Multi-targeted nanoarrays for early broad-spectrum detection of lung cancer based on blood biopsy of tumor exosomes.

Liquid biopsies utilizing tumor exosomes offer a noninvasive approach for cancer diagnosis. However, validation studies consistently report that in the early stages of cancer, the secretion of exosomes by cancer cells is relatively low, while bodily fluids exhibit a high abundance of other interfering biomolecules. Additionally, target mutations or differences in biomarker expression among various lung cancer subtypes may contribute to detection failures. In this study, we propose a targeted nanoarray-based early cancer diagnostic approach for multiple subtypes of lung cancer. The targeted nanoarray was constructed by modifying five targeting aptamers onto mesoporous silica nanoparticles through the conjugation between amino and carboxyl groups. The flow cytometry experiments demonstrated the specific recognition ability of the targeted nanoarray to tumor exosomes in PBS, even at biomarker expression levels as low as 1.5 %. Moreover, the TEM results indicated that the targeted nanoarray could isolate tumor exosomes in the blood of tumor-bearing mice. Furthermore, the targeted nanoarray could detect tumor exosomes in the blood of various lung cancer bearing mice, including at the early stages of cancer, which has just been established for 7 days. Overall, the targeted nanoarray represents a promising tool for the early detection of various subtypes of lung cancer.

Effects of returning paddy field to wetland on composition and stability of soil aggregates in the Yellow River Delta.

The composition and stability of soil aggregates are important indicators for measuring soil quality, which would be affected by land use changes. Taking wetlands with different returning years (2 and 15 years) in the Yellow River Delta as the research object, paddy fields and natural wetlands as control, we analyzed the changes in soil physicochemical properties and soil aggregate composition. The results showed that soil water content, total organic carbon, dissolved organic carbon and total phosphorus of the returning soil (0-40 cm) showed an overall increasing trend with returning period, while soil pH and bulk density was in adverse. There was no significant change in clay content, electrical conductivity, and total nitrogen content. The contents of macro-aggregates and micro-aggregates showed overall increasing and decreasing trend with returning period, respectively. The stability of aggregates in the topsoil (0-10 cm) increased with returning years. Geometric mean diameter and mean weight diameter increased by 8.9% and 40.4% in the 15th year of returning, respectively, while the mass proportion of >2.5 mm fraction decreased by 10.5%. There was no effect of returning on aggregates in subsoil (10-40 cm). Our results indicated that returning paddy field to wetland in the Yellow River Delta would play a positive role in improving soil structure and aggregate stability.

Influencing factors and risk assessment of phthalate ester pollution in the agricultural soil on a tropical island.

Phthalate esters (PAEs) are widely prevalent in agricultural soil and pose potential risks to crop growth and food safety. However, the current understanding of factors influencing the behavior and fate of PAEs is limited. This study conducted a large-scale investigation (106 sites in 18 counties with 44 crop types) of 16 types of PAEs on a tropical island. Special attention was given to the impacts of land use type, soil environmental conditions, agricultural activity intensity, and urbanization level. The health risks to adults and children from soil PAEs via multiple routes of exposure were also evaluated. The results showed that the mean concentration of PAEs was 451.87 ± 284.08 µg kg-1 in the agricultural soil. Elevated agricultural and urbanization activities contributed to more pronounced contamination by PAEs in the northern and southern regions. Land use type strongly affected the concentration and composition of PAEs in agricultural soils, and the soil PAE concentration decreased in the order of vegetable fields, orchards, paddy fields, and woodlands. In paddy fields, di-isobutyl phthalate and di-n-butyl phthalate made more substantial contributions to the process through which the overlying water inhibited volatilization. Soil microplastic abundance, pesticide usage, crop yield, gross domestic product, and distance to the nearest city were calculated to be the major factors influencing the concentration and distribution of PAEs. Soil pH, organic matter content, microplastic abundance and the fertilizer application rate can affect the adsorption of PAEs by changing the soil environment. A greater risk was detected in the northern region and paddy fields due to the higher soil PAE concentrations and the dietary structure of the population. This study reveals important pathways influencing the sources and fate of PAE pollution in agricultural soils, providing fundamental data for controlling PAE contamination.

A distinct class of pan-cancer susceptibility genes revealed by an alternative polyadenylation transcriptome-wide association study.

