent anti-CRC activity in vivo with the tumor growth inhibition (TGI) of 75.99 % and regulated the tumor immune microenvironment.

Superscattering of water waves.

Inspired by the concept of superscattering in optics, we for the first time theoretically predict and experimentally demonstrate the superscattering phenomenon in water waves. The subwavelength superscatterer is constructed by multi-layered concentric cylinders with an inhomogeneous depth profile. The superscatterer breaks the long-held single-channel scattering limit by several times and thus significantly enhances the total scattering strength. The underlying mechanism originates from the near degeneracy of the resonances of multiple channels. We fabricate the superscatterer prototype and experimentally measure the near-field patterns, which are consistent with theoretical prediction and numerical simulation. Our study opens a new avenue to strengthen water-wave scattering and deepen the understanding in water waves, which can be useful for ocean energy harvesting and harbor protection.

Application and evaluation of fused deposition modeling technique in customized medical products.

The fused deposition modeling (FDM) technique has enormous potential for developing customized medical products with complicated structures. In this study, the application of the FDM technique to three medical products was investigated, and the risk factors affecting product quality were evaluated. For FDM-printed matrix and reservoir preparations, special attention should be paid to spacing width reduction and layered coating thickness. Therefore, spacing printing fidelity and interlayer bonding strength was established as unique indexes to characterize the effectiveness and safety of FDM-printed medicine. For FDM-printed orthopedic implants, layer height affected the dimensional deviation of surface morphology, which could be digitally evaluated. Moreover, internal structure affected the biomechanical behavior, which could be investigated using in silico simulation. The results reveal the broad application of FDM technology in customized medical products and might help to establish scientific and reasonable evaluation systems for them.

The antitumor effect of mycelia extract of the medicinal macrofungus Inonotus hispidus on HeLa cells via the mitochondrial-mediated pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Inonotus hispidus (I. hispidus), known as shaggy bracket, has been used extensively in China and some East Asian countries as a traditional medicinal macrofungus to treat difficult diseases, such as diabetes, gout, and arthritis. Modern pharmacological research has shown that I. hispidus has an important application value in antitumor treatment. However, the main anti-cervical cancer activity substances from its mycelia and its mechanisms are still not clear. AIMS OF THE STUDY: To enrich the germplasm resources of I. hispidus, to reveal the antitumor activity of the extract from the mycelium of I. hispidus against cervical cancer, and to preliminarily analyze its action mechanism. MATERIALS AND METHODS: The SH3 strain was isolated from wild fruiting bodies and identified by morphology and molecular biology. The antitumor active component from the mycelium of I. hispidus was isolated and identified with liquid chromatography-tandem mass spectrometry. The cell viability was assessed by MTT assay. The cell cycle distribution, apoptotic cell detection, and mitochondrial membrane potential were detected by flow cytometer. The expression of apoptosis-related proteins was assessed by Western blotting. The inhibition of tumor growth in vivo was assessed by a mouse xenograft model. RESULTS: The SH3 strain was isolated and identified as a new strain of I. hispidus. The antitumor active component containing cyclic peptides from the mycelium of I. hispidus (CCM) was isolated for the first time. In addition, we found that CCM had a strong inhibitory effect on HeLa proliferation in vitro and in vivo. Mechanically, the CCM blocked the cell cycle at the G0/G1 phase, decreased the mitochondrial membrane potential, and eventually promoted apoptosis of HeLa cells through the mitochondria-mediated pathway by upregulating the expression levels of Bax, cytochrome C, cleaved caspase-9, and cleaved caspase-3 and downregulating the expression level of Bcl-2. CONCLUSIONS: Our study not only enriches the strain resources of I. hispidus but also confirms that the mycelium of this strain has active components that can inhibit cervical cancer. This is highly significant for the development of active drugs and drug lead molecules for treating cervical cancer.

