Autism patient-derived SHANK2BY29X mutation affects the development of ALDH1A1 negative dopamine neuron.

Autism spectrum disorder (ASD) encompasses a range of neurodevelopmental conditions. Different mutations on a single ASD gene contribute to heterogeneity of disease phenotypes, possibly due to functional diversity of generated isoforms. SHANK2, a causative gene in ASD, demonstrates this phenomenon, but there is a scarcity of tools for studying endogenous SHANK2 proteins in an isoform-specific manner. Here, we report a point mutation on SHANK2, which is found in a patient with autism, located on exon of the SHANK2B transcript variant (NM_133266.5), hereby SHANK2BY29X. This mutation results in an early stop codon and an aberrant splicing event that impacts SHANK2 transcript variants distinctly. Induced pluripotent stem cells (iPSCs) carrying this mutation, from the patient or isogenic editing, fail to differentiate into functional dopamine (DA) neurons, which can be rescued by genetic correction. Available SMART-Seq single-cell data from human midbrain reveals the abundance of SHANK2B transcript in the ALDH1A1 negative DA neurons. We then show that SHANK2BY29X mutation primarily affects SHANK2B expression and ALDH1A1 negative DA neurons in vitro during early neuronal developmental stage. Mice knocked in with the identical mutation exhibit autistic-like behavior, decreased occupancy of ALDH1A1 negative DA neurons and decreased dopamine release in ventral tegmental area (VTA). Our study provides novel insights on a SHANK2 mutation derived from autism patient and highlights SHANK2B significance in ALDH1A1 negative DA neuron.

Organ-Specific Gene Expression Control Using DNA Origami-Based Nanodevices.

Nanodevices that function in specific organs or cells are one of the ultimate goals of synthetic biology. The recent progress in DNA nanotechnology such as DNA origami has allowed us to construct nanodevices to deliver a payload (e.g., drug) to the tumor. However, delivery to specific organs remains difficult due to the fragility of the DNA nanostructure and the low targeting capability of the DNA nanostructure. Here, we constructed tough DNA origami that allowed us to encapsulate the DNA origami into lipid-based nanoparticles (LNPs) under harsh conditions (low pH), harnessing organ-specific delivery of the gene of interest (GOI). We found that DNA origami-encapsulated LNPs can increase the functionality of payload GOIs (mRNA and siRNA) inside mouse organs through the contribution from different LNP structures revealed by cryogenic electron microscope (Cryo-EM). These data should be the basis for future organ-specific gene expression control using DNA origami nanodevices.

Size-Selective Capturing of Exosomes Using DNA Tripods.

Fractionating and characterizing target samples are fundamental to the analysis of biomolecules. Extracellular vesicles (EVs), containing information regarding the cellular birthplace, are promising targets for biology and medicine. However, the requirement for multiple-step purification in conventional methods hinders analysis of small samples. Here, we apply a DNA origami tripod with a defined aperture of binders (e.g., antibodies against EV biomarkers), which allows us to capture the target molecule. Using exosomes as a model, we show that our tripod nanodevice can capture a specific size range of EVs with cognate biomarkers from a broad distribution of crude EV mixtures. We further demonstrate that the size of captured EVs can be controlled by changing the aperture of the tripods. This simultaneous selection with the size and biomarker approach should simplify the EV purification process and contribute to the precise analysis of target biomolecules from small samples.

SIRPG expression positively associates with an inflamed tumor microenvironment and response to PD-1 blockade.