Alternative polyadenylation plays an important role in cancer initiation and progression; however, current transcriptome-wide association studies mostly ignore alternative polyadenylation when identifying putative cancer susceptibility genes. Here, we perform a pan-cancer 3' untranslated region alternative polyadenylation transcriptome-wide association analysis by integrating 55 well-powered (n > 50,000) genome-wide association studies datasets across 22 major cancer types with alternative polyadenylation quantification from 23,955 RNA sequencing samples across 7,574 individuals. We find that genetic variants associated with alternative polyadenylation are co-localized with 28.57% of cancer loci and contribute a significant portion of cancer heritability. We further identify 642 significant cancer susceptibility genes predicted to modulate cancer risk via alternative polyadenylation, 62.46% of which have been overlooked by traditional expression- and splicing- studies. As proof of principle validation, we show that alternative alleles facilitate 3' untranslated region lengthening of CRLS1 gene leading to increased protein abundance and promoted proliferation of breast cancer cells. Together, our study highlights the significant role of alternative polyadenylation in discovering new cancer susceptibility genes and provides a strong foundational framework for enhancing our understanding of the etiology underlying human cancers.

Farmland Microhabitat Mediated by a Residual Microplastic Film: Microbial Communities and Function.

How the plastisphere mediated by the residual microplastic film in farmlands affects microhabitat systems is unclear. Here, microbial structure, assembly, and biogeochemical cycling in the plastisphere and soil in 33 typical farmland sites were analyzed by amplicon sequencing of 16S rRNA genes and ITS and metagenome analysis. The results indicated that residual microplastic film was colonized by microbes, forming a unique niche called the plastisphere. Notable differences in the microbial community structure and function were observed between soil and plastisphere. Residual microplastic film altered the microbial symbiosis and assembly processes. Stochastic processes significantly dominated the assembly of the bacterial community in the plastisphere and soil but only in the plastisphere for the fungal community. Deterministic processes significantly dominated the assembly of fungal communities only in soil. Moreover, the plastisphere mediated by the residual microplastic film acted as a preferred vector for pathogens and microorganisms associated with plastic degradation and the nitrogen and sulfur cycle. The abundance of genes associated with denitrification and sulfate reduction activity in the plastisphere was pronouncedly higher than that of soil, which increase the potential risk of nitrogen and sulfur loss. The results will offer a scientific understanding of the harm caused by the residual microplastic film in farmlands.

Glioblastoma evolution and heterogeneity from a 3D whole-tumor perspective.

Treatment failure for the lethal brain tumor glioblastoma (GBM) is attributed to intratumoral heterogeneity and tumor evolution. We utilized 3D neuronavigation during surgical resection to acquire samples representing the whole tumor mapped by 3D spatial coordinates. Integrative tissue and single-cell analysis revealed sources of genomic, epigenomic, and microenvironmental intratumoral heterogeneity and their spatial patterning. By distinguishing tumor-wide molecular features from those with regional specificity, we inferred GBM evolutionary trajectories from neurodevelopmental lineage origins and initiating events such as chromothripsis to emergence of genetic subclones and spatially restricted activation of differential tumor and microenvironmental programs in the core, periphery, and contrast-enhancing regions. Our work depicts GBM evolution and heterogeneity from a 3D whole-tumor perspective, highlights potential therapeutic targets that might circumvent heterogeneity-related failures, and establishes an interactive platform enabling 360° visualization and analysis of 3D spatial patterns for user-selected genes, programs, and other features across whole GBM tumors.

scQTLbase: an integrated human single-cell eQTL database.

Genome-wide association studies (GWAS) have identified numerous genetic variants associated with diseases and traits. However, the functional interpretation of these variants remains challenging. Expression quantitative trait loci (eQTLs) have been widely used to identify mutations linked to disease, yet they explain only 20-50% of disease-related variants. Single-cell eQTLs (sc-eQTLs) studies provide an immense opportunity to identify new disease risk genes with expanded eQTL scales and transcriptional regulation at a much finer resolution. However, there is no comprehensive database dedicated to single-cell eQTLs that users can use to search, analyse and visualize them. Therefore, we developed the scQTLbase (http://bioinfo.szbl.ac.cn/scQTLbase), the first integrated human sc-eQTLs portal, featuring 304 datasets spanning 57 cell types and 95 cell states. It contains ∼16 million SNPs significantly associated with cell-type/state gene expression and ∼0.69 million disease-associated sc-eQTLs from 3 333 traits/diseases. In addition, scQTLbase offers sc-eQTL search, gene expression visualization in UMAP plots, a genome browser, and colocalization visualization based on the GWAS dataset of interest. scQTLbase provides a one-stop portal for sc-eQTLs that will significantly advance the discovery of disease susceptibility genes.

Immune-response 3'UTR alternative polyadenylation quantitative trait loci contribute to variation in human complex traits and diseases.

