Deciphering cell types by integrating scATAC-seq data with genome sequences.

The single-cell assay for transposase-accessible chromatin using sequencing (scATAC-seq) technology provides insight into gene regulation and epigenetic heterogeneity at single-cell resolution, but cell annotation from scATAC-seq remains challenging due to high dimensionality and extreme sparsity within the data. Existing cell annotation methods mostly focus on the cell peak matrix without fully utilizing the underlying genomic sequence. Here we propose a method, SANGO, for accurate single-cell annotation by integrating genome sequences around the accessibility peaks within scATAC data. The genome sequences of peaks are encoded into low-dimensional embeddings, and then iteratively used to reconstruct the peak statistics of cells through a fully connected network. The learned weights are considered as regulatory modes to represent cells, and utilized to align the query cells and the annotated cells in the reference data through a graph transformer network for cell annotations. SANGO was demonstrated to consistently outperform competing methods on 55 paired scATAC-seq datasets across samples, platforms and tissues. SANGO was also shown to be able to detect unknown tumor cells through attention edge weights learned by the graph transformer. Moreover, from the annotated cells, we found cell-type-specific peaks that provide functional insights/biological signals through expression enrichment analysis, cis-regulatory chromatin interaction analysis and motif enrichment analysis.

Anti-DNA antibody-targeted D-peptide nanoparticles ameliorate lupus nephritis in MRL/lpr mice.

Peptide ALW (ALWPPNLHAWVP) targeting anti-dsDNA antibodies has shown promising therapeutic effects in alleviating lupus nephritis, but is potentially limited by poor stability and non-kidney targeting. We recently developed a D-form modified ALW, called D-ALW, which has the capacity to widely inhibit pathogenic polyclonal anti-dsDNA antibody reactions. Further modification of D-ALW using PEG-PLGA nanoparticles to enhance good kidney-targeting ability and extend half-life. Here, we demonstrate that the D-form modified ALW maintains higher binding and inhibition efficiencies and achieves higher stability. Most importantly, D-ALW nanoparticles exhibit excellent kidney-targeting ability and prolong the half-life of the peptides in BALB/c mice. Additionally, compared to D-ALW, D-ALW nanoparticles significantly reduce the glomerular deposition of IgG and C3, improve renal histopathologies, such as glomerular proliferation and inflammatory cells infiltration, and markedly prolong lifespan in MRL/lpr lupus-prone mice. Overall, these results establish that the D-ALW nanoparticles offer synergistic benefits in both safety and efficacy, providing long-term renal preservation and treatment advantages in lupus nephritis.

Semi-wrapped gold nanoparticles for surface-enhanced Raman scattering detection.

Researchers have struggled to develop highly reliable and sensitive surface-enhanced Raman scattering (SERS) substrates for detecting compounds in complicated systems. In this work, a strategy by constructing Au cores with incompletely wrapped Prussian blue (PB) for highly reliable and sensitive SERS substrate is proposed. The wrapped PB layers can provide the internal standard (IS) to calibrate the SERS signal floatation, whereas the exposed surface of Au cores offers the enhancement effect. The balance between the signal self-calibration and enhancement (hence the trade-off between SERS reliability and sensitivity) is obtained by the approximate semi-wrapping configuration of PB layers on Au cores (i.e., SW-Au@PB). The proposed SW-Au@PB nanoparticles (NPs) exhibit the similar enhancement factor as the pristine Au NPs and contribute to the ultralow RSD (8.55%) of calibrated SERS signals using R6G as probe molecules. The simultaneously realized reliability and sensitivity of SW-Au@PB NPs also enables the detection of hazardous pesticide residues such as paraquat and thiram in herbal plants, with the average detection accuracy up to 92%. Overall, this work mainly provides a controllable synthetic strategy for incompletely wrapped NPs, and most importantly, explores the potential with a proof-of-concept practical application in accurate and sensitive Raman detection of hazardous substances with varying solubility.

Identifying spatial domain by adapting transcriptomics with histology through contrastive learning.