BACKGROUND: This study aimed to investigate the relationship between signal regulatory protein gamma (SIRPG) and tumor immune microenvironment phenotypes or T cell mediated-adaptive antitumor immunity, and its predictive value for response to PD-1 blockade in cancers. METHODS: Pan-cancer analysis of SIRPG expression and immune deconvolution was performed using transcriptomic data across 33 tumor types. Transcriptomic and clinical data from 157 patients with non-small-cell lung cancer (NSCLC) and melanoma received PD-1 blockade were analyzed. Expression characteristics of SIRPG were investigated using single-cell RNA sequencing (scRNA-seq) data of 103,599 cells. The effect of SIRPG expression was evaluated via SIRPG knockdown or overexpression in Jurkat T cells. RESULTS: The results showed that most cancers with high SIRPG expression had significantly higher abundance of T cells, B cells, NK cells, M1 macrophages and cytotoxic lymphocytes and increased expression level of immunomodulatory factors regulating immune cell recruitment, antigen presentation, T cell activation and cytotoxicity, but markedly lower abundance of neutrophils, M2 macrophages, and myeloid-derived suppressor cells. High SIRPG expression was associated with favorable response to PD-1 blockade in both NSCLC and melanoma. scRNA-seq data suggested SIRPG was mainly expressed in CD8+ exhausted T and CD4+ regulatory T cells, and positively associated with immune checkpoint expression including PDCD1 and CTLA4. In vitro test showed SIRPG expression in T cells could facilitate expression of PDCD1 and CTLA4. CONCLUSION: High SIRPG expression is associated with an inflamed immune phenotype in cancers and favorable response to PD-1 blockade, suggesting it would be a promising predictive biomarker for PD-1 blockade and novel immunotherapeutic target.

Photoaged Nanopolystyrene Affects Neurotransmission to Induce Transgenerational Neurotoxicity in Caenorhabditis elegans.

Nanopolystyrene (NPS), a frequently employed nanoplastic, is an emerging environmental contaminant known to cause neurotoxicity in various organisms. However, the potential for transgenerational neurotoxic effects, especially from photoaged NPS (P-NPS), remains underexplored. This study investigated the aging of virgin NPS (V-NPS) under a xenon lamp to simulate natural sunlight exposure, which altered the physicochemical characteristics of the NPS. The parental generation (P0) of Caenorhabditis elegans was exposed to environmental concentrations (0.1-100 µg/L) of V-NPS and P-NPS, with subsequent offspring (F1-F4 generations) cultured under NPS-free conditions. Exposure to 100 µg/L P-NPS resulted in more pronounced deterioration in locomotion behavior in the P0 generation compared to V-NPS; this deterioration persisted into the F1-F2 generations but returned to normal in the F3-F4 generations. Additionally, maternal exposure to P-NPS damaged dopaminergic, glutamatergic, and serotonergic neurons in subsequent generations. Correspondingly, there was a significant decrease in the levels of dopamine, glutamate, and serotonin, associated with reduced expression of neurotransmission-related genes dat-1, eat-4, and tph-1 in the P0 and F1-F2 generations. Further analysis showed that the effects of P-NPS on locomotion behavior were absent in subsequent generations of eat-4(ad572), tph-1(mg280), and dat-1(ok157) mutants, highlighting the pivotal roles of these genes in mediating P-NPS-induced transgenerational neurotoxicity. These findings emphasize the crucial role of neurotransmission in the transgenerational effects of P-NPS on locomotion behavior, providing new insights into the environmental risks associated with exposure to photoaged nanoplastics.

First report of sweet cherry root rot caused by Fusarium solani in China.

