Effect of genistein supplementation on microenvironment regulation of breast tumors in obese mice.

Obesity is an important risk factor for breast cancer in women before and after menopause. Adipocytes, key mediators in the tumor microenvironment, play a pivotal role in the relationship between obesity with cancer. However, the potential of dietary components in modulating this relationship remains underexplored. Genistein, a soy-derived isoflavone, has shown promise in reducing breast cancer risk, attenuating obesity-associated inflammation, and improving insulin resistance. However, there are no reports examining whether genistein has the ability to reduce the effects of obesity on breast tumor development. In this study, we constructed a mammary tumor model in ovariectomized obese mice and examined the effects of genistein on body condition and tumor growth. Moreover, the effects of genistein on the tumor microenvironment were examined via experimental observation of peritumoral adipocytes and macrophages. In addition, we further investigated the effect of genistein on adipocyte and breast cancer cell crosstalk via coculture experiments. Our findings indicate that dietary genistein significantly alleviates obesity, systemic inflammation, and metabolic disorders induced by a high-fat diet in ovariectomized mice. Notably, it also inhibits tumor growth in vivo. The impact of genistein extends to the tumor microenvironment, where it reduces the production of cancer-associated adipocytes (CAAs) and the recruitment of M2d-subtype macrophages. In vitro, genistein mitigates the transition of adipocytes into CAAs and inhibits the expression of inflammatory factors by activating PPAR-γ pathway and degrading nuclear NF-κB. Furthermore, it impedes the acquisition of invasive properties and epithelial‒mesenchymal transition in breast cancer cells under CAA-induced inflammation, disrupting the Wnt3a/ß-catenin pathway. Intriguingly, the PPAR-γ inhibitor T0070907 counteracted the effects of genistein in the coculture system, underscoring the specificity of its action. Our study revealed that genistein can mitigate the adverse effects of obesity on breast cancer by modulating the tumor microenvironment. These findings provide new insights into how genistein intake and a soy-based diet can reduce breast cancer risk.

A Candy Defect Detection Method Based on StyleGAN2 and Improved YOLOv7 for Imbalanced Data.

Quality management in the candy industry is a vital part of food quality management. Defective candies significantly affect subsequent packaging and consumption, impacting the efficiency of candy manufacturers and the consumer experience. However, challenges exist in candy defect detection on food production lines due to the small size of the targets and defects, as well as the difficulty of batch sampling defects from automated production lines. A high-precision candy defect detection method based on deep learning is proposed in this paper. Initially, pseudo-defective candy images are generated based on Style Generative Adversarial Network-v2 (StyleGAN2), thereby enhancing the authenticity of these synthetic defect images. Following the separation of the background based on the color characteristics of the defective candies on the conveyor belt, a GAN is utilized for negative sample data enhancement. This effectively reduces the impact of data imbalance between complete and defective candies on the model's detection performance. Secondly, considering the challenges brought by the small size and random shape of candy defects to target detection, the efficient target detection method YOLOv7 is improved. The Spatial Pyramid Pooling Fast Cross Stage Partial Connection (SPPFCSPC) module, the C3C2 module, and the global attention mechanism are introduced to enhance feature extraction precision. The improved model achieves a 3.0% increase in recognition accuracy and a 3.7% increase in recall rate while supporting real-time recognition scenery. This method not only enhances the efficiency of food quality management but also promotes the application of computer vision and deep learning in industrial production.

Exploring shared biomarkers and shared pathways in insomnia and atherosclerosis using integrated bioinformatics analysis.