Genome-wide association studies (GWASs) have identified thousands of non-coding variants that are associated with human complex traits and diseases. The analysis of such GWAS variants in different contexts and physiological states is essential for deciphering the regulatory mechanisms underlying human disease. Alternative polyadenylation (APA) is a key post-transcriptional modification for most human genes that substantially impacts upon cell behavior. Here, we mapped 9,493 3'-untranslated region APA quantitative trait loci in 18 human immune baseline cell types and 8 stimulation conditions (immune 3'aQTLs). Through the comparison between baseline and stimulation data, we observed the high responsiveness of 3'aQTLs to immune stimulation (response 3'aQTLs). Co-localization and mendelian randomization analyses of immune 3'aQTLs identified 678 genes where 3'aQTL are associated with variation in complex traits, 27.3% of which were derived from response 3'aQTLs. Overall, these analyses reveal the role of immune 3'aQTLs in the determination of complex traits, providing new insights into the regulatory mechanisms underlying disease etiologies.

Divergent total syntheses of ITHQ-type bis-ß-carboline alkaloids by regio-selective formal aza-[4 + 2] cycloaddition and late-stage C-H functionalization.

We herein report the first total syntheses of several bis-ß-carboline alkaloids, picrasidines G, S, R, and T, and natural product-like derivatives in a divergent manner. Picrasidines G, S, and T feature an indolotetrahydroquinolizinium (ITHQ) skeleton, while picrasidine R possesses a 1,4-diketone linker between two ß-carboline fragments. The synthesis of ITHQ-type bis-ß-carboline alkaloids could be directly achieved by a late-stage regio-selective aza-[4 + 2] cycloaddition of vinyl ß-carboline alkaloids, suggesting that this remarkable aza-[4 + 2] cycloaddition might be involved in the biosynthetic pathway. Computational studies revealed that such aza-[4 + 2] cycloaddition is a stepwise process and explained the unique regioselectivity (ΔΔG = 3.77 kcal mol-1). Moreover, the successful application of iridium-catalyzed C-H borylation on ß-carboline substrates enabled the site-selective C-8 functionalization for efficient synthesis and structural diversification of this family of natural products. Finally, concise synthesis of picrasidine R by the thiazolium-catalyzed Stetter reaction was also accomplished.

A New Target Detection Method of Ferrography Wear Particle Images Based on ECAM-YOLOv5-BiFPN Network.

For mechanical equipment, the wear particle in the lubrication system during equipment operation can reflect the lubrication condition, wear mechanism, and severity of wear between equipment friction pairs. To solve the problems of false detection and missed detection of small, dense, and overlapping wear particles in the current ferrography wear particle detection model in a complex oil background environment, a new ferrography wear particle detection network, EYBNet, is proposed. Firstly, the MSRCR algorithm is used to enhance the contrast of wear particle images and reduce the interference of complex lubricant backgrounds. Secondly, under the framework of YOLOv5s, the accuracy of network detection is improved by introducing DWConv and the accuracy of the entire network is improved by optimizing the loss function of the detection network. Then, by adding an ECAM to the backbone network of YOLOv5s, the saliency of wear particles in the images is enhanced, and the feature expression ability of wear particles in the detection network is enhanced. Finally, the path aggregation network structure in YOLOv5s is replaced with a weighted BiFPN structure to achieve efficient bidirectional cross-scale connections and weighted feature fusion. The experimental results show that the average accuracy is increased by 4.46%, up to 91.3%, compared with YOLOv5s, and the detection speed is 50.5FPS.

Identification of Basement Membrane-Related Signatures in Gastric Cancer.

BACKGROUND: The basement membrane (BM) serves as a major barrier to impede tumor cell invasion and extravasation during metastasis. However, the associations between BM-related genes and GC remain unclear. METHODS: RNA expression data and corresponding clinical information of STAD samples were downloaded from the TCGA database. We identified BM-related subtypes and constructed a BM-related gene prognostic model using lasso-Cox regression analysis. We also investigated the single-cell properties of prognostic-related genes and the TME characteristic, TMB status, and chemotherapy response in high- and low-risk groups. Finally, we verified our results in the GEPIA database and human tissue specimens. RESULTS: A six-gene lasso Cox regression model (APOD, CAPN6, GPC3, PDK4, SLC7A2, SVEP1) was developed. Activated CD4+ T cells and follicular T cells were shown to infiltrate more widely in the low-risk group. The low-risk group harbored significantly higher TMB and better prognosis, favoring immunotherapy. CONCLUSIONS: We constructed a six-gene BM-related prognostic model for predicting GC prognosis, immune cell infiltration, TMB status, and chemotherapy response. This research provides new ideas for developing more effective individualized treatment of GC patients.