Sweet cherry (Prunus avium L.) has become an economically important fruit in China. And its cultivation area has significantly expanded over the last three decades (Wang et al. 2020; Zhao et al. 2023). In July 2023, wilting of cherry trees was observed in a cherry plantation in Wenchuan County (31°51'N, 103°56'E, altitude: 1,510 m) in Sichuan Province and approximately 27% of the trees showed symptoms of root rot including soft roots, dark brown to black lesions, yellowing and wilted leaves, and a distinct yellow-brown core discoloration of the inner root core when cut in cross-section. To isolate the causal pathogens, six infected sweet cherry plants with rootstock 'Daqingye' from Cerasus pseudocerasus were randomly selected from the orchard and then the intertwined diseased and healthy roots (5mm× 5mm × 2mm) were washed with sterile water to remove surface soil. The root samples were surface sterilized with 75% ethanol for 30 seconds and NaClO for 30 seconds and washed three times with distilled water. The disinfected tissues were placed on potato dextrose agar (PDA) and incubated at 27°C in darkness for 5 days (Zhao et al. 2024). A total of nine fungal isolates with similar morphological characteristics were obtained. The colony obtained through single-spore purification displays a red reverse side and a concentric ring pattern on the front, with a sparse surface. Macroconidia were relatively slender with a curve, like sickle shape, 0 to 3 septate measuring (25.8 to 46.1) µm× (4.2 to 7.5) µm, respectively (n=20). The morphological characteristics were consistent with the description of Fusarium spp. (Li et al. 2021). Among these isolates, only HB5 was selected for additional molecular identification. Three target genes, including the internal transcribed spacer (ITS), partial translation elongation factor 1-alpha (TEF), and RNA polymerase second largest subunit (RPB2) were amplified using the primers ITS1/ITS4, TEF1-728/FTEF1-re, and fRPB2-5F/fRPB2-7r, respectively (Groenewald et al. 2013; Carbone and Kohn 1999; Reeb et al. 2004). Sequences of HB5 was deposited in GenBank (ITS, PP388208; TEF, PP580036; RPB2, PP580035). A BLAST search revealed high similarity to those of F. solani sequences with 99%, 100% and 100% respectively (MN013858.1, JF740846.1, OR371902.1), and a multilocus phylogenetic tree was generated to represent the molecular identification results. Pathogenicity studies were conducted on the rootstocks from 'Daqingye' of Cerasus pseudocerasus in 1 liter plastic flowerpots. The seedlings were incubated in a constant temperature incubator at 25°C with a humidity level of 65% for two weeks. Following the growth of green leaves, 200ml (1x106 spores/ml) of spore suspensions were poured into pots. After 4 weeks of inoculation, the same symptoms of the inoculated plants were observed consistent with those shown in the field , while control plants were inoculated with distill water with asymptomatic. The inoculated pathogen was confirmed both morphologically and molecularly as described earlier, thereby fulfilling Koch's postulates. It has been reported that Fusarium solani has been reported to cause root rot in various plants in China, including Actinidia sppt, Zanthoxylum bungeanum, Fragaria×ananassa Duch (Song et al.2022; Li et al. 2023; Zhao et al. 2024). To our knowledge, this is the first report of Fusarium solani causing root rot in sweet cherry (Prunus avium). We here also report the severity and outbreak of this disease, which has been found in other regions in recent years and may become prevalent. Further research on disease management strategies is urgently needed to protect sweet cherry production.

A Multi-Modal Deep-Learning Air Quality Prediction Method Based on Multi-Station Time-Series Data and Remote-Sensing Images: Case Study of Beijing and Tianjin.

The profound impacts of severe air pollution on human health, ecological balance, and economic stability are undeniable. Precise air quality forecasting stands as a crucial necessity, enabling governmental bodies and vulnerable communities to proactively take essential measures to reduce exposure to detrimental pollutants. Previous research has primarily focused on predicting air quality using only time-series data. However, the importance of remote-sensing image data has received limited attention. This paper proposes a new multi-modal deep-learning model, Res-GCN, which integrates high spatial resolution remote-sensing images and time-series air quality data from multiple stations to forecast future air quality. Res-GCN employs two deep-learning networks, one utilizing the residual network to extract hidden visual information from remote-sensing images, and another using a dynamic spatio-temporal graph convolution network to capture spatio-temporal information from time-series data. By extracting features from two different modalities, improved predictive performance can be achieved. To demonstrate the effectiveness of the proposed model, experiments were conducted on two real-world datasets. The results show that the Res-GCN model effectively extracts multi-modal features, significantly enhancing the accuracy of multi-step predictions. Compared to the best-performing baseline model, the multi-step prediction's mean absolute error, root mean square error, and mean absolute percentage error increased by approximately 6%, 7%, and 7%, respectively.

[Identification method of 2-methylisoborneol and geosmin in water by purge and trap-gas chromatography-mass spectrometry].