Background: Insomnia (ISM) is one of the non-traditional drivers of atherosclerosis (AS) and an important risk factor for AS-related cardiovascular disease. Our study aimed to explore the shared pathways and diagnostic biomarkers of ISM-related AS using integrated bioinformatics analysis. Methods: We download the datasets from the Gene Expression Omnibus database and the GeneCards database. Weighted gene co-expression network analysis and gene differential expression analysis were applied to screen the AS-related gene set. The shared genes of ISM and AS were obtained by intersecting with ISM-related genes. Subsequently, candidate diagnostic biomarkers were identified by constructing protein-protein interaction networks and machine learning algorithms, and a nomogram was constructed. Moreover, to explore potential mechanisms, a comprehensive analysis of shared genes was carried out, including enrichment analysis, protein interactions, immune cell infiltration, and single-cell sequencing analysis. Results: We successfully screened 61 genes shared by ISM and AS, of which 3 genes (IL10RA, CCR1, and SPI1) were identified as diagnostic biomarkers. A nomogram with excellent predictive value was constructed (the area under curve of the model constructed by the biomarkers was 0.931, and the validation set was 0.745). In addition, the shared genes were mainly enriched in immune and inflammatory response regulation pathways. The biomarkers were associated with a variety of immune cells, especially myeloid immune cells. Conclusion: We constructed a diagnostic nomogram based on IL10RA, CCR1, and SPI1 and explored the inflammatory-immune mechanisms, which indicated new insights for early diagnosis and treatment of ISM-related AS.

Benchmarking Large Language Models in Evidence-Based Medicine.

Evidence-based medicine (EBM) represents a paradigm of providing patient care grounded in the most current and rigorously evaluated research. Recent advances in large language models (LLMs) offer a potential solution to transform EBM by automating labor-intensive tasks and thereby improving the efficiency of clinical decision-making. This study explores integrating LLMs into the key stages in EBM, evaluating their ability across evidence retrieval (PICO extraction, biomedical question answering), synthesis (summarizing randomized controlled trials), and dissemination (medical text simplification). We conducted a comparative analysis of seven LLMs, including both proprietary and open-source models, as well as those fine-tuned on medical corpora. Specifically, we benchmarked the performance of various LLMs on each EBM task under zero-shot settings as baselines, and employed prompting techniques, including in-context learning, chain-of-thought reasoning, and knowledge-guided prompting to enhance their capabilities. Our extensive experiments revealed the strengths of LLMs, such as remarkable understanding capabilities even in zero-shot settings, strong summarization skills, and effective knowledge transfer via prompting. Promoting strategies such as knowledge-guided prompting proved highly effective (e.g., improving the performance of GPT-4 by 13.10% over zero-shot in PICO extraction). However, the experiments also showed limitations, with LLM performance falling well below state-of-the-art baselines like PubMedBERT in handling named entity recognition tasks. Moreover, human evaluation revealed persisting challenges with factual inconsistencies and domain inaccuracies, underscoring the need for rigorous quality control before clinical application. This study provides insights into enhancing EBM using LLMs while highlighting critical areas for further research. The code is publicly available on Github.

Mating behaviour and cholesterol nutritional strategies promoted ovarian development of female swimming crab (Portunus trituberculatus).

Female crabs enter a stage of rapid ovarian development after mating, and cholesterol is a substrate for steroid hormone synthesis. Therefore, in this experiment, an 8-week feeding trial was conducted to investigate the effects of mating treatments (mated crab and unmated crab) and three dietary cholesterol levels (0·09 %, 0·79 % and 1·40 %) on ovarian development, cholesterol metabolism and steroid hormones metabolism of adult female swimming crab (Portunus trituberculatus). The results indicated that crabs fed the diet with 0·79 % cholesterol significantly increased gonadosomatic index (GSI) and vitellogenin (VTG) content than other treatments in the same mating status. Moreover, mated crabs had markedly increased GSI and VTG content in the ovary and hepatopancreas than unmated crabs. The histological observation found that exogenous vitellogenic oocytes appeared in the mated crabs, while previtellogenic oocytes and endogenous vitellogenic oocytes were the primary oocytes in unmated crabs. The transmission electron microscopy analysis showed that when fed diet with 0·79 % cholesterol, the unmated crabs contained more rough endoplasmic reticulum and mated crabs had higher yolk content than other treatments. Furthermore, mating treatment and dietary 0·79 % cholesterol level both promoted cholesterol deposition by up-regulation of the mRNA and protein expression levels of class B scavenger receptors 1 (Srb1), while stimulating the secretion of steroid hormones by up-regulation of the mRNA and protein expression of steroidogenic acute regulatory protein (Star). Overall, the present results indicated that mating behaviour plays a leading role in promoting ovarian development, and dietary 0·79 % cholesterol level can further promote ovarian development after mating.