Recent advances in spatial transcriptomics have enabled measurements of gene expression at cell/spot resolution meanwhile retaining both the spatial information and the histology images of the tissues. Accurately identifying the spatial domains of spots is a vital step for various downstream tasks in spatial transcriptomics analysis. To remove noises in gene expression, several methods have been developed to combine histopathological images for data analysis of spatial transcriptomics. However, these methods either use the image only for the spatial relations for spots, or individually learn the embeddings of the gene expression and image without fully coupling the information. Here, we propose a novel method ConGI to accurately exploit spatial domains by adapting gene expression with histopathological images through contrastive learning. Specifically, we designed three contrastive loss functions within and between two modalities (the gene expression and image data) to learn the common representations. The learned representations are then used to cluster the spatial domains on both tumor and normal spatial transcriptomics datasets. ConGI was shown to outperform existing methods for the spatial domain identification. In addition, the learned representations have also been shown powerful for various downstream tasks, including trajectory inference, clustering, and visualization.

Conjugation of the Fn14 Ligand to a SMAC Mimetic Selectively Suppresses Experimental Squamous Cell Carcinoma in Mice.

The mimetic of SMAC induced cell death in cancers by depleting the inhibitor of apoptosis proteins. Recent studies showed that Fn14 is overexpressed in the cells of squamous cell carcinoma (SCC), providing a promising candidate target for selective antitumor therapy. In this study, we conjugated a small-molecule SMAC mimetic MV1 to the ligand of Fn14, TWEAK. Our results showed that TWEAK‒MV1 conjugate retained adequate binding specificity to Fn14-positive SCC cells in vitro and accumulated selectively in tumor tissue of cutaneous SCC xenografts mice after intraperitoneal administration. This conjugation compound exhibited remarkable effectiveness in suppressing tumor growth and extending overall survival without causing significant side effects in SCC xenograft mice. Moreover, TWEAK‒MV1 conjugate greatly enhanced both apoptotic and necroptotic cell death both in vitro and in vivo, accompanied by a cellular inhibitor of apoptosis proteins degradation as well as activation of receptor-interacting protein kinase. Taken together, our preclinical data suggested that the designed conjugation compound of TWEAK and MV1 might provide a potential therapeutic strategy for cutaneous SCC with improved antitumor efficacy and negligible toxicity.

Fluorescent noble metal nanoclusters for contaminants analysis in food matrix.

Recently, food safety issues caused by contaminants have aroused great public concern. The development of innovative and efficient sensing techniques for contaminants detection in food matrix is in urgent demand. As fluorescent nanomaterials, noble metal nanoclusters have attracted much attention because of their ease of synthesis, enhanced catalytic activity and biocompatibility, and most importantly, excellent photoluminescence property that provides promising analytical applications. This review comprehensively introduced the synthesis method of noble metal nanoclusters, and summarized the application of metal nanoclusters as fluorescent sensing materials in the detection of pollutants, including pesticides, heavy metal, mycotoxin, food additives, and other contaminants in food. The detection mechanism of pesticide residues mostly relies on the inhibition of natural enzymes. For heavy metals, the detection mechanism is mainly related to the interaction between metal ions and nanoclusters or ligands. It is evidenced that metal nanoclusters have great potential application in the field of food safety monitoring. Moreover, challenges and future trends of nanoclusters were discussed. We hope that this review can provide insights and directions for the application of nanoclusters in contaminants detection.

Prevention and inhibition of nasopharyngeal carcinoma growth by attenuated salmonella SGN1 / 中国药理学通报

Aim To study the inhibitory effect of attenuated salmonella SGN1, overexpressing methioninase, on nasopharyngeal carcinoma (NPC) and the underlying mechanism. Methods The cell proliferation, cell cycle, cell apoptosis, clony formation and migration a-bility of 5-8F, HNE-2, CNE-2 cells were measured u-sing flow cytometry assay, clone formation assay, and wound assay after the methionine restriction treatment. 5-8F, HNE-2, CNE-2 cells were infected with SGN1 at the multiplicity of infection (MOI) of 1: 100 for 5 hours, followed with the measurement of cell growth. A xenograft model was constructed by subcutaneous injection of 5-8F cells in mice to observe the inhibitory effect of SGN1 on nasopharyngeal carcinoma. Results Compared with the control group, methionine restriction significantly inhibited the proliferation, migration ability, and clone formation of nasopharyngeal carcinoma cells and blocked the G

A two-step strategy for simultaneous dual-mode detection of methyl-paraoxon and Ni (â ¡).