OBJECTIVE: To establishe an analysis and identification method for 2-methylisoborneol(2-MIB) and geosmin(GSM) in water using purge and trap-gas chromatography-mass spectrometry. METHODS: The samples were enriched and analyzed using a purge and trap system, followed by the separation on a DB-624(30 m×0.25 mm, 1.4 µm) chromatographic column. Quantification was performed using gas chromatography-mass spectrometry with the selected ion monitoring and internal standard calibration. RESULTS: The calibration curves for 2-MIB and GSM showed an excellent linearity in the range of 1 to 100 ng/L with R~2 values greater than 0.999. The detection limit and quantification limit for both 2-MIB and GSM were 0.33 ng/L and 1.0 ng/L, respectively. Spike recovery experiments were further carried on the source water and drinking water at three concentration levels. It showed that the average recoveries were from 82.0% to 111.0% for 2-MIB while 84.0% to 110% for GSM. Additionally, the test precision of 2-MIB and GSM ranged from 1.9% to 7.3% and 1.9% to 5.0%(n=6), respectively. The analysis of multiple samples including the local source water, treated water and distribution network water confirmed the existence of 2-MIB and GSM. CONCLUSION: Compared to the national standard(GB/T 5750.8-2023), the proposed method enables fully automated sample introduction and analysis without the extra pre-treatment. It provides the advantages of simplicity, good repeatability and high accuracy.

Brominated flame retardants in surface sediment from Western Guangdong, South China: Occurrence, distribution and toxicity in Caenorhabditis elegans.

Sediment is the ultimate sink of environmental pollutants. A total of 128 surface sediment samples were collected from 8 rivers and 3 reservoirs in Maoming City, Guangdong Province. This study assessed the content and distribution of brominated flame retardants in sediments. The acute toxicity effects of tetrabromobisphenol A (TBBPA) and hexabromocyclododecane (HBCDs) in sediments were evaluated using Caenorhabditis elegans as model organisms. The concentration of TBBPA in sediments ranged from not detected (ND) to 12.59 µg/kg and was mainly distributed in the central area, which was affected by the emission of TBBPA from residential and factory. The concentration of HBCDs ranged from ND to 6.31 µg/kg, and the diastereoisomer distribution was consistent, showing a trend close to the South China Sea. The composition pattern of HBCDs in the surface sediments from rivers were 41.73%-62.33%, 7.89%-25.54%, and 18.76%-40.65% for α-, ß-, and γ-HBCD, respectively, and in the sediments from reservoirs were 26.15%-45.52%, 7.44%-19.23%, and 47.04%-61.89% for α-, ß-, and γ-HBCD, respectively. When the sum of concentrations of TBBPA and HBCD in sediments were above high levels, reactive oxygen species in nematodes significantly increased, resulting in an oxidative stress response. Intestinal permeability was also enhanced, causing intestinal damage. In addition, in terms of this study, TBBPA had a greater impact on biotoxicity compared to HBCDs, and more attention should be paid to the toxic effects of the river ecosystem organisms in Maoming City, Guangdong Province. This study can complement the pollution database in the study area and provide basic data for pollution control.

The influence mechanism of self-transcendence on green consumption: The chain-mediating effect of construction of meaning in life and connectedness.

A transition to a more sustainable society is occurring worldwide and necessitates a change in people's ways of consuming. Self-transcendence (ST) is recognized as a key predictor of green consumption. Thus, a multiple intermediary model was developed to clarify the psychological mechanisms underlying ST and its influence on consumption. The model was tested using data from a nationally representative sample of 428 Chinese participants. The results show that ST's overall positive effect on green consumption is realized via four indirect paths: (1) the simple mediating role of nature connectedness between ST and green consumption, (2) the simple mediating role of social connectedness between ST and green consumption; (3) the chain-mediating role of construction of meaning in life (CoMIL) and nature connectedness, and (4) the chain-mediating role of CoMIL and social connectedness. Among these paths, nature connectedness plays the most critical mediating role for the Chinese, accounting for the greatest proportion of the total indirect effect. The study advances understanding of the influence and path of ST on green consumption, and provides theoretical and practical support for guiding people toward sustainable lifestyles.

Environmentally persistent free radicals on photoaged microplastics from disposable plastic cups induce the oxidative stress-associated toxicity.

