Characteristics of Mirabilis jalapa Nanoemulsion: Its Application on Mortality and Morphological Changes of Spodoptera frugiperda: Third Instar Larvae.

<b>Background and Objective:</b> Previously the <i>Mirabilis jalapa</i> nanoemulsion formulations was characterized through PSA analysis, UV-VIS spectrophotometry, SEM to observe the morphology of the formed nanoemulsion and FTIR analysis. But, this study aims to characterize <i>M. jalapa</i> nanoemulsion formulations and its application on the mortality and morphology of 3rd instar <i>Spodoptera frugiperda</i> larva. <b>Materials and Methods:</b> Several <i>M. jalapa</i> nanoemulsion formulations were applied to observe the mortality of 3rd instar <i>S. frugiperda</i> larvae using the Completely Randomized Design (CRD) method. The best formulation was tested from the characterization results to determine the level of larval mortality. The data obtained were analyzed using ANOVA and Tukey's <i>post hoc</i> test. <b>Results:</b> The 3rd instar <i>S. frugiperda</i> larvae showed a 67%±12 mortality rate 48 hrs after the 5th treatment (T5) application compared to the control group and causing the bodies of insects experiencing mortality to turn black and dehydrated. The results showed that <i>M. jalapa</i> nanoemulsion had a significant effect (p-value 0.016<0.05). <b>Conclusion:</b> The potential of using <i>M. jalapa</i> in the form of nanoemulsions as an effective alternative to control the pest <i>S. frugiperda</i>.

Environmental and Sublethal Concentrations of Polystyrene Nanoplastics Induced Antioxidant System, Transcriptomic Responses, and Disturbed Gut Microbiota in Oyster Magallana Hongkongensis.

Nanoplastics (NPs) are emerging contaminants having persistent nature, diverse ecological impacts, and potential food safety risks. Here, we examined the ecotoxicity of 80 nm polystyrene nanoplastics (PS-NPs) at environmentally relevant concentrations (ERCs, 10 and 100 µg/L), and sublethal concentrations (SLCs, 500 and 2500 µg/L) in Magallana hongkongensis. Results showed that SLCs significantly (p < 0.05) increased superoxide dismutase (SOD), catalase (CAT), and alkaline phosphatase (AKP) activities and altered tnfα, cat, gst, sod, and se-gpx genetic expressions. Further, PS-NP exposure at both levels reduced beneficial bacteria and increased potentially pathogenic bacteria in the gut. In transcriptomic analysis, 5118 and 4180 differentially expressed genes (DEGs) were identified at ERCs, while 5665 and 4817 DEGs were found at SLCs, respectively. Upregulated DEGs enriched lysosomes, ABC transporters, and apoptosis pathways, while downregulated DEGs enriched ribosomal pathways. Overall, ERCs significantly altered gut microbiota and transcriptomic responses, while SLCs, in addition, also impacted the antioxidant and immune systems.

Environmental nanoplastics quantification by pyrolysis-gas chromatography-mass spectrometry in the Pearl River, China: First insights into spatiotemporal distributions, compositions, sources and risks.