Effect, Fate and Remediation of Pharmaceuticals and Personal Care Products (PPCPs) during Anaerobic Sludge Treatment: A Review.

Biomass energy recovery from sewage sludge through anaerobic treatment is vital for environmental sustainability and a circular economy. However, large amounts of pharmaceutical and personal care products (PPCPs) remain in sludge, and their interactions with microbes and enzymes would affect resource recovery. This article reviews the effects and mechanisms of PPCPs on anaerobic sludge treatment. Most PPCPs posed adverse impacts on methane production, while certain low-toxicity PPCPs could stimulate volatile fatty acids and biohydrogen accumulation. Changes in the microbial community structure and functional enzyme bioactivities were also summarized with PPCPs exposure. Notably, PPCPs such as carbamazepine could bind with the active sites of the enzyme and induce microbial stress responses. The fate of various PPCPs during anaerobic sludge treatment indicated that PPCPs featuring electron-donating groups (e.g., ·-NH2 and ·-OH), hydrophilicity, and low molecular weight were more susceptible to microbial utilization. Key biodegrading enzymes (e.g., cytochrome P450 and amidase) were crucial for PPCP degradation, although several PPCPs remain refractory to biotransformation. Therefore, remediation technologies including physical pretreatment, chemicals, bioaugmentation, and their combinations for enhancing PPCPs degradation were outlined. Among these strategies, advanced oxidation processes and combined strategies effectively removed complex and refractory PPCPs mainly by generating free radicals, providing recommendations for improving sludge detoxification.

The role of nonhistone lactylation in disease.

In 2019, a novel post-translational modification termed lactylation was identified, which established a connection among lactate, transcriptional regulation and epigenetics. Lactate, which is traditionally viewed as a metabolic byproduct, is now recognized for its significant functional role, including modulating the tumor microenvironment, engaging in signaling and interfering in immune regulation. While research on lactylation (KLA) is advancing, the focus has primarily been on histone lactylation. This paper aims to explore the less-studied area of nonhistone lactylation, highlighting its involvement in certain diseases and physiological processes. Additionally, the clinical relevance and potential implications of nonhistone lactylation will be discussed.

A hyaluronic acid-based dissolving microneedle patch loaded with 5-aminolevulinic acid for improved oral leukoplakia treatment.

INTRODUCTION: A local microneedle patch loaded with 5-aminolevulinic acid (ALA) was constructed to improve the efficiency of ALA photodynamic treatment of oral leukoplakia, reduce local photosensitivity reactions, and promote the healing of lesions. METHODS: The microneedle patch loaded with ALA was constructed with the hyaluronic acid (HA) solution (ALA-HAMN), and its morphology, strength, mucosal penetration, and biocompatibility were tested. RESULTS: In vivo safety and permeability tests confirmed that ALA-HAMN had good biocompatibility and could penetrate the mucosal barrier and quickly dissolve and release ALA for in situ transdermal administration. The 4-nitroquinoline oxide (NQO) rat model experiment showed that ALA-HAMN can significantly improve photodynamic therapy (PDT) efficiency and has no damage to mucosal tissue compared with the commonly used ALA cotton ball dressing. CONCLUSIONS: The ALA-loaded microneedle patch was successfully constructed for the photodynamic treatment of oral leukoplakia, and the photodynamic efficiency and comfort of oral leukoplakia were improved, which provided an effective delivery mode to improve clinical ALA-PDT treatment of oral leukoplakia (OLK).

Transcriptomic and Metabolomic Analysis Reveal the Effects of Light Quality on the Growth and Lipid Biosynthesis in Chlorella pyrenoidosa.