Microplastics (MPs) are ubiquitous environmental contaminants that exerting multiple toxicological effects. Most studies have focused primarily on the models of unaged MPs and lack environmental relevance. The generation and toxicity of environmentally persistent free radicals (EPFRs) on photoaging MPs from disposable plastic cups (DPC-MPs) have not been well studied. Here, the formation of EPFRs on photoaged DPC-MPs and their toxic effects in nematodes were investigated. UV irradiation generated EPFRs, which influenced the characterization of DPC-MPs. Exposure to photoaged DPC-MPs at environmentally relevant concentrations （100-1000 µg/L） reduced the locomotion behavior, body length, and brood size. The Reactive oxygen species (ROS) production, lipofuscin accumulation, malondialdehyde (MDA), and 8-hydroxy-2'-deoxyguanosine (8-OHdG) levels were increased along with the downregulation of the expression levels of associated genes, such as clk-1, clt-1, and gst-4，in nematodes. Moreover, the toxicity and oxidative stress response of nematodes were significantly inhibited due to N-acetyl-l-cysteine (NAC). Pearson's correlation analysis revealed that the oxidative stress was significantly associated with adverse physiological effects. Therefore, EPFRs on photoaged DPC-MPs cause toxicity in nematodes, and oxidative stress is important for regulating toxicity. This study offers novel insights into the potential risks of DPC-MPs under UV irradiation, highlighting the need to consider the role of EPFRs in toxicity assessments of DPC-MPs.

[Potential Ecological Risk Characteristics and Source Apportionment of Heavy Metals in Farmland Soils around Typical Factories in Hunan Province Based on Monte-Carlo Simulation].

In order to explore the pollution characteristics， ecological risks， and pollution sources of heavy metals in farmland soils around typical factories in Hunan Province， the content characteristics of eight heavy metals in farmland soils around fluoride factories， leather factories， and plating plants were analyzed. The geo-accumulation index and potential ecological risk index were used to evaluate the pollution and environmental risk of heavy metals. The correlation analysis， hierarchical cluster analysis， and principal component analysis were used to analyze the sources of heavy metals. The Monte-Carlo model was used to evaluate the probability risk of regional ecological risk. The results showed that the main pollution elements in the soil were Cd and Zn， and their mean values were 4.46 and 2.73 times the background values， respectively. Zn was at a mild pollution level in the soil of the three typical factories， and Cd was at a moderate pollution level in the whole fluoride factory. The pollution sources of heavy metals in the typical factories were mainly natural sources， industrial activity sources （industrial waste discharge， mineral mining， and smelting activities）， traffic sources， etc. The results of potential ecological risk assessment showed that the ecological risk of the fluoride factory was at a high risk level， and the ecological risk of the leather factory and plating plants was at a high risk level. Cd was the main contributing element. The results of Monte-Carlo probabilistic ecological risk assessment reduced the uncertainty of deterministic assessment， which could provide scientific basis for accurate risk management and control in the regions.

Generation of environmentally persistent free radicals on photoaged tire wear particles and their neurotoxic effects on neurotransmission in Caenorhabditis elegans.

Tire wear particles (TWP) are a prevalent form of microplastics (MPs) extensively distributed in the environment, raising concerns about their environmental behaviors and risks. However, knowledge regarding the properties and toxicity of these particles at environmentally relevant concentrations, specifically regarding the role of environmentally persistent free radicals (EPFRs) generated during TWP photoaging, remains limited. In this study, the evolution of EPFRs on TWP under different photoaging times and their adverse effects on Caenorhabditis elegans were systematically investigated. The photoaging process primarily resulted in the formation of EPFRs and reactive oxygen species (O2•-, ⋅OH, and 1O2), altering the physicochemical properties of TWP. The exposure of nematodes to 100 µg/L of TWP-50 (TWP with a photoaging time of 50 d) led to a significant decrease in locomotory behaviors (e.g., head thrashes, body bends, and wavelength) and neurotransmitter contents (e.g., dopamine, glutamate, and serotonin). Similarly, the expression of neurotransmission-related genes was reduced in nematodes exposed to TWP-50. Furthermore, the addition of free-radical inhibitors significantly suppressed TWP-induced neurotoxicity. Notably, correlation analysis revealed a significantly negative correlation between EPFRs levels and the locomotory behaviors and neurotransmitter contents of nematodes. Thus, it was concluded that EPFRs on photoaged TWP induce neurotoxicity by affecting neurotransmission. These findings elucidate the toxicity effects and mechanisms of EPFRs, emphasizing the importance of considering their contributions when evaluating the environmental risks associated with TWP.