[The In Vivo Intervention and Relative Mechanism of Genistein on the Inflammation and Thrombophilia in Lymphoma-Bearing Mice].

OBJECTIVE: To investigate the in vivo intervention and relative mechanism of Genistein (GEN) on tumor-associated inflammatory and tumor thrombophilia in lymphoma-bearing mice. METHODS: Forty female Balb/c mice aged 5-6 weeks were injected with murine-derived Pro B-cell lymphoma cell line 38B9 to establish a lymphoma mouse model, which was randomly divided into control group, tumor-bearing group, GEN drug intervention group and cyclophosphamide (CTX）drug intervention group. Histopathologic was used to evaluate the tumorigenesis. Tumor formation was observed, and tumor tissues were collected of HE and immunohistochemical staining. ELISA and flow cytometry were used to detect the expression of inflammatory factors and the changes of thrombus indices in plasma after intervention of GEN and Cyclophosphamide (CTX) respectively. Immunohistochemistry method was used to detect the expression of CD19 in tomor tissues of tummor bearing mice. RESULTS: After 14 days of tumor bearing, the mice were tumorigenic. The lymphoma cells were diffusely distributed in the tumor tissue and the expression of CD19 in the tumor tissue was positive. The inflammatory factors such as IL-6, NETs and CLEC-2, and thrombotic indices such as TF, FIB and D-D in lymphoma-bearing mice were significantly higher than those before tumor-injection and lower than those after drug-intervention (all P<0.05). The levels of CLEC-2 and D-D in GEN group were significantly lower than those in CTX group (P<0.05). CONCLUSION: Tumor-associated inflammation and thrombophilia exist in lymphoma-bearing mice. GEN shows better anti-inflammatory and anti-thrombotic effects compared with CTX by interfering with tumor inflammatory factors.

Discovery of Novel 3-Phenylpiperidine Derivatives Targeting the ß-Catenin/B-Cell Lymphoma 9 Interaction as a Single Agent and in Combination with the Anti-PD-1 Antibody for the Treatment of Colorectal Cancer.

Direct disruption of the ß-catenin/B-cell lymphoma 9 (BCL9) protein-protein interaction (PPI) is a potential strategy for colorectal cancer (CRC) treatment through inhibiting oncogenic Wnt activity. Herein, a series of 3-phenylpiperidine derivatives were synthesized and evaluated as ß-catenin/BCL9 PPI inhibitors. Among them, compound 41 showed the best IC50 (0.72 µM) in a competitive fluorescence polarization assay and a KD value of 0.26 µM for the ß-catenin protein. This compound selectively inhibited the growth of CRC cells, suppressed Wnt signaling transactivation, and downregulated oncogenic Wnt target gene expression. In vivo, 41 showed potent anti-CRC activity and promoted the infiltration and function of cytotoxic T lymphocytes while decreasing the infiltration of regulatory T-cells (Tregs). Furthermore, the combination of 41 and the anti-PD-1 antibody (Ab) efficiently enhanced anti-CRC efficacy, first verifying the in vivo efficacy of the small-molecule ß-catenin/BCL9 PPI inhibitor and anti-PD-1 Ab in combination.

Design, synthesis and biological evaluation of quercetin derivatives as novel ß-catenin/B-cell lymphoma 9 protein-protein interaction inhibitors.

The ß-catenin/B-cell lymphoma 9 (BCL9) protein-protein interaction (PPI) is a potential target for the suppression of hyperactive Wnt/ß-catenin signaling that is vigorously involved in cancer initiation and development. Herein, we first described quercetin and its derivatives had potential inhibitory effects on ß-catenin/BCL9 PPI. The most potent compound, quercetin-3'-O-(4-methylpiperazine-1-yl) propyl (C1), directly binded with ß-catenin and disrupted the ß-catenin/BCL9 interaction in both the protein level and the cellular context. C1 also effectively inhibited colorectal cancer in vitro and showed better selectivity in inhibiting hyperactive Wnt/ß-catenin signaling cells like CT26 and HCT116. And we further confirmed that C1 could inhibit CT26 tumor growth in vivo and regulate the tumor immune microenvironment. This study provides a good chemical probe to explore ß-catenin-related biology and a drug-like quercetin derivative as novel ß-catenin/BCL9 PPI inhibitors for further drug development.

