Ozone stress-induced DNA methylation variations and their transgenerational inheritance in foxtail millet.

Elevated near-surface ozone (O3) concentrations have surpassed the tolerance limits of plants, significantly impacting crop growth and yield. To mitigate ozone pollution, plants must evolve a rapid and effective defense mechanism to alleviate ozone-induced damage. DNA methylation, as one of the most crucial epigenetic modifications, plays a pivotal role in maintaining gene stability, regulating gene expression, and enhancing plant resilience to environmental stressors. However, the epigenetic response of plants to O3 stress, particularly DNA methylation variations and their intergenerational transmission, remains poorly understood. This study aims to explore the epigenetic mechanisms underlying plant responses to ozone stress across generations and to identify potential epigenetic modification sites or genes crucial in response to ozone stress. Using Open Top Chambers (OTCs), we simulated ozone conditions and subjected foxtail millet to continuous ozone stress at 200 nmol mol-1 for two consecutive generations (S0 and S1). Results revealed that under high-concentration ozone stress, foxtail millet leaves exhibited symptoms ranging from yellowing and curling to desiccation, but the damage in the S1 generation was not more severe than that in the S0 generation. Methylation Sensitive Amplified Polymorphism (MSAP) analysis of the two generations indicated that ozone stress-induced methylation variations ranging from 10.82% to 13.59%, with demethylation events ranged from 0.52% to 5.58%, while hypermethylation occurred between 0.35% and 2.76%. Reproductive growth stages were more sensitive to ozone than vegetative stages. Notably, the S1 generation exhibited widespread demethylation variations, primarily at CNG sites, compared to S0 under similar stress conditions. The inheritance pattern between S0 and S1 generations was mainly of the A-A-B-A type. By recovering and sequencing methylation variant bands, we identified six stress-related differential amplification sequences, implicating these variants in various biological processes. These findings underscore the potential significance of DNA methylation variations as a critical mechanism in plants' response to ozone stress, providing theoretical insights and references for a comprehensive understanding of plant adaptation mechanisms to ozone stress and the epigenetic role of DNA methylation in abiotic stress regulation.

Prevalence and association with environmental factors and establishment of prediction model of atopic dermatitis in pet dogs in China.

Canine atopic dermatitis (CAD) is a common skin disease in dogs. Various pathogenic factors contribute to CAD, with dust mites, environmental pathogens, and other substances being predominant. This research involved comprehensive statistical analysis and prediction of CAD in China, using data from 14 cities. A distributed lag nonlinear model (DLNM) was developed to evaluate the impact of environmental factors on CAD incidence. Additionally, a seasonal auto-regressive moving average (ARIMA) model was used to forecast the monthly number of CAD cases. The findings indicated that CAD mainly occurs during June, July, August, and September in China. There was a positive correlation found between CAD incidence and temperature and humidity, while a negative correlation was observed with CO, PM2.5, and other pollutants.

Exploiting lignin-based nanomaterials for enhanced anticancer therapy: A comprehensive review and future direction.

Lignin, a renewable and abundant natural polymer, has emerged as a promising candidate for anticancer therapy due to its unique properties and biocompatibility. This review provides a comprehensive overview of recent advancements in the utilization of lignin-based nanomaterials for enhancing anticancer drug delivery and therapeutic outcomes. A detailed examination of the literature reveals several synthesis methods, including nanoprecipitation, microemulsion, and solvent exchange, which produce lignin nanoparticles with improved drug solubility and bioavailability. The anticancer mechanisms of lignin nanoparticles, such as the generation of reactive oxygen species (ROS), induction of apoptosis, and enhanced cellular uptake, are also explored. Lignin nanoparticles loaded with drugs like curcumin, doxorubicin, camptothecin, and resveratrol have demonstrated the ability to improve drug efficacy, selectively target cancer cells, overcome multidrug resistance, and minimize toxicity in both in vitro and in vivo studies. These nanoparticles have shown significant potential in suppressing tumor growth, inducing cell death through apoptotic pathways, and enhancing the synergistic effects of combination therapies, such as chemo-phototherapy. Future research directions include optimizing lignin nanoparticle formulations for clinical applications, refining targeted delivery mechanisms to cancer cells, and conducting thorough biocompatibility and toxicity assessments. Overall, this review highlights the significant progress made in utilizing lignin-based nanomaterials for cancer therapy and outlines promising areas for further exploration in this rapidly evolving field.

Study on the Design Method of High-Resolution Volume-Phase Holographic Gratings.

Volume-phase holographic gratings are suitable for use in greenhouse gas detection imaging spectrometers, enabling the detection instruments to achieve high spectral resolution, high signal-to-noise ratios, and high operational efficiency. However, when utilized in the infrared wavelength band with high dispersion requirements, gratings struggle to meet the demands for low polarization sensitivity due to changes in diffraction performance caused by phase delays in the incidence of light waves with distinct polarization states, and current methods for designing bulk-phase holographic gratings require a large number of calculations that complicate the balance of diffraction properties. To overcome this problem, a design method for transmissive bulk-phase holographic gratings is proposed in this study. The proposed method combines two diffraction theories (namely, Kogelnik coupled-wave theory and rigorous coupled-wave theory) and establishes a parameter optimization sequence based on the influence of design parameters on diffraction characteristics. Kogelnik coupled-wave theory is employed to establish the initial Bragg angle range, ensuring that the diffraction efficiency and phase delay of the grating thickness curve meet the requirements for incident light waves in various polarization states. Utilizing rigorous coupled-wave theory, we optimize grating settings based on criteria such as a center wavelength diffraction efficiency greater than 95%, polarization sensitivity less than 10%, maximum bandwidth, and spectral diffraction efficiency exceeding 80%. The ideal grating parameters are ultimately determined, and the manufacturing tolerances for various grating parameters are analyzed. The design results show that the grating stripe frequency is 1067 lines per millimeter, and the diffraction efficiencies of TE and TM waves are 96% and 99.89%, respectively. The diffraction efficiency of unpolarized light is more than 88% over the whole spectral range with an average efficiency of 94.49%, an effective bandwidth of 32 nm, and a polarization sensitivity of less than 7%. These characteristics meet the performance requirements for dispersive elements based on greenhouse gas detection, the spectral resolution of the detection instrument is up to 0.1 nm, and the signal-to-noise ratio and working efficiency are improved by increasing the transmittance of the instrument.

A PHR-dependent reciprocal antagonistic interplay between UV response and P-deficiency adaptation in plants.

Plants are often simultaneously stressed by both UV radiation and phosphorus (P) deficiency in agricultural ecosystems. Coordinated responses and adaptations to these stressors are critical for plant growth, development, and survival. However, the underlying molecular response and adaptation mechanisms in plants remain elusive. Here, we show that plants use a reciprocal antagonistic strategy in response to UV radiation and P deficiency. UV radiation inhibited P-starvation response (PSR) processes and disrupted phosphate (Pi) homeostasis by suppressing the function of PHOSPHATE STARVATION RESPONSE PROTEINS (PHRs), the Pi central regulators. Conversely, P availability modulated the plant UV tolerance and the expression level of UV radiation response (URR) genes in a PHR-dependent manner. Therefore, reducing P supply or increasing PHRs activities can improve the tolerance to UV stress in rice. Moreover, this antagonistic interaction is