The Antioxidant Dendrobium officinale Polysaccharide Modulates Host Metabolism and Gut Microbiota to Alleviate High-Fat Diet-Induced Atherosclerosis in ApoE-/- Mice.

BACKGROUND: The discovery of traditional plants' medicinal and nutritional properties has opened up new avenues for developing pharmaceutical and dietary strategies to prevent atherosclerosis. However, the effect of the antioxidant Dendrobium officinale polysaccharide (DOP) on atherosclerosis is still not elucidated. PURPOSE: This study aims to investigate the inhibitory effect and the potential mechanism of DOP on high-fat diet-induced atherosclerosis in Apolipoprotein E knockout (ApoE-/-) mice. STUDY DESIGN AND METHODS: The identification of DOP was measured by high-performance gel permeation chromatography (HPLC) and Fourier transform infrared spectroscopy (FTIR). We used high-fat diet (HFD)-induced atherosclerosis in ApoE-/- mice as an animal model. In the DOP intervention stage, the DOP group was treated by gavage with 200 µL of 200 mg/kg DOP at regular times each day and continued for eight weeks. We detected changes in serum lipid profiles, inflammatory factors, anti-inflammatory factors, and antioxidant capacity to investigate the effect of the DOP on host metabolism. We also determined microbial composition using 16S rRNA gene sequencing to investigate whether the DOP could improve the structure of the gut microbiota in atherosclerotic mice. RESULTS: DOP effectively inhibited histopathological deterioration in atherosclerotic mice and significantly reduced serum lipid levels, inflammatory factors, and malondialdehyde (F/B) production. Additionally, the levels of anti-inflammatory factors and the activity of antioxidant enzymes, including superoxide dismutase (SOD) and glutathione peroxidase (GSH-PX), were significantly increased after DOP intervention. Furthermore, we found that DOP restructures the gut microbiota composition by decreasing the Firmicutes/Bacteroidota (F/B) ratio. The Spearman's correlation analysis indicated that serum lipid profiles, antioxidant activity, and pro-/anti-inflammatory factors were associated with Firmicutes, Bacteroidota, Allobaculum, and Coriobacteriaceae_UCG-002. CONCLUSIONS: This study suggests that DOP has the potential to be developed as a food prebiotic for the treatment of atherosclerosis in the future.

Inventorization and ecological risk assessment of tetrabromobisphenol A and hexabromocyclododecane in sediments from Guangdong coastal area of South China Sea.

Brominated flame retardants (BFRs) exhibit excellent flame retardant properties and are widely used in various industries. Among the common BFRs, tetrabromobisphenol A (TBBPA) and hexabromocyclododecane (HBCDs) pose substantial ecological and human health risks due to their extensive application and long-range transport. This study established 131 sample collection sites along the coast of the South China Sea (SCS) in Guangdong Province to assess the concentration, distribution, inventory, and ecological risk of TBBPA and HBCDs in surface sediments. The concentrations of TBBPA in SCS sediments ranged from < limit of detection (LOD) to 80 µg/kg dry weight (dw), and those of HBCDs from < LOD to 18 µg/kg dw. The diastereoisomers of HBCDs (α-, ß-, and γ-HBCD) in the sediment samples accounted for 36 %, 13 %, and 51 %, respectively. Human activities, particularly those associated with nearby electronic waste disassembly and textile and garment industries, considerably influenced the dispersion of TBBPA and HBCDs. The inventories of TBBPA and HBCDs in Guangdong Province's SCS were estimated to be 3.2 × 105 kg and 7.2 × 104 kg, respectively. The average risk quotient values ranged from <0.01 to 0.016, indicating a low to negligible environmental risk. This study provides deeper insights into the distribution and scientific significance of HBCDs and TBBPA in SCS sediment samples, elucidates the current state of BFR contamination, and offers recommendations for future research on environmental safety and human health in the region.