Impact of the COVID-19 kindergarten closure on overweight and obesity among 3- to 7-year-old children.

BACKGROUND: Knowledge on the impact of the temporary kindergarten closure policy under COVID-19 in 2020 on childhood overweight and obesity is inadequate. We aimed to examine differences in rates of overweight and obesity from 2018 to 2021 among kindergarten children aged 3-7 years. METHODS: Overweight was defined as body mass index (BMI) > 1 standard deviation (SD) for age and sex, and obesity was defined as BMI > 2 SD for age and sex. Generalized linear mixed modeling was used for analysis. RESULTS: A total of 44,884 children and 71,216 growth data points from all 57 public kindergartens in Jiading District, Shanghai, China were analyzed. The rates of obesity from 2018 to 2021 were 6.9%, 6.6%, 9.5%, and 7.3% in boys and 2.8%, 2.8%, 4.5%, and 3.1% in girls, respectively. The rates of overweight from 2018 to 2021 were 14.3%, 14.3%, 18.2%, and 15.3% in boys and 10.6%, 10.9%, 13.9%, and 11.6% in girls. The rates of obesity and overweight among kindergarten children in 2020 were significantly higher than those in 2018, 2019, and 2021. Compared to 2020, the odds ratios of the obesity rate in 2018, 2019, and 2021 were 0.67 [95% confidence interval (CI) = 0.58-0.77, P < 0.001], 0.72 (95% CI = 0.64-0.80, P < 0.001) and 0.81 (95% CI = 0.72-0.92, P = 0.001), respectively. The odds ratios of the overweight rate in 2018, 2019, and 2021 were 0.75 (95% CI = 0.69-0.82, P < 0.001), 0.78 (95% CI = 0.72-0.84, P < 0.001), and 0.89 (95% CI = 0.81-0.97, P = 0.008), respectively, compared to 2020. CONCLUSIONS: The rates of overweight and obesity significantly increased among kindergarten children in 2020 after the 5-month kindergarten closure. It was critical to provide guidance to caregivers on fostering a healthy lifestyle for children at home under public health emergencies.

Exploring the role of Hmox1 in ferroptosis and immune infiltration during renal ischemia-reperfusion injury.

Ischemia-reperfusion injury (IRI) is inevitable in kidney transplantations and, as a complex pathophysiological process, it can be greatly impacted by ferroptosis and immune inflammation. Our study aimed to identify the biomarkers of renal IRI (RIRI) and elucidate their relationship with immune infiltration. In this study, the GSE148420 database was used as a training set to analyze differential genes and overlap them with ferroptosis-related genes to identify hub genes using a protein-protein interaction (PPI) network, the least absolute shrinkage and selection operator (LASSO), and random forest algorithm (RFA). We verified the hub gene and ferroptosis-related phenotypes in a verification set and animal experiments involving unilateral IRI with contralateral nephrectomy in rats. Gene set enrichment analysis (GSEA) of single genes was conducted according to the hub gene to predict related endogenous RNAs (ceRNAs) and drugs to establish a network. Finally, we used the Cibersort to analyze immunological infiltration and conducted Spearman's correlation analysis. We identified 5456 differential genes and obtained 26 ferroptosis-related differentially expressed genes. Through PPI, LASSO, and RFA, Hmox1 was identified as the only hub gene and its expression levels were verified using verification sets. In animal experiments, Hmox1 was verified as a key biomarker. GSEA of single genes revealed the seven most related pathways, and the ceRNAs network included 138 mRNAs and miRNAs. We predicted 11 related drugs and their three-dimensional structural maps. Thus, Hmox1 was identified as a key biomarker and regulator of ferroptosis in RIRI and its regulation of ferroptosis was closely related to immune infiltration.