Nanoplastics (NPs, size <1000 nm) are ubiquitous plastic particles, potentially more abundant than microplastics in the environment; however, studies highlighting their distribution dynamics in freshwater are rare due to analytical limitations. Here, we investigated spatiotemporal levels of nine polymers of NPs in surface water samples (n = 30) from the full stretch of the Pearl River (sites, n = 15) using pyrolysis gas chromatography-mass spectrometry (Py-GC/MS). Six polymers were detected, including polystyrene (PS), polyvinyl chloride (PVC), nylon/polyamide 66 (PA66), polyester (PES), poly(methyl methacrylate) (PMMA) and polyethylene (PE), where three polymers showed high detection frequencies; PS (100 % in winter and summer), followed by PVC (73 % in winter and 87 % in summer) and PA66 (53 % in winter and 67 % in summer). The spatiotemporal distribution revealed the sites related to aquaculture (AQ) and shipping (SHP) showed higher NP levels than those of human settlement (HS) and wastewater treatment plants (WWTPs) (p = 0.004), and relatively high average levels of NPs in the urban sites compared to rural sites (p = 0.04), albeit showed no obvious seasonal differences (p = 0.78). For instance, the average PS levels in the Pearl River were in the following order: AQ 411.55 µg/L > SHP 81.75 µg/L > WWTP 56.66 µg/L > HS 47.75 µg/L in summer and HS 188.1 µg/L > SHP 103.55 µg/L > AQ 74.7 µg/L > WWTP 62.1 µg/L in winter. Source apportionment showed a higher contribution through domestic plastic waste emissions among urban sites, while rural sites showed an elevated contribution via aquaculture, agriculture, and surface run-off to the NP pollution. Risk assessment revealed that NPs at SHP and AQ sites posed a higher integrated risk in terms of pollution load index (PLI) than those at WWTP and HS sites. Regarding polymer hazard index (HI), 80 % of sampling sites in summer and 60 % of sampling sites in winter posed level III polymer risk, with PVC posing the highest risk. This study provides novel insights into the seasonal contamination and polymer risks of NP in the Pearl River, which will help to regulate the production and consumption of plastics in the region. ENVIRONMENTAL IMPLICATIONS: The contamination dynamics of field nanoplastics (NPs) in freshwater resources remain little understood, mainly attributed to analytical constraints. This study aims to highlight the spatiotemporal distribution of NPs in the Pearl River among various land use types, urban-rural comparison, seasonal comparison, their compositional profiles, potential sources, interaction with environmental factors, and ecological and polymer hazard assessments of investigated polymers in the full stretch of the Pearl River from Liuxi Reservoir to the Pearl River Delta (PRD) region. This study, with a comparatively large number of samples and NP polymers, will offer novel insights into the contamination profiles of nano-sized plastic particles in one of the important freshwater riverine systems in China.

Exacerbated interfacial impacts of nanoplastics and 6:2 chlorinated polyfluorinated ether sulfonate by natural organic matter in adult zebrafish: Evidence through histopathology, gut microbiota, and transcriptomic analysis.

Nanoplastics (NPs) interact with cooccurring chemicals and natural organic matter (NOM) in the environment, forming complexes that can change their bioavailability and interfacial toxicity in aquatic organisms. This study aims to elucidate the single and combined impacts of 21-day chronic exposure to low levels of polystyrene NPs (size 80 nm) at 1 mg/L and 6:2 chlorinated polyfluorinated ether sulfonate (Cl-PFAES or F53B) at 200 µg/L in the presence and absence of NOM (humic acid-HA and bovine serum albumin-BSA at 10 mg/L) in adult zebrafish (Danio rerio). Our findings through multiple bioassays, revealed that the mixture group (M), comprising of NPs, F53B, HA, and BSA, caused a higher level of toxicity compared to the single NPs (AN), single F53B (AF), and combined NPs+F53B (ANF) groups. The mixture exposure caused the highest level of vacuolization and nuclear condensation in hepatocytes, and most of the intestinal villi were fused and highly reduced in villi length and crypt depth. Further, the T-AOC levels were significantly lower (p < 0.05), while the MDA levels in the liver and intestine were significantly higher (p < 0.05) in the M group with downregulation of nfkbiaa, while upregulation of prkcda, csf1ra, and il1b apoptosis genes in the liver. Pairwise comparison of gut microbiota showed significantly higher (p < 0.05) abundances of various genera in the M group, including Gordonia, Methylobacterium, Tundrisphaera, GKS98, Pedomicrobium, Clostridium, Candidatus and Anaerobacillus, as well as higher abundance of genera including pathogenic strains, while control group showed higher abundance of probiotic genus ZOR0006 than exposed group (p < 0.01). The transcriptomic analysis revealed highest number of DEGs in the M group (2815), followed by the AN group (506) and ANF group (206) with the activation of relaxin signaling pathway-RSP (slc9a1, slc9a2) and AMP-activated protein kinase (AMPK) pathway (plin1), and suppression of the toll-like receptor (TLR) pathway (tlr4a, tlr2, tlr1), cytokine-cytokine receptor interaction (CCRI) pathway (tnfb, il21r1, il21, ifng1), and peroxisome proliferator-activated receptors (PPAR) pathway (pfkfb3). Overall, toxicity in the M group was higher, indicating that the HA and BSA elevated the interfacial impacts of NPs and F53B in adult zebrafish after chronic environmentally relevant exposure, implying the revisitation of the critical interaction of NOM with co-occurring chemicals and associated impacts.