Light quality has significant effects on the growth and metabolite accumulation of algal cells. However, the related mechanism has not been fully elucidated. This study reveals that both red and blue light can promote the growth and biomass accumulation of Chlorella pyrenoidosa, with the enhancing effect of blue light being more pronounced. Cultivation under blue light reduced the content of total carbohydrate in Chlorella pyrenoidosa, while increasing the content of protein and lipid. Conversely, red light decreased the content of protein and increased the content of carbohydrate and lipid. Blue light induces a shift in carbon flux from carbohydrate to protein, while red light transfers carbon flux from protein to lipid. Transcriptomic and metabolomic analysis indicated that both red and blue light positively regulate lipid synthesis in Chlorella pyrenoidosa, but they exhibited distinct impacts on the fatty acid compositions. These findings suggest that manipulating light qualities can modulate carbon metabolic pathways, potentially converting protein into lipid in Chlorella pyrenoidosa.

Electrochemical production of HO2- and O2 for sulfide removal from sewage.

In this study, a comparative analysis of two electrochemical methods for sulfide control in sewer networks was performed for the first time. In addition, the mechanism of sulfide control by HO2- was elucidated, and an analysis of the device operation and electrolyte selection was performed. The two-electron oxygen reduction reaction (2e--ORR) using untreated gas diffusion electrode (GDE) was superior to the hydrogen evolution reaction (HER) using stainless-steel mesh in terms of cell voltage, product formation, and sulfide suppression. The GDE maintained a stable HO2⁻ production capacity, achieving a concentration of 4566.6 ± 173.3 mg L⁻¹ with a current efficiency (CE) of 84.13 ± 3.5 %. During the electrolysis period, a stable dissolved oxygen (DO) level in sewage was consistently observed due to continuous in-situ oxygen production in anode. HO2- exhibited a notable increase in sewage pH (10.20 ± 0.01), effectively inhibiting the release of 99.93 % of sulfides. Moreover, the combined treatment of HO2- and DO significantly surpassed that of individual treatments. Seawater treated with cation exchange resin (CER) emerged as the most promising alternative to freshwater as the electrolyte. Overall, this study demonstrates that in-situ generation of HO2⁻ and oxygen is a more effective strategy for sulfide control in sewer systems.

Hydrocyclone combines with alkali-thermal pretreatment to enhance short-chain fatty acids production from anaerobic fermentation of waste activated sludge.

The production of short-chain fatty acids (SCFAs) through anaerobic fermentation of waste activated sludge (WAS) is commonly constrained by limited substrate availability, particularly for WAS with low organic content. Combining the hydrocyclone (HC) selection with alkali-thermal (AT) pretreatment is a promising solution to address this limitation. The results indicated that HC selection modified the sludge properties by enhancing the ratio of mixed liquid volatile suspended solids (MLVSS)/mixed liquid suspended solids (MLSS) by 19.0% and decreasing the mean particle size by 17.4%, which were beneficial for the subsequent anaerobic fermentation process. Under the optimal HC + AT condition, the peak value of SCFAs production reached 4951.9 mg COD/L, representing a 23.2% increase compared to the raw sludge with only AT pretreatment. Mechanism investigations revealed such enhancement beyond mechanical separation. It involved an increase in bound extracellular polymeric substances (EPS) through HC selection and the disruption of sludge spatial structure by AT pretreatment. Consequently, this combination pretreatment accelerated the transfer of particulate organics (i.e., bound EPS and intracellular components) to the supernatant, thus increasing the accessibility of WAS substrate to hydrolytic and acidifying bacteria. Furthermore, the microbial structure was altered with the enrichment of key functional microorganisms, probably due to the facilitation of substrate biotransformation and product output. Meanwhile, the activity of hydrolases and SCFAs-forming enzymes increased, while that of methanogenic enzymes decreased. Overall, this strategy successfully enhanced SCFAs production from WAS while reducing the environmental risks of WAS disposal.

Prefrontal cortex astrocytes in major depressive disorder: exploring pathogenic mechanisms and potential therapeutic targets.