Exogenous pollution of Chinese medicinal materials by pesticide residues and heavy metal ions has attracted great attention. Relying on the rapid development of nanotechnology and multidisciplinary fields, fluorescent techniques have been widely applied in contaminant detection and pollution monitoring due to their advantages of simple preparation, low cost, high throughput and others. Most importantly, synchronous detection of multi-targets has always been pursued as one of the major goals in the design of fluorescent probes. Herein, we firstly develop a simultaneous sensing method for methyl-paraoxon (MP) and Nickel ion (Ni, Ⅱ) by using carbon based fluorescent nanocomposite with ratiometric signal readout and nanozyme. Notably, the designed system showed excellent effectiveness even when the two pollutants co-exist. Under the optimum conditions, this method provides low limits of detection of 1.25 µM for methyl-paraoxon and 0.01 µM for Ni (Ⅱ). To further verify the reliability, recovery studies of these two analytes were performed on ginseng radix et rhizoma, nelumbinis semen, and water samples. In addition, smartphone-based visual analysis has been introduced to expand its applicability in point of care detection. This work not only expands the application of the dual-mode approach to pollutant detection, but also provides insights into the analysis of multiple pollutants in a single assay.

A ratiometric fluorescent sensing system for the selective and ultrasensitive detection of pesticide residues via the synergetic effects of copper nanoclusters and carbon quantum dots.

Agricultural products, such as foodstuffs and herbal medicines, may be contaminated by pesticides. Therefore, developing sensitive methods for pesticide detection are urgently needed for the assurance of food safety. In this study, a ratiometric fluorescent sensing system based on blue-emitted nitrogen-doped carbon quantum dots (N-CQDs) and red-emitted copper nanoclusters (CuNCs) complex was fabricated for pesticide detection. The selective detection of thiram and paraquat, two typical widely used pesticides, can be easily realized by changing the solvent environment. The detection limit can be reached as low as 7.49 nM and 3.03 nM, respectively. A good linear correlation was found over the concentration range from 10 to 500 nM for thiram and 5 to 100 nM for paraquat. More interestingly, fast and visual detection of thiram and paraquat can be achieved via smartphone-based colorimetric analysis, which has provided an effective implementation for on-site monitoring of the levels of pesticide residues in food.

Copper ions assisted fluorescent detection of some dithiocarbamates based on nickel nanocluster with aggregation-induced emission enhancement behavior.

Pesticide residue contamination has become an urgent issue since it threatens both the natural environment and public health. In this study, a fluorescent method for detecting dithiocarbamate (DTC) compounds was constructed based on novel nickel nanoclusters (Ni NCs) and copper ions (Cu2+). The water-soluble fluorescent Ni NCs were synthesized for the first time through a one-pot method using glutathione as stabilizer and ascorbic acid as reducing agent. The as-prepared Ni NCs exhibited a maximum fluorescence emission at 445 nm when excited by 380 nm. And they displayed aggregation-induced emission enhancement when ethylene glycol was introduced into the nanocluster aqueous solution. Based on the Ni NCs, a label-free fluorescence quenching sensor was established for sensitive and selective detection of DTC compounds with the assistance of Cu2+. The complex formed by DTC and Cu2+ led to fluorescence quenching of Ni NCs through inner filter effect. The sensing method was successfully applied to two typical DTC compounds, thiram and disulfiram, with good linearity over a wide linear range and a low detection limit. Moreover, the proposed approach was capable of thiram detection in real samples, which confirms the potential of this sensing method as a platform for DTC compound detection.

Synthesis of Copper Nanocluster and Its Application in Pollutant Analysis.

Copper nanoclusters (Cu NCs) with their inherent optical and chemical advantages have gained increasing attention as a kind of novel material that possesses great potential, primarily in the use of contaminants sensing and bio-imaging. With a focus on environmental safety, this article comprehensively reviews the recent advances of Cu NCs in the application of various contaminants, including pesticide residues, heavy metal ions, sulfide ions and nitroaromatics. The common preparation methods and sensing mechanisms are summarized. The typical high-quality sensing probes based on Cu NCs towards various target contaminants are presented; additionally, the challenges and future perspectives in the development and application of Cu NCs in monitoring and analyzing environmental pollutants are discussed.