Interfacial effects of perfluorooctanoic acid and its alternative hexafluoropropylene oxide dimer acid with polystyrene nanoplastics on oxidative stress, histopathology and gut microbiota in Crassostrea hongkongensis oysters.

The increasing interfacial impacts of polystyrene nanoplastics (PS) and per- and polyfluoroalkyl substances (PFAS) complex aquatic environments are becoming more evident, drawing attention to the potential risks to aquatic animal health and human seafood safety. This study aims to investigate the relative impacts following exposure (7 days) of Crassostrea hongkongensis oysters to the traditional PFAS congener, perfluorooctanoic acid (PFOA) at 50 µg/L, and its novel alternative, hexafluoropropylene oxide dimer acid (HFPO-DA), also known as GenX at 50 µg/L, in conjunction with fluorescent polystyrene nanoplastics (PS, 80 nm) at 1 mg/L. The research focuses on assessing the effects of combined exposure on oxidative stress responses and gut microbiota in the C. hongkongensis. Comparing the final results of PS + GenX (PG) and PS + PFOA (PF) groups, we observed bioaccumulation of PS in both groups, with the former causing more pronounced histopathological damage to the gills and intestines. Furthermore, the content of antioxidant enzymes induced by PG was higher than that of PF, including Superoxide Dismutase (SOD), Catalase (CAT), Glutathione Reductase (GR) and Glutathione Peroxidase (GSH). Additionally, in both PG and PF groups, the expression levels of several immune-related genes were significantly upregulated, including tnfα, cat, stat, tlr-4, sod, and ß-gbp, with no significant difference between these two groups (p > 0.05). Combined exposure induced significant changes in the gut microbiota of C. hongkongensis at its genus level, with a significant increase in Legionella and a notable decrease in Endozoicomonas and Lactococcus caused by PG. These shifts led to beneficial bacteria declining and pathogenic microbes increasing. Consequently, the microbial community structure might be disrupted. In summary, our findings contribute to a deeper understanding of the comparative toxicities of marine bivalves under combined exposure of traditional and alternative PFAS.

Deciphering Microbiome, Transcriptome, and Metabolic Interactions in the Presence of Probiotic Lactobacillus acidophilus against Salmonella Typhimurium in a Murine Model.