Major depressive disorder (MDD) is a prevalent mental health condition characterized by persistent feelings of sadness and hopelessness, affecting millions globally. The precise molecular mechanisms underlying MDD remain elusive, necessitating comprehensive investigations. Our study integrates transcriptomic analysis, functional assays, and computational modeling to explore the molecular landscape of MDD, focusing on the DLPFC. We identify key genomic alterations and co-expression modules associated with MDD, highlighting potential therapeutic targets. Functional enrichment and protein-protein interaction analyses emphasize the role of astrocytes in MDD progression. Machine learning is employed to develop a predictive model for MDD risk assessment. Single-cell and spatial transcriptomic analyses provide insights into cell type-specific expression patterns, particularly regarding astrocytes. We have identified significant genomic alterations and co-expression modules associated with MDD in the DLPFC. Key genes involved in neuroactive ligand-receptor interaction pathways, notably in astrocytes, have been highlighted. Additionally, we developed a predictive model for MDD risk assessment based on selected key genes. Single-cell and spatial transcriptomic analyses underscored the role of astrocytes in MDD. Virtual screening of compounds targeting GPR37L1, KCNJ10, and PPP1R3C proteins has identified potential therapeutic candidates. In summary, our comprehensive approach enhances the understanding of MDD's molecular underpinnings and offers promising opportunities for advancing therapeutic interventions, ultimately aiming to alleviate the burden of this debilitating mental health condition. KEY MESSAGES: Our investigation furnishes insightful revelations concerning the dysregulation of astrocyte-associated processes in MDD. We have pinpointed specific genes, namely KCNJ10, PPP1R3C, and GPR37L1, as potential candidates warranting further exploration and therapeutic intervention. We incorporate a virtual screening of small molecule compounds targeting KCNJ10, PPP1R3C, and GPR37L1, presenting a promising trajectory for drug discovery in MDD.

The causal relationship between hydatidiform mole and nutrients: A two-sample Mendelian randomization study.

BACKGROUND: Hydatidiform mole (HM), a subset of gestational trophoblastic disease, is considered precancerous and exhibits geographical variation. The incidence of HM is linked to nutritional factors. This study aimed to investigate the causal relationship between nutrients and HM using a bidirectional two-sample Mendelian randomization (MR) approach. METHODS: We utilized publicly available genome-wide association study data to assess the causal associations between levels of specific vitamins (retinol, vitamins B12, B6, C, D, E, folate, and carotene) and minerals (iron, calcium, and magnesium) with HM. The MR analysis was conducted and reported following the STROBE-MR guidelines, employing MR Egger and inverse variance weighted (IVW) methods to estimate associations, with MR-PRESSO for pleiotropy testing. RESULTS: The study revealed vitamin B6 as a significant protective factor against HM (MR-Egger OR: 0.094, 95 % CI: 0.011-0.0778, P < 0.05; IVW OR: 0.365, 95 % CI: 0.142-0.936, P < 0.05). Folate and magnesium showed suggestive associations with HM, whereas most other nutrients did not exhibit a causal relationship. MR-PRESSO analysis supported the absence of horizontal pleiotropy of vitamin B6. Besides, reverse MR analysis did not reveal a significant causal association between HM and serum nutrient levels, suggesting that differences of nutrients in HM patients may not be directly attributed to the mole. CONCLUSION: This MR study provides evidence that vitamin B6 may protect against HM, and suggests potential roles for folate and magnesium in HM development, while highlighting the need for further research to confirm these findings.

Interaction of poly dimethyl diallyl ammonium chloride with sludge components: Anaerobic digestion performance and adaptive changes of anaerobic microbes.

The wide utilization of poly dimethyl diallyl ammonium chloride (polyDADMAC) in industrial conditions leads to its accumulation in waste activated sludge (WAS), thereby affecting subsequent WAS treatment processes. This work investigated the interaction between polyDADMAC and WAS components from the perspective of anaerobic digestion (AD) performance and anaerobes adaptability variation. The results showed that polyDADMAC decreased the content of biodegradable organic substrates (i.e., soluble protein and carbohydrate) by binding with the functional groups and then settling to the solid phase, thus impeding the subsequent utilization. Higher concentrations of polyDADMAC prompted an initial protective response of excreting organic substrates into extracellular environment, but its toxicity to archaea was irreversible. Consequently, polyDADMAC inhibited the processes of AD and induced a 30 % reduction in methane production with 0.05 g polyDADMAC/g total suspended solid (TSS) addition. Changes in microbial community structure indicated that archaea involved in methane production (e.g., Anaerolineaceae sp. and Methanosaeta sp.) were inhibited when exposed to polyDADMAC. However, several adaptive bacteria with the ability of utilizing complex organics and participating in nitrogen cycle (e.g., Aminicenantales sp. and Ellin6067 sp.) were enriched with the above dosage. Specifically, the decreased abundance of genes relevant to methane metabolism pathway (i.e., mer and cdh) and increased abundance of genes involved in metabolism of cofactors and vitamins (e.g., nad and thi) indicated the toxicity of polyDADMAC and the irritant response of microflora. Moreover, polyDADMAC underwent degradation in AD system, resulting in a 12 % reduction in 15 days, accompanied by an increase in the -NO2 functional group. In general, this study provided a thorough understanding of the interaction between polyDADMAC and WAS components, raising concerns regarding the elimination of endogenous pollutants during AD.