Conjugated Polymers: Optical Toolbox for Bioimaging and Cancer Therapy.

Conjugated polymers (CPs) are capable of coordinating the electron coupling phenomenon to bestow powerful optoelectronic features. The light-harvesting and light-amplifying properties of CPs are extensively used in figuring out the biomedical issues with special emphasis on accurate diagnosis, effective treatment, and precise theranostics. This review summarizes the recent progress of CP materials in bioimaging, cancer therapeutics, and introduces the design strategies by rationally tuning the optical properties. The recent advances of CPs in bioimaging applications are first summarized and the challenges to clear the future directions of CPs in the respective area are discussed. In the following sections, the focus is on the burgeoning applications of CPs in phototherapy of the tumor, and illustrates the underlying photo-transforming mechanism for further molecular designing. Besides, the recent progress in the CPs-assistant drug therapy, mainly including drug delivery, gene therapeutic, the optical-activated reversion of tumor resistance, and synergistic therapy has also been discussed elaborately. In the end, the potential challenges and future developments of CPs on cancer diagnosis and therapy are also illuminated for the improvement of optical functionalization and the promotion of clinical translation.

Inhibition of fibroblast growth factor-inducible 14 attenuates experimental tubulointerstitial fibrosis and profibrotic factor expression of proximal tubular epithelial cells.

BACKGROUND AND AIM: As a proinflammatory cytokine, tumor necrosis factor-like weak inducer of apoptosis (TWEAK) participates in the progression of renal fibrosis by binding to its receptor, fibroblast growth factor-inducible 14 (Fn14). However, the effect of Fn14 inhibition on tubular epithelial cell-mediated tubulointerstitial fibrosis remains unclear. This study aimed to elucidate the role of TWEAK/Fn14 interaction in the development of experimental tubulointerstitial fibrosis as well as the protective effect of Fn14 knockdown on proximal tubular epithelial cells. METHODS: A murine model of unilateral ureteral obstruction was constructed in both wild-type and Fn14-deficient BALB/c mice, followed by observation of the tubulointerstitial pathologies. RESULTS: Fn14 deficiency ameliorated the pathological changes, including inflammatory cell infiltration and cell proliferation, accompanied by reduced production of profibrotic factors and extracellular matrix deposition. In vitro experiments showed that TWEAK dose-dependently enhanced the expression of collagen I, fibronectin, and α-smooth muscle actin in proximal tubular epithelial cells. Interestingly, TWEAK also upregulated the expression levels of Notch1/Jagged1. Fn14 knockdown and Notch1/Jagged1 inhibition also mitigated the effect of TWEAK on these cells. CONCLUSIONS: In conclusion, TWEAK/Fn14 signals contributed to tubulointerstitial fibrosis by acting on proximal tubular epithelial cells. Fn14 inhibition might be a therapeutic strategy for protecting against renal interstitial fibrosis.

Chemoproteomics-enabled discovery of covalent RNF114-based degraders that mimic natural product function.

The translation of functionally active natural products into fully synthetic small-molecule mimetics has remained an important process in medicinal chemistry. We recently discovered that the terpene natural product nimbolide can be utilized as a covalent recruiter of the E3 ubiquitin ligase RNF114 for use in targeted protein degradation-a powerful therapeutic modality within modern-day drug discovery. Using activity-based protein profiling-enabled covalent ligand-screening approaches, here we report the discovery of fully synthetic RNF114-based recruiter molecules that can also be exploited for PROTAC applications, and demonstrate their utility in degrading therapeutically relevant targets, such as BRD4 and BCR-ABL, in cells. The identification of simple and easily manipulated drug-like scaffolds that can mimic the function of a complex natural product is beneficial in further expanding the toolbox of E3 ligase recruiters, an area of great importance in drug discovery and chemical biology.

Fibroblast growth factor inducible 14 signaling facilitates anti-dsDNA IgG penetration into mesangial cells.