Salmonella enterica serovar Typhimurium (S. Typhimurium), a foodborne pathogen that poses significant public health risks to humans and animals, presents a formidable challenge due to its antibiotic resistance. This study explores the potential of Lactobacillus acidophilus (L. acidophilus 1.3251) probiotics as an alternative strategy to combat antibiotic resistance associated with S. Typhimurium infection. In this investigation, twenty-four BALB/c mice were assigned to four groups: a non-infected, non-treated group (CNG); an infected, non-treated group (CPG); a group fed with L. acidophilus but not infected (LAG); and a group fed with L. acidophilus and challenged with Salmonella (LAST). The results revealed a reduction in Salmonella levels in the feces of mice, along with restored weight and improved overall health in the LAST compared to the CPG. The feeding of L. acidophilus was found to downregulate pro-inflammatory cytokine mRNA induced by Salmonella while upregulating anti-inflammatory cytokines. Additionally, it influenced the expression of mRNA transcript, encoding tight junction protein, oxidative stress-induced enzymes, and apoptosis-related mRNA expression. Furthermore, the LEfSe analysis demonstrated a significant shift in the abundance of critical commensal genera in the LAST, essential for maintaining gut homeostasis, metabolic reactions, anti-inflammatory responses, and butyrate production. Transcriptomic analysis revealed 2173 upregulated and 506 downregulated differentially expressed genes (DEGs) in the LAST vs. the CPG. Functional analysis of these DEGs highlighted their involvement in immunity, metabolism, and cellular development. Kyoto Encyclopedia of Genes and Genome (KEGG) pathway analysis indicated their role in tumor necrosis factor (TNF), mitogen-activated protein kinase (MAPK), chemokine, Forkhead box O (FOXO), and transforming growth factor (TGF-ß) signaling pathway. Moreover, the fecal metabolomic analysis identified 929 differential metabolites, with enrichment observed in valine, leucine, isoleucine, taurine, glycine, and other metabolites. These findings suggest that supplementation with L. acidophilus promotes the growth of beneficial commensal genera while mitigating Salmonella-induced intestinal disruption by modulating immunity, gut homeostasis, gut barrier integrity, and metabolism.

Corrigendum: GC-MS analysis and gastroprotective evaluations of crude extracts, isolated saponins, and essential oil from polygonum hydropiper L.

[This corrects the article DOI: 10.3389/fchem.2017.00058.].

Impact and mitigation of lead, cadmium and micro/nano plastics in fragrant rice.

Heavy metals (HMs) and micro(nano)plastics (MNPs), represent a significant risk to global food supply as well as a potential risk to humankind. Over 50% of the worldwide population eat rice every day, and rice aroma is a significant qualitative trait that is highly valued by consumers and fetches premium prices in the global market. Despite the huge commercial importance of fragrant rice, limited studies were directed to investigate the influence of HMs and MNPs on yield related traits and 2-Acetyl-1-pyrroline (2-AP) compound, mainly responsible for aroma production in fragrant rice. In this review, we found that the interaction of HMs and MNPs in fragrant rice is complex and accumulation of HMs and MNPs was higher in root as compared to the grains. Nutrients and phytohormones mediated mitigation of HMs and MNPs were most effective sustainable strategies. In addition, monitoring the checkpoints of 2-AP biosynthesis and its interaction with HMs and MNPs is challenging. Finally, we explained the potential challenges that fragrant rice faces considering the continuous rise in environmental pollutants and discussed the future avenues of research to improve fragrant rice's yield and qualitative traits.

Elucidating environmental factors and their combined effects on CKDu in Sri Lanka using zebrafish.

Chronic kidney disease with uncertain etiology (CKDu) in Sri Lanka has attracted much attention as a global health issue. However, how environmental factors in local drinking water induce kidney damage in organisms is still elusive. We investigated multiple environmental factors including water hardness and fluoride (HF), heavy metals (HM), microcystin-LR (MC-LR), and their combined exposure (HFMM) to elucidate their toxic effects on CKDu risk in zebrafish. Acute exposure affected renal development and inhibited the fluorescence of Na, K-ATPase alpha1A4:GFP zebrafish kidney. Chronic exposure influenced the body weight of both genders of adult fish and induced kidney damage by histopathological analyses. Furthermore, the exposure significantly disturbed differential expression genes (DEGs), diversity and richness of gut microbiota, and critical metabolites related to renal functions. The transcriptomic analysis revealed that kidney-related DEGs were linked with renal cell carcinoma, proximal tubule bicarbonate reclamation, calcium signaling pathway, and HIF-1 signaling pathway. The significantly disrupted intestinal microbiota was closely related to the environmental factors and H&E score, which demonstrated the mechanisms of kidney risks. Notably, the Spearman correlation analysis indicated that the changed bacteria such as Pseudomonas, Paracoccus, and ZOR0006, etc were significantly connected to the DEGs and metabolites. Therefore, the assessment of multiple environmental factors provided new insights on "bio-markers" as potential therapies of the target signaling pathways, metabolites, and gut bacteria to monitor or protect residents from CKDu.