Sirt1 Mitigates Hepatic Lipotoxic Injury Induced by High-Fat-Diet in Fish Through Ire1α Deacetylation.

BACKGROUND: Silent information regulator protein 1 (Sirt1) is crucial in regulating lipid metabolism, but its specific role and mechanism in fish hepatic lipotoxic injury remain undefined. OBJECTIVES: This study aimed to elucidate the regulatory role of Sirt1 and the underlying mechanisms in dietary lipid-induced hepatic lipotoxic injury in a marine teleost black seabream. METHODS: Black seabream were fed a control diet (12% lipid level), high-fat diet (HFD) [18% lipid level, oleic acid (OA)-rich], or HFD supplemented with 0.25%, 0.50%, or 1.00% resveratrol (RSV) for 8 wk. The cultured hepatocytes were stimulated by OA (200 µM), OA supplemented with RSV (20 µM), or transfection with sirt1-small interfering RNA (sisirt1). Biochemical indices, gene expression (qPCR), histology, transmission electron microscope, immunofluorescence, Western blot, flow cytometry, and immunoprecipitation assays were conducted to evaluate hepatic lipid deposition, lipid metabolism, endoplasmic reticulum stress, inflammation and apoptosis, and determine protein interactions between Sirt1 and Ire1α. RESULTS: In vivo, RSV supplementation increased mRNA and protein expression levels of sirt1 (236.2% ± 16.1% and 53.1% ± 14.3%) and downregulated the mRNA and phosphorylated protein expression levels of ire1α/Ire1α (46.0% ± 7.6% and 38.6% ± 7.0%), jnk/Jnk (57.6% ± 7.3% and 122.1%), and nuclear factor κ B (nf-κb/Nf-κb) p65 (41.7% ± 7.1% and 24.6% ± 0.8%) compared with the HFD group. Similar patterns were found in the in vitro experiments; however, after knockdown of sirt1, although the cells were incubated with RSV, the expression levels of ire1α/ Ire1α, jnk/Jnk, and nf-κb/Nf-κb p65 showed no significant differences compared with the OA treatment. Moreover, we found that mutation of K61 to arginine to mimic Ire1α deacetylation confers protection against Ire1α-mediated OA-rich HFD-induced inflammation and apoptosis. CONCLUSIONS: The findings revealed that Sirt1 protects against OA-rich HFD-induced hepatic lipotoxic injury via the deacetylation of Ire1α on K61, hence reducing Ire1α autophosphorylation level, and suppressing Jnk and Nf-κb p65 activation. This mechanism is elucidated for the first time in fish.

Catalytic divergence of O-methyltransferases shapes the chemo-diversity of polymethoxylated bibenzyls in Dendrobium catenatum.