Anti-double-stranded DNA (dsDNA) antibodies induce renal damage in patients with systemic lupus erythematosus by triggering fibrotic processes in kidney cells. However, the precise mechanism underlying penetration of anti-dsDNA immunoglubolin G (IgG) into cells remains unclear. This study was designed to investigate the effect of tumor necrosis factor-like weak inducer of apoptosis (TWEAK)/fibroblast growth factor inducible 14 (Fn14) signaling on anti-dsDNA IgG penetration into cells. Mesangial cells were cultured in vitro, and stimulated with TWEAK and anti-dsDNA IgG. The results revealed that TWEAK dose-dependently enhanced cellular internalization of anti-dsDNA IgG and the expression of high-mobility group box 1 (HMGB1). In addition, TWEAK and anti-dsDNA IgG synthetically downregulate suppressor of cytokine signaling 1, and induce the expression of various fibrotic factors. Furthermore, inhibition of HMGB1 attenuates the enhancement effect of TWEAK on anti-dsDNA IgG internalization. The TWEAK upregulation of HMGB1 involves the nuclear factor-κB and phosphatidylinositide 3-kinase/protein kinase B pathways. Therefore, TWEAK/Fn14 signaling contributes to the penetration of anti-dsDNA IgG and relevant fibrotic processes in mesangial cells.

Bardoxolone conjugation enables targeted protein degradation of BRD4.

Targeted protein degradation (TPD) has emerged as a powerful tool in drug discovery for the perturbation of protein levels using heterobifunctional small molecules. E3 ligase recruiters remain central to this process yet relatively few have been identified relative to the ~ 600 predicted human E3 ligases. While, initial recruiters have utilized non-covalent chemistry for protein binding, very recently covalent engagement to novel E3's has proven fruitful in TPD application. Herein we demonstrate efficient proteasome-mediated degradation of BRD4 by a bifunctional small molecule linking the KEAP1-Nrf2 activator bardoxolone to a BRD4 inhibitor JQ1.

Inhibition of suppressor of cytokine signaling 1 mediates the profibrotic effect of TWEAK/Fn14 signaling on kidney cells.

Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) engagement with the receptor Fn14 contributes to the fibrotic process of kidney cells in systemic lupus erythematosus. Downregulation of the protein suppressor of cytokine signaling 1 (SOCS1) correlates with amplified production of proinflammatory factors and cell apoptosis, which participate in the pathogenesis of lupus nephritis. To elucidate the potential role of SOCS1 in TWEAK/Fn14 signaling, we determined the SOCS1 levels in primary kidney cells from MRL/MpJ (control strain) or MRL/lpr (lupus-prone) mice. These cells (mesangial cells, glomerular endothelial cells, and tubular epithelial cells) were also evaluated after stimulation with TWEAK (0 to 250 ng/mL). The results showed that the lupus-prone cells exhibited reduced SOCS1 expression. TWEAK induced the production of profibrotic factors (laminin, fibronectin, (CC motif) ligand 20, etc.) in kidney cells from both mouse strains. TWEAK stimulation also decreased both the mRNA and protein levels of SOCS1 in all cells. Moreover, the effect of TWEAK on mesangial cells was amplified by pre-transfection of SOCS1 siRNA but was partly reduced with SOCS1 overexpression by adenoviral delivery. Therefore, TWEAK/Fn14 activation contributes to renal fibrosis in lupus nephritis involving the depression of SOCS1 function.

New insight into the mechanism of POP-induced obesity: Evidence from DDE-altered microbiota.

Although epidemiological studies demonstrate that persistent organic pollutants (POPs) could lead to metabolic syndrome, the mechanism has remained unclear. The dysbiosis of gut microbiota and the lipid metabolome have been put forward in the pathophysiology of metabolic syndrome. In this study, we used dichlorodiphenyldichloroethylene (DDE) as an example to study the effects of POP-impaired microbial composition and metabolome homeostasis on metabolic syndrome. The results showed that DDE exposure increased body weight and fat content and impaired glucose homeostasis. Further investigation revealed that DDE induced gut dysbiosis as indicated by an increased Firmicutes-to-Bacteroidetes ratio, which may impact energy harvest efficiency. Meanwhile, the plasma lipid metabolome profile was significantly altered by DDE. Furthermore, phosphatidylcholine, phosphatidylserine, phosphatidylethanolamine, and triacylglycerol were identified as key metabolites affected by DDE treatment, and these altered lipid metabolites were highly correlated with changed microbiota composition. This study provides novel insight into the underlying mechanism of POP-induced obesity and diabetes, pointing to gut microbiota as one of the targets.