Interactive effects of polystyrene nanoplastics and 6:2 chlorinated polyfluorinated ether sulfonates on the histomorphology, oxidative stress and gut microbiota in Hainan Medaka (Oryzias curvinotus).

Nanoplastics adsorb surrounding organic contaminants in the environment, which alters the physicochemical properties of contaminants and affects associated ecotoxicological effects on aquatic life. The current work aims to explore the individual and combined toxicological implications of polystyrene nanoplastics (80 nm) and 6:2 chlorinated polyfluorinated ether sulfonate (Cl-PFAES, trade name: F-53B) in an emerging freshwater fish model Hainan Medaka (Oryzias curvinotus). Therefore, O. curvinotus were exposed to 200 µg/L of PS-NPs or 500 µg/L of F-53B in the single or mixture exposure for 7 days to investigate the effects on fluorescence accumulation, tissue damage, antioxidant capacity and intestinal flora. The PS-NPs fluorescence intensity was significantly higher in the single exposure treatment than it in combined exposure treatment (p < 0.01). Histopathological results showed that exposure to PS-NPs or F-53B inflicted varying degree of damages to the gill, liver, and intestine, and these damage were also present in the corresponding tissues of the combined treatment group, illustrating a stronger extent of destruction of these tissues by the combined treatment. Compared to the control group, combined exposure group elevated the malondialdehyde (MDA) content, superoxide dismutase (SOD) and catalase (CAT) activities except in the gill. In addition, the adverse contribution of PS-NPs and F-53B on the enteric flora in the single and combined exposure groups was mainly characterised in the form of reductions in the number of probiotic bacteria (Firmicutes) and this reduction was aggravated by the combined exposure group. Collectively, our results indicated that the toxicological effects of PS-NPs and F-53B on pathology, antioxidant capacity and microbiomics of medaka may be modulated by the interaction of two contaminants with mutually interactive effects. And our work offers fresh information on the combined toxicity of PS-NPs and F-53B to aquatic creatures along with a molecular foundation for the environmental toxicological mechanism.

One-Step Solvothermal Synthesis by Ethylene Glycol to Produce N-rGO for Supercapacitor Applications.

Graphene and its derivatives have emerged as peerless electrode materials for energy storage applications due to their exclusive electroactive properties such as high chemical stability, wettability, high electrical conductivity, and high specific surface area. However, electrodes from graphene-based composites are still facing some substantial challenges to meet current energy demands. Here, we applied one-pot facile solvothermal synthesis to produce nitrogen-doped reduced graphene oxide (N-rGO) nanoparticles using an organic solvent, ethylene glycol (EG), and introduced its application in supercapacitors. Electrochemical analysis was conducted to assess the performance using a multi-channel electrochemical workstation. The N-rGO-based electrode demonstrates the highest specific capacitance of 420 F g-1 at 1 A g-1 current density in 3 M KOH electrolyte with the value of energy (28.60 Whkg-1) and power (460 Wkg-1) densities. Furthermore, a high capacitance retention of 98.5% after 3000 charge/discharge cycles was recorded at 10 A g-1. This one-pot facile solvothermal synthetic process is expected to be an efficient technique to design electrodes rationally for next-generation supercapacitors.

A review of piezoelectric MEMS sensors and actuators for gas detection application.

Piezoelectric microelectromechanical system (piezo-MEMS)-based mass sensors including the piezoelectric microcantilevers, surface acoustic waves (SAW), quartz crystal microbalance (QCM), piezoelectric micromachined ultrasonic transducer (PMUT), and film bulk acoustic wave resonators (FBAR) are highlighted as suitable candidates for highly sensitive gas detection application. This paper presents the piezo-MEMS gas sensors' characteristics such as their miniaturized structure, the capability of integration with readout circuit, and fabrication feasibility using multiuser technologies. The development of the piezoelectric MEMS gas sensors is investigated for the application of low-level concentration gas molecules detection. In this work, the various types of gas sensors based on piezoelectricity are investigated extensively including their operating principle, besides their material parameters as well as the critical design parameters, the device structures, and their sensing materials including the polymers, carbon, metal-organic framework, and graphene.