Multifield-Controlled Terahertz Hybrid Metasurface for Switches and Logic Operations.

Terahertz (THz) meta-devices are considered to be a promising framework for constructing integrated photonic circuitry, which is significant for processing the upsurge of data brought about by next-generation telecommunications. However, present active metasurfaces are typically restricted by a single external driving field, a single modulated frequency, fixed switching speed, and deficiency in logical operation functions which prevents devices from further practical applications. Here, to overcome these limitations, we propose a hybrid THz metasurface consisting of vanadium dioxide (VO2) and germanium (Ge) that enables electrical and optical tuning methods individually or simultaneously and theoretically investigate its performance. Each of the two materials is arranged in the meta-atom to dominate the resonance strength of toroidal or magnetic dipoles. Controlled by either or both of the external excitations, the device can switch on or off at four different frequencies, possessing two temporal degrees of freedom in terms of manipulation when considering the nonvolatility of VO2 and ultrafast photogenerated carriers of Ge. Furthermore, the "AND" and "OR" logic operations are respectively achieved at two adjacent frequency bands by weighing normalized transmission amplitude. This work may provide an auspicious paradigm of THz components, such as dynamic filters, multiband switches, and logical modulators, potentially promoting the design and implementation of multifunctional electro-optical devices in future THz computing and communication.

Stealth radome with an ultra-broad transparent window and a high selectivity transition band.

Stealth radome (SR), especially with an ultra-broad and nearly transparent window between two absorption bands, plays a crucial role in stealth techniques, antenna radomes, and so on. However, current devices have the defects of narrow transmission bands, high insertion loss, and wide transition bands between the transmission and absorption bands, which are unfavorable for the stealth of broadband radar and communication systems. In this paper, a novel SR with an ultra-broad and high-efficiency inter-absorption band transparent window is proposed by combining broadband resonance lumped circuits with a multi-layer cascaded frequency-selective surface (FSS). The equivalent circuit model (ECM) and transmission line method (TLM) are provided and analyzed as a guideline for the SR design. The SR consists of a resistive lossy layer loaded with wide passband lumped circuits and two stacked lossless FSS layers to collectively achieve the high selectivity and ultra-broad transmission band. Simulated results indicate that the proposed SR exhibits an ultra-broad passband from 8.2 to 11.2 GHz (31%) with transmission amplitude more than 0.85 and two 90% absorption bands over 6.8-7.8 GHz and 12-13 GHz, and the transition bands at both sides are only 0.4 GHz and 0.8 GHz, respectively. Our findings can stimulate the promising applications of SR in broadband stealth devices with integrated ultra-broad communication capability or in other electromagnetic (EM) compatibility facilities.

Tumor-infiltrated activated B cells suppress liver metastasis of colorectal cancers.

More than 40% of patients with late-stage colorectal cancer (CRC) develop liver metastasis (LM). Which immune cells play important roles in CRC-LM and contribute to the difference between left-sided CRC (LCC) and right-sided CRC (RCC) remain unclear. By single-cell RNA sequencing (scRNA-seq), we not only find that activated B cells are significantly depleted in CRC with LM, but also find a subtype of B cells developed from activated B cells, namely immature plasma cell population alpha (iMPA), highly correlated with metastasis. Mechanistically, inhibition of the Wnt and transforming growth factor ß (TGF-ß) pathways in cancer cell promotes activated B cell migration via the SDF-1-CXCR4 axis. This study reveals that B cell subpopulations in the tumor immune microenvironment (TIME) play a key role in CRC-LM as well as in LCC and RCC. The preventive effects of modulating B cell subpopulations in CRC may provide a rationale for subsequent drug development and CRC-LM management.