Erianin, crepidatin, and chrysotobibenzyl are typical medicinal polymethoxylated bibenzyls (PMBs) that are commercially produced in Dendrobium species. PMBs' chemo-diversity is mediated by the manifold combinations of O-methylation and hydroxylation in a definite order, which remains unsolved. To unequivocally elucidate the methylation mechanism of PMBs, 15 possible intermediates in the biosynthetic pathway of PMBs were chemically synthesized. DcOMT1-5 were highly expressed in tissues where PMBs were biosynthesized, and their expression patterns were well-correlated with the accumulation profiles of PMBs. Moreover, cell-free orthogonal tests based on the synthesized intermediates further confirmed that DcOMT1-5 exhibited distinct substrate preferences and displayed hydroxyl-group regiospecificity during the sequential methylation process. The stepwise methylation of PMBs was discovered from SAM to dihydro-piceatannol (P) in the following order: P → 3-MeP → 4-OH-3-MeP → 4-OH-3,5-diMeP → 3,3'(4'),5-triMeP → 3,4,4',5-tetraMeP (erianin) or 3,3',4,5-tetraMeP (crepidatin) → 3,3',4,4',5-pentaMeP (chrysotobibenzyl). Furthermore, the regioselectivities of DcOMTs were investigated by ligand docking analyses which corresponded precisely with the catalytic activities. In summary, the findings shed light on the sequential catalytic mechanisms of PMB biosynthesis and provide a comprehensive PMB biosynthetic network in D. catenatum. The knowledge gained from this study may also contribute to the development of plant-based medicinal applications and the production of high-value PMBs.

Biodegradable microplastics aggravate greenhouse gas emissions from urban lake sediments more severely than conventional microplastics.

Freshwater ecosystems, such as urban lake sediments, have been identified as important sources of greenhouse gases (GHGs) to the atmosphere, as well as persistent sinks for ubiquitous microplastics due to the high population density and frequent anthropogenic activity. The potential impacts of microplastics on GHG production, however, remain underexplored. In this study, four types of common biodegradable microplastics (BMPs) versus four conventional non-biodegradable microplastics (NBMPs) were artificially exposed to urban lake sediments to investigate the responses of nitrous oxide (N2O) and methane (CH4) production, and make a comparison regarding how the biodegradability of microplastics affected GHG emissions. Importantly, results suggested that BMPs aggravated N2O and CH4 production in urban lake sediments more severely than conventional NBMPs. The production rates of N2O and CH4 increased by 48.78-71.88 % and 30.87-69.12 %, respectively, in BMPs groups, while those increased by only 0-25.69 % and 6.46-10.46 % with NBMPs exposure. Moreover, BMPs insignificantly affected nitrification but facilitated denitrification, while NBMPs inhibited both processes. BMPs not only created more oxygen-limited microenvironment, greatly promoting N2O production via nitrifier denitrification pathway, but also provided dissolved organic carbon favoring heterotrophic denitrification, which was primarily supported by the enriched denitrifiers and functional genes. In contrast, NBMPs slightly upregulated nitrifier denitrification pathway to generate N2O, and showed a toxic inhibition on both nitrifiers and denitrifiers. In addition, both BMPs and NBMPs promoted hydrogen-dependent methanogenic pathway but suppressed acetate-dependent pathway. The greater enhancement of CH4 production with BMPs exposure was attributed to the additional organic carbon substrates derived from BMPs and the stimulated microbial methane metabolism activities.

Autocrine IL-8 Contributes to Propionibacterium Acnes-induced Proliferation and Differentiation of HaCaT Cells via AKT/FOXO1/ Autophagy.

OBJECTIVE: Proprionibacterium acnes (P. acnes)-induced inflammatory responses, proliferation and differentiation of keratinocytes contribute to the progression of acne vulgaris (AV). P. acnes was found to enhance the production of interleukin-8 (IL-8) by keratinocytes. This study aimed to investigate the role of IL-8 in P. acnes-induced proliferation and differentiation of keratinocytes and the underlying mechanism. METHODS: The P. acnes-stimulated HaCaT cell (a human keratinocyte cell line) model was established. Western blotting and immunofluorescence were performed to detect the expression of the IL-8 receptors C-X-C motif chemokine receptor 1 (CXCR1) and C-X-C motif chemokine receptor 2 (CXCR2) on HaCaT cells. Cell counting kit-8 (CCK-8) assay, 5-ethynyl-20-deoxyuridine (EdU) assay and Western blotting were performed to examine the effects of IL-8/CXCR2 axis on the proliferation and differentiation of HaCaT cells treated with P. acnes, the IL-8 neutralizing antibody, the CXCR2 antagonist (SB225002), or the CXCR1/CXCR2 antagonist (G31P). Western blotting, nuclear and cytoplasmic separation, CCK-8 assay, and EdU assay were employed to determine the downstream pathway of CXCR2 after P. acnes-stimulated HaCaT cells were treated with the CXCR2 antagonist, the protein kinase B (AKT) antagonist (AZD5363), or the constitutively active forkhead box O1 (FOXO1) mutant. Finally, autophagy markers were measured in HaCaT cells following the transfection of the FOXO1 mutant or treatment with the autophagy inhibitor 3-methyladenine (3-MA). RESULTS: The expression levels of CXCR1 and CXCR2 were significantly increased on the membrane of HaCaT cells following P. acnes stimulation. The IL-8/CXCR2 axis predominantly promoted the proliferation and differentiation of P. acnes-induced HaCaT cells by activating AKT/FOXO1/autophagy signaling. In brief, IL-8 bound to its receptor CXCR2 on the membrane of keratinocytes to activate the AKT/FOXO1 axis. Subsequently, phosphorylated FOXO1 facilitated autophagy to promote the proliferation and differentiation of P. acnes-induced keratinocytes. CONCLUSION: This study demonstrated the novel autocrine effect of IL-8 on the proliferation and differentiation of P. acnes-induced keratinocytes, suggesting a potential therapeutic target for AV.