Compressibility and porosity modulate the mechanical properties of giant gas vesicles.

Gas vesicles used as contrast agents for noninvasive ultrasound imaging must be formulated to be stable, and their mechanical properties must be assessed. We report here the formation of perfluoro-n-butane microbubbles coated with surface-active proteins that are produced by filamentous fungi (hydrophobin HFBI from Trichoderma reesei). Using pendant drop and pipette aspiration techniques, we show that these giant gas vesicles behave like glassy polymersomes, and we discover novel gas extraction regimes. We develop a model to analyze the micropipette aspiration of these compressible gas vesicles and compare them to incompressible liquid-filled vesicles. We introduce a sealing parameter to characterize the leakage of gas under aspiration through the pores of the protein coating. Utilizing this model, we can determine the elastic dilatation modulus, surface viscosity, and porosity of the membrane. These results demonstrate the engineering potential of protein-coated bubbles for echogenic and therapeutic applications and extend the use of the pipette aspiration technique to compressible and porous systems.

Organochlorine pesticides (OCPs) in freshwater resources of Pakistan: A review on occurrence, spatial distribution and associated human health and ecological risk assessment.

The extensive use of organochlorine pesticides (OCPs) has resulted in the widespread contamination of different environmental matrices in Pakistan. Freshwater bodies are also prone to OCPs contamination as they receive agricultural and industrial runoff from different sources. In the present study, the data regarding OCPs' fate and distribution in freshwater resources of Pakistan was reviewed and associated risks to human and ecological health were assessed. Among all the OCPs, DDTs were more prevalent with the highest mean concentration of 2290 ng/L observed in River Ravi (Lahore and Sahiwal District). Human health risk assessment showed a higher risk to the children with high Hazard Quotient (HQ) values ranging between 4.1 × 10-9- 295 for Aldrin. The River Ravi (Lahore and Sahiwal District), the River Sutlej (Kasur & Bahawalpur District), and the River Kabul (Nowshehra District) were categorized as high-risk water bodies based on Hazard Index (HI) and Non-Cancer Risk (CRI) index values > 10. Ecological risk assessment revealed a higher risk posed to invertebrate species from DDT exposure. In summary, this review highlights the occurrence and distribution of OCPs and their associated human health and ecological risks in freshwater bodies of Pakistan and also contributes to signifying the need for proper management and regulation of banned pesticides and future research perspectives.

Validation of catalytic site residues of Ubiquitin Specific Protease 2 (USP2) by molecular dynamic simulation and novel kinetics assay for rational drug design.

Post-translational modifications of proteins such as protein ubiquitination are crucial for regulating conformation, stability and localization of the modified protein. Ubiquitin-specific protease 2 (USP2), a multifunctional cysteine protease is reported to be a key regulator of ubiquitylation events in numerous oncogenic proteins e.g., fatty acid synthetase, Mdm2, EGFR, cyclin A1, and cyclin-D1, etc. Thus targeting USP2 is a promising strategy for cancer therapy. USP2 is characterized by a catalytic triad comprising of cysteine, histidine and aspartic acid residues. Five residues including three from the catalytic triad and two from outside of the catalytic triad have been reported as a catalytic site of USP2 that catalyze hydrolysis and stabilizes the oxyanion formed in the intermediate step of catalysis. Here, we report two more novel residues (L269 and Y558) on USP2 involved in the catalysis of Ubiquitin using computational alanine scanning (CAS) followed by molecular dynamic simulation studies. The results obtained from CAS were further validated by a highly reliable, time- and cost-effective SDS-PAGE-based kinetics assay using UBA52 which is a natural substrate of USP2. Our results showed that mutating L269 and Y558 significantly compromised the catalytic efficiency of USP2 in hydrolyzing UBA52 which can further be extended to rational drug design of USP2 selective inhibitors and to explore the catalytic sites of other USPs. Two novel residues take part in catalytic activity of USP2 which were depicted by MD Simulations and were further validated by novel SDS-PAGE-based reliable time- and cost-effective kinetics assay.