Transgenerational reproductive toxicity induced by carboxyl and amino charged microplastics at environmental concentrations in Caenorhabditis elegans: Involvement of histone methylation.

Microplastics, recognized as emerging contaminants, are commonly observed to be charged in the environment, potentially exerting toxic effects on various organisms. However, the transgenerational reproductive toxicity and underlying mechanisms of polystyrene (PS), particularly carboxyl-modified PS (PS-COOH) and amino-modified PS (PS-NH2), remain largely unexplored. In this study, the parental generation (P0) of Caenorhabditis elegans was subjected to environmental concentrations (0.1-100 µg/L) of PS, PS-COOH, and PS-NH2, with subsequent generations (F1-F4) cultured under normal conditions. Exposure to PS-NH2 at concentrations of 10-100 µg/L exhibited more pronounced reproductive toxicity compared to PS or PS-COOH, resulting in decreased brood size, egg ejection rate, number of fertilized eggs, and cell corpses per gonad. Similarly, maternal exposure to 100 µg/L of PS-NH2 induced more severe transgenerational reproductive effects in C. elegans. Significant increases in H3 on lysine 4 dimethylation (H3K4me2) and H3 on lysine 9 trimethylation (H3K9me3) levels were observed in the subsequent generation, concurrent with the transgenerational upregulation of set-30 and met-2 following parental exposure to PS, PS-COOH, and PS-NH2. Correlation analyses revealed significant associations between the expression of these genes with the reproductive ability. Molecular docking studies suggested that PS-NH2 exhibited higher affinity for SET-30 and MET-2. Further analysis demonstrated that transgenerational effects on reproduction were absent in set-30(gk315) and met-2(n4256) mutants, highlighting the pivotal role of set-30 and met-2 in mediating the transgenerational effect. This study provides novel insights into the environmental risks associated with negatively and positively charged microplastics.

Photoaging enhances combined toxicity of microplastics and tetrabromobisphenol A by inducing intestinal damage and oxidative stress in Caenorhabditis elegans.

Microplastics (MPs) are emerging environmental contaminants that often co-exist with tetrabromobisphenol A (TBBPA) in the environment. However, the joint effect of TBBPA and photoaged MPs at ambient concentrations remains unknown largely. In this study, the combined toxicity of ultraviolet-aged polystyrene (UV-PS) and TBBPA was investigated in Caenorhabditis elegans. UV irradiation could change the physical and chemical characteristics of polystyrene (PS), and UV-PS (90.218 µg/g) showed a stronger adsorption capacity than PS of 79.424 µg/g. Toxicity testing showed that 1 µg/L UV-PS enhanced the toxic effect of 1 µg/L TBBPA by reducing body length, locomotion behavior, and brood size in nematodes. Using ROS production, lipofuscin accumulation, and expression of gst-4::GFP as endpoints, the combined exposure of UV-PS and TBBPA induced stronger oxidative stress than TBBPA alone. Joint exposure to UV-PS and TBBPA significantly increased of Nile red and blue food dye in its intestinal tract compared to that in the TBBPA exposure group, indicating that co-exposure enhanced intestinal permeability. After co-exposure to UV-PS and TBBPA, the expression of the associated genes detected increased significantly. Therefore, UV-PS enhances the adverse effects of TBBPA through intestinal damage and oxidative stress in nematodes. These findings suggest that the co-presence of photoaged PS and TBBPA results in high environmental risks.

Targeting focal adhesion kinase boosts immune response in KRAS/LKB1 co-mutated lung adenocarcinoma via remodeling the tumor microenvironment.