Targeting CHAF1B Enhances IFN Activity against Myeloproliferative Neoplasm Cells.

Interferons (IFNs) are cytokines with potent antineoplastic and antiviral properties. IFNα has significant clinical activity in the treatment of myeloproliferative neoplasms (MPN), but the precise mechanisms by which it acts are not well understood. Here, we demonstrate that chromatin assembly factor 1 subunit B (CHAF1B), an Unc-51-like kinase 1 (ULK1)-interactive protein in the nuclear compartment of malignant cells, is overexpressed in patients with MPN. Remarkably, targeted silencing of CHAF1B enhances transcription of IFNα-stimulated genes and promotes IFNα-dependent antineoplastic responses in primary MPN progenitor cells. Taken together, our findings indicate that CHAF1B is a promising newly identified therapeutic target in MPN and that CHAF1B inhibition in combination with IFNα therapy might offer a novel strategy for treating patients with MPN. Significance: Our findings raise the potential for clinical development of drugs targeting CHAF1B to enhance IFN antitumor responses in the treatment of patients with MPN and should have important clinical translational implications for the treatment of MPN and possibly in other malignancies.

Stachydrine, a Bioactive Equilibrist for Synephrine, Identified from Four Citrus Chinese Herbs.

Four Chinese herbs from the Citrus genus, namely Aurantii Fructus Immaturus (Zhishi), Aurantii Fructus (Zhiqiao), Citri Reticulatae Pericarpium Viride (Qingpi) and Citri Reticulatae Pericarpium (Chenpi), are widely used for treating various cardiovascular and gastrointestinal diseases. Many ingredients have already been identified from these herbs, and their various bioactivities provide some interpretations for the pharmacological functions of these herbs. However, the complex functions of these herbs imply undisclosed cholinergic activity. To discover some ingredients with cholinergic activity and further clarify possible reasons for the complex pharmacological functions presented by these herbs, depending on the extended structure-activity relationships of cholinergic and anti-cholinergic agents, a simple method was established here for quickly discovering possible choline analogs using a specific TLC method, and then stachydrine and choline were first identified from these Citrus herb decoctions based on their NMR and HRMS data. After this, two TLC scanning (TLCS) methods were first established for the quantitative analyses of stachydrine and choline, and the contents of the two ingredients and synephrine in 39 samples were determined using the valid TLCS and HPLC methods, respectively. The results showed that the contents of stachydrine (3.04‱) were 2.4 times greater than those of synephrine (1.25‱) in Zhiqiao and about one-third to two-thirds of those of Zhishi, Qingpi and Chenpi. Simultaneously, the contents of stachydrine, choline and synephrine in these herbs present similar decreasing trends with the delay of harvest time; e.g., those of stachydrine decrease from 5.16‱ (Zhishi) to 3.04‱ (Zhike) and from 1.98‱ (Qingpi) to 1.68‱ (Chenpi). Differently, the contents of synephrine decrease the fastest, while those of stachydrine decrease the slowest. Based on these results, compared with the pharmacological activities and pharmacokinetics reported for stachydrine and synephrine, it is indicated that stachydrine can be considered as a bioactive equilibrist for synephrine, especially in the cardio-cerebrovascular protection from these citrus herbs. Additionally, the results confirmed that stachydrine plays an important role in the pharmacological functions of these citrus herbs, especially in dual-directionally regulating the uterus, and in various beneficial effects on the cardio-cerebrovascular system, kidneys and liver.

Therapeutic targeting of metabolic vulnerabilities in cancers with MLL3/4-COMPASS epigenetic regulator mutations.

Epigenetic status-altering mutations in chromatin-modifying enzymes are a feature of human diseases, including many cancers. However, the functional outcomes and cellular dependencies arising from these mutations remain unresolved. In this study, we investigated cellular dependencies, or vulnerabilities, that arise when enhancer function is compromised by loss of the frequently mutated COMPASS family members MLL3 and MLL4. CRISPR dropout screens in MLL3/4-depleted mouse embryonic stem cells (mESCs) revealed synthetic lethality upon suppression of purine and pyrimidine nucleotide synthesis pathways. Consistently, we observed a shift in metabolic activity toward increased purine synthesis in MLL3/4-KO mESCs. These cells also exhibited enhanced sensitivity to the purine synthesis inhibitor lometrexol, which induced a unique gene expression signature. RNA-Seq identified the top MLL3/4 target genes coinciding with suppression of purine metabolism, and tandem mass tag proteomic profiling further confirmed upregulation of purine synthesis in MLL3/4-KO cells. Mechanistically, we demonstrated that compensation by MLL1/COMPASS was underlying these effects. Finally, we demonstrated that tumors with MLL3 and/or MLL4 mutations were highly sensitive to lometrexol in vitro and in vivo, both in culture and in animal models of cancer. Our results depicted a targetable metabolic dependency arising from epigenetic factor deficiency, providing molecular insight to inform therapy for cancers with epigenetic alterations secondary to MLL3/4 COMPASS dysfunction.