Current understanding of gliomagenesis: from model to mechanism.

Glioma, a kind of central nervous system (CNS) tumor, is hard to cure and accounts for 32% of all CNS tumors. Establishing a stable glioma model is critically important to investigate the underlying molecular mechanisms involved in tumorigenesis and tumor progression. Various core signaling pathways have been identified in gliomagenesis, such as RTK/RAS/PI3K, TP53, and RB1. Traditional methods of establishing glioma animal models have included chemical induction, xenotransplantation, and genetic modifications (RCAS/t-va system, Cre-loxP, and TALENs). Recently, CRISPR/Cas9 has emerged as an efficient gene editing tool with high germline transmission and has extended the scope of stable and efficient glioma models that can be generated. Therefore, this review will highlight the documented evidence about the molecular characteristics, critical genetic markers, and signaling pathways responsible for gliomagenesis and progression. Moreover, methods of establishing glioma models using gene editing techniques and therapeutic aspects will be discussed. Finally, the prospect of applying gene editing in glioma by using CRISPR/Cas9 strategy and future research directions to establish a stable glioma model are also included in this review. In-depth knowledge of glioma signaling pathways and use of CRISPR/Cas9 can greatly assist in the development of a stable, efficient, and spontaneous glioma model, which can ultimately improve the effectiveness of therapeutic responses and cure glioma patients.

Transcriptional Heterogeneity of Cellular Senescence in Cancer.

Cellular senescence plays a paradoxical role in tumorigenesis through the expression of diverse senescence-associated (SA) secretory phenotypes (SASPs). The heterogeneity of SA gene expression in cancer cells not only promotes cancer stemness but also protects these cells from chemotherapy. Despite the potential correlation between cancer and SA biomarkers, many transcriptional changes across distinct cell populations remain largely unknown. During the past decade, single-cell RNA sequencing (scRNA-seq) technologies have emerged as powerful experimental and analytical tools to dissect such diverse senescence-derived transcriptional changes. Here, we review the recent sequencing efforts that successfully characterized scRNA-seq data obtained from diverse cancer cells and elucidated the role of senescent cells in tumor malignancy. We further highlight the functional implications of SA genes expressed specifically in cancer and stromal cell populations in the tumor microenvironment. Translational research leveraging scRNA-seq profiling of SA genes will facilitate the identification of novel expression patterns underlying cancer susceptibility, providing new therapeutic opportunities in the era of precision medicine.

Machine Learning-based Virtual Screening for STAT3 Anticancer Drug Target.

BACKGROUND: Signal transducers and activators of the transcription (STAT) family is composed of seven structurally similar and highly conserved members, including STAT1, STAT2, STAT3, STAT4, STAT5a, STAT5b, and STAT6. The STAT3 signaling cascade is activated by upstream kinase signals and undergoes phosphorylation, homo-dimerization, nuclear translocation, and DNA binding, resulting in the expression of target genes involved in tumor cell proliferation, metastasis, angiogenesis, and immune editing. STAT3 hyperactivation has been documented in a number of tumors, including head and neck, breast, lung, liver, kidney, prostate, pancreas cancer, multiple myeloma, and acute myeloid leukemia. Drug discovery is a timeconsuming and costly process; it may take ten to fifteen years to bring a single drug to the market. Machine learning algorithms are very fast and effective and commonly used in the field, such as drug discovery. These algorithms are ideal for the virtual screening of large compound libraries to classify molecules as active or inactive. OBJECTIVE: The present work aims to perform machine learning-based virtual screening for the STAT3 drug target. METHODS: Machine learning models, such as k-nearest neighbor, support vector machine, Gaussian naïve Bayes, and random forest for classifying the active and inactive inhibitors against a STAT3 drug target, were developed. Ten-fold cross-validation was used for model validation. Then the test dataset prepared from the zinc database was screened using the random forest model. A total of 20 compounds with 88% accuracy was predicted as active against STAT3. Furthermore, these twenty compounds were docked into the active site of STAT3. The two complexes with good docking scores as well as the reference compound were subjected to MD simulation. A total of 100ns MD simulation was performed. RESULTS: Compared to all other models, the random forest model revealed better results. Compared to the standard reference compound, the top two hits revealed greater stability and compactness. CONCLUSION: In conclusion, our predicted hits have the ability to inhibit STAT3 overexpression to combat STAT3-associated diseases.