A clinical-radiomics nomogram for the prediction of the risk of upper gastrointestinal bleeding in patients with decompensated cirrhosis.

Objective: To develop a model that integrates radiomics features and clinical factors to predict upper gastrointestinal bleeding (UGIB) in patients with decompensated cirrhosis. Methods: 104 decompensated cirrhosis patients with UGIB and 104 decompensated cirrhosis patients without UGIB were randomized according to a 7:3 ratio into a training cohort (n = 145) and a validation cohort (n = 63). Radiomics features of the abdominal skeletal muscle area (SMA) were extracted from the cross-sectional image at the largest level of the third lumbar vertebrae (L3) on the abdominal unenhanced multi-detector computer tomography (MDCT) images. Clinical-radiomics nomogram were constructed by combining a radiomics signature (Rad score) with clinical independent risk factors associated with UGIB. Nomogram performance was evaluated in calibration, discrimination, and clinical utility. Results: The radiomics signature was built using 11 features. Plasma prothrombin time (PT), sarcopenia, and Rad score were independent predictors of the risk of UGIB in patients with decompensated cirrhosis. The clinical-radiomics nomogram performed well in both the training cohort (AUC, 0.902; 95% CI, 0.850-0.954) and the validation cohort (AUC, 0.858; 95% CI, 0.762-0.953) compared with the clinical factor model and the radiomics model and displayed excellent calibration in the training cohort. Decision curve analysis (DCA) demonstrated that the predictive efficacy of the clinical-radiomics nomogram model was superior to that of the clinical and radiomics model. Conclusion: Clinical-radiomics nomogram that combines clinical factors and radiomics features has demonstrated favorable predictive effects in predicting the occurrence of UGIB in patients with decompensated cirrhosis. This helps in early diagnosis and treatment of the disease, warranting further exploration and research.

CliqueFluxNet: Unveiling EHR Insights with Stochastic Edge Fluxing and Maximal Clique Utilisation Using Graph Neural Networks.

Electronic Health Records (EHRs) play a crucial role in shaping predictive are models, yet they encounter challenges such as significant data gaps and class imbalances. Traditional Graph Neural Network (GNN) approaches have limitations in fully leveraging neighbourhood data or demanding intensive computational requirements for regularisation. To address this challenge, we introduce CliqueFluxNet, a novel framework that innovatively constructs a patient similarity graph to maximise cliques, thereby highlighting strong inter-patient connections. At the heart of CliqueFluxNet lies its stochastic edge fluxing strategy - a dynamic process involving random edge addition and removal during training. This strategy aims to enhance the model's generalisability and mitigate overfitting. Our empirical analysis, conducted on MIMIC-III and eICU datasets, focuses on the tasks of mortality and readmission prediction. It demonstrates significant progress in representation learning, particularly in scenarios with limited data availability. Qualitative assessments further underscore CliqueFluxNet's effectiveness in extracting meaningful EHR representations, solidifying its potential for advancing GNN applications in healthcare analytics.