A convenient fluorescent/electrochemical dual-mode biosensor for accurate detection of Pb2+ based on DNAzyme cycle.

The presence of heavy metals in the ecological environment is a serious threat to human health. Therefore, it is very important to establish a simple and sensitive method for the detection of heavy metals. Currently, most of the methods are single-channel sensing, and these methods are prone to false-positive signals, which reduces the accuracy. In this work, Pb2+-DNAzyme was immobilized on magnetic beads (MBs) using a linkage of biotin and streptavidin and successfully applied to the construction of a fluorescent/electrochemical dual-mode (DM) biosensor. The supernatant after magnetic separation formed a double strand on the electrode, which was combined with methylene blue (MB) for electrochemical detection (EC). At the same time, FAM-d was added to the precipitate, and after magnetic separation, the supernatant was subjected to fluorescent detection (FL). Under optimal conditions, the signal response of the constructed dual-mode biosensor showed a good linear relationship with the concentration of Pb2+. The DNAzyme-based dual-mode biosensor achieved sensitive and selective detection of Pb2+ with good accuracy and reliability, opening a new way for the development of biosensing strategies for the detection of Pb2+. More importantly, the sensor has high sensitivity and accuracy for the detection of Pb2+ in actual sample analysis.

Modeling interaction of Glioma cells and CAR T-cells considering multiple CAR T-cells bindings.

Chimeric antigen receptor (CAR) T-cell based immunotherapy has shown its potential in treating blood cancers, and its application to solid tumors is currently being extensively investigated. For glioma brain tumors, various CAR T-cell targets include IL13Rα2, EGFRvIII, HER2, EphA2, GD2, B7-H3, and chlorotoxin. In this work, we are interested in developing a mathematical model of IL13Rα2 targeting CAR T-cells for treating glioma. We focus on extending the work of Kuznetsov et al. (1994) by considering binding of multiple CAR T-cells to a single glioma cell, and the dynamics of these multi-cellular conjugates. Our model more accurately describes experimentally observed CAR T-cell killing assay data than the models which do not consider multi-cellular conjugates. Moreover, we derive conditions in the CAR T-cell expansion rate that determines treatment success or failure. Finally, we show that our model captures distinct CAR T-cell killing dynamics from low to high antigen receptor densities in patient-derived brain tumor cells.

Efficiency and mechanism of micro- and nano-plastic removal with polymeric Al-Fe bimetallic coagulants: Role of Fe addition.

The occurrence of microplastics (MPs) and even nanoplastics (NPs) in tap water has raised considerable attention. As a pre-treatment and also the most important process in drinking water treatment plants, coagulation has been widely studied to remove MPs, but few studies focused on the removal pattern and mechanism of NPs, especially no study paid attention to the coagulation enhanced by prehydrolysed Al-Fe bimetallic coagulants. Therefore, in this study, polymeric species and coagulation behaviour of MPs and NPs influenced by Fe fraction in polymeric Al-Fe coagulants were investigated. Special attention was given to the residual Al and the floc formation mechanism. The results showed that asynchronous hydrolysis of Al and Fe sharply decreases the polymeric species in coagulants and that the increase of Fe proportion changes the sulfate sedimentation morphology from dendritic to layered structures. Fe weakened the electrostatic neutralization effect and inhibited the removal of NPs but enhanced that of MPs. Compared with monomeric coagulants, the residual Al decreased by 17.4 % and 53.2 % in the MP and NP systems (p < 0.01), respectively. With no new bonds detected in flocs, the interaction between micro/nanoplastics and Al/Fe was merely electrostatic adsorption. According to the mechanism analysis, sweep flocculation and electrostatic neutralization were the dominant removal pathways of MPs and NPs, respectively. This work provides a better coagulant option for removing micro/nanoplastics and minimizing Al residue, which has promising potential for application in water purification.

Enhancer Coamplification and Hijacking Promote Oncogene Expression in Liposarcoma.

SIGNIFICANCE: Comprehensive profiling of the enhancer landscape and 3D genome structure in liposarcoma identifies extensive enhancer-oncogene coamplification and enhancer hijacking events, deepening the understanding of how oncogenes are regulated in cancer.