Toxicological effects of polystyrene nanoplastics and perfluorooctanoic acid to Gambusia affinis.

Plastic pollution has attracted huge attention from public and scientific community in recent years. In the environment, nanoplastics (NPs, <100 nm) can interact with persistent organic pollutants (POPs) such as perfluorooctanoic acid (PFOA) and may exacerbate associated toxic impacts. The present study aims to explore the single and combined ecotoxicological effects of PFOA and polystyrene nanoplastics (PS-NPs, 80 nm) on the PI3K/AKT3 signaling pathway using a freshwater fish model Gambusia affinis. Fish were exposed individually to PS-NPs (200 µg/L) and PFOA (50, 500, 5000 µg/L) and their chemical mixtures for 96 h. Our results showed that the co-exposure significantly altered the mRNA relative expression of PI3K, AKT3, IKKß and IL-1ß, compared to corresponding single exposure and control groups, indicating that the PFOA-NP co-exposure can activate the PI3K/AKT3 signaling pathway. The bioinformatic analyses showed that AKT3 had more probes and exhibited a significantly sensitive correlation with DNA methylation, compared to other genes (PIK3CA, IKBKB, and IL1B). Further, the mRNA expressions of PIK3CA, AKT3, and IKBKB had a significant correlation with copy number variation (CNV) in human liver hepatocellular carcinoma (LIHC). And PIK3CA had the highest mutation rate among other genes of interest for LIHC. Moreover, AKT3 showed a relatively lower expression in TAM and CAF cells, compared to PIK3CA, IKBKB, and IL1B. Besides, hsa-mir-155-5p was closely correlated with AKT3, PIK3CA, IKBKB, and IL1B. In summary, these results provide evidence that NPs could enhance the carcinogenic effects of POPs on aquatic organisms and highlight possible targets of LIHC induced by PFOA-NP co-exposure.

Structure-based virtual screening for PDL1 dimerizers: Evaluating generic scoring functions.

The interaction between PD1 and its ligand PDL1 has been shown to render tumor cells resistant to apoptosis and promote tumor progression. An innovative mechanism to inhibit the PD1/PDL1 interaction is PDL1 dimerization induced by small-molecule PDL1 binders. Structure-based virtual screening is a promising approach to discovering such small-molecule PD1/PDL1 inhibitors. Here we investigate which type of generic scoring functions is most suitable to tackle this problem. We consider CNN-Score, an ensemble of convolutional neural networks, as the representative of machine-learning scoring functions. We also evaluate Smina, a commonly used classical scoring function, and IFP, a top structural fingerprint similarity scoring function. These three types of scoring functions were evaluated on two test sets sharing the same set of small-molecule PD1/PDL1 inhibitors, but using different types of inactives: either true inactives (molecules with no in vitro PD1/PDL1 inhibition activity) or assumed inactives (property-matched decoy molecules generated from each active). On both test sets, CNN-Score performed much better than Smina, which in turn strongly outperformed IFP. The fact that the latter was the case, despite precluding any possibility of exploiting decoy bias, demonstrates the predictive value of CNN-Score for PDL1. These results suggest that re-scoring Smina-docked molecules with CNN-Score is a promising structure-based virtual screening method to discover new small-molecule inhibitors of this therapeutic target.