BACKGROUND: KRAS mutation is one of the most common oncogenic drivers in NSCLC, however, the response to immunotherapy is heterogeneous owing to the distinct co-occurring genomic alterations. KRAS/LKB1 co-mutated lung adenocarcinoma displays poor response to PD-1 blockade whereas the mechanism remains undetermined. METHODS: We explored the specific characteristics of tumor microenvironment (TME) in KL tumors using syngeneic KRASG12DLKB1-/- (KL) and KRASG12DTP53-/- (KP) lung cancer mouse models. The impact of focal adhesion kinase (FAK) inhibitor on KL lung tumors was investigated in vitro and in vivo through evaluation of both KL cell lines and KL lung cancer mouse models. RESULTS: We identified KL tumors as "immune-cold" tumors with excessive extracellular matrix (ECM) collagen deposition that formed a physical barrier to block the infiltration of CD8+T cells. Mechanistically, abundant activated cancer-associated fibroblasts (CAFs) resulted from FAK activation contributed to the formation of the unique TME of KL tumors. FAK inhibition with a small molecular inhibitor could remodel the TME by inhibiting CAFs activation, decreasing collagen deposition and further facilitating the infiltration of anti-tumor immune cells, including CD8+ T cells, DC cells and M1-like macrophages into tumors, hence, converting "immune-cold" KL tumors into "immune-hot" tumors. The combined FAK inhibitor and PD-1 blockade therapy synergistically retarded primary and metastatic tumor growth of KL tumors. CONCLUSIONS: Our study identified FAK as a promising intervention target for KL tumors and provided basis for the combination of FAK inhibitor with PD-1 blockade in the management of KL lung cancers.

A photoelectrochemical sensor based on In2S3/AgInS2 in situ Z-type heterojunction with "photo-modulated interface charge" for sensitive detection of Programmed Death-Ligand 1.

The construction of heterostructure photoelectrodes can enhance the performance of photoelectrochemical (PEC) sensors. However, it is still a critical challenge to achieve efficient transfer of interface carriers. In this paper, we propose a strategy of "photo-modulated interface charge" to design a PEC sensor based on a hollow hexagonal tubular In2S3/AgInS2 in situ Z-type heterojunction for the susceptible detection of Programmed Death-ligand 1 (PD-L1). The hollow structured In2S3/AgInS2 is ingeniously synthesized employing indium-sourced MIL-68 as a sacrificial template and in situ cation exchange technique. This composite material has close contact interfaces due to in situ growth, which facilitates the spontaneous establishment of a robust and stable built-in electric field between the interfaces. Moreover, the inner cavity structure promotes multiple light refractions and scatterings, significantly enhancing light trapping capability. Under the influence of both light irradiation and electric field force, the migration direction of the interfacial charge is reversed, forming a Z-transfer path, which effectively delays the compounding of the electron-hole pairs (e-/h+) and further improves the sensitivity of the sensor. The minimum detection threshold of the PEC sensor is 26.58 fg/mL, and the feasibility of real samples is investigated, providing new insights for early diagnosis and prognostic treatment of diseases.

Efficacy and safety of local ablative therapy for patients with NSCLC and coexisting interstitial lung disease.

BACKGROUND: The effective therapeutic approach is still an unmet need for patients diagnosed with both lung cancer and interstitial lung disease (ILD). This is primarily due to the possible risk of ILD exacerbation caused by surgery or radiotherapy. The current study aimed to investigate the efficacy and safety of local ablative therapy (LAT) for this specific population. METHODS: Consecutive patients with non-small cell lung cancer (NSCLC) and ILD who received LAT between January 2018 and August 2022 were enrolled, and propensity score matching (PSM) was utilized to match the non-ILD group. The primary endpoint was recurrence-free survival (RFS), and secondary endpoints included overall survival (OS), adverse events (AEs) and hospital length of stay (HLOS). RESULTS: The PSM algorithm yielded matched pairs in the ILD group (n = 25) and non-ILD group (n = 72) at a ratio of 1:3. There were no statistically significant differences in RFS (median 16.4 vs. 18 months; HR = 1.452, p = 0.259) and OS (median: not reached vs. 47.9 months; HR = 1.096, p = 0.884) between the two groups. Meanwhile, no acute exacerbation of ILD was observed in the ILD group. However, the incidence of pneumothorax, especially pneumothorax requiring chest tube drainage, was significantly higher (36.0% vs. 11.2%, p = 0.005) among patients with NSCLC and co-existing ILD, which resulted in longer HLOS (p = 0.045). CONCLUSION: Although ILD was associated with a higher incidence of pneumothorax, the efficacy of LAT for NSCLC patients with ILD was comparable to those without ILD, suggesting that LAT might be a reliable and effective treatment option for this population, particularly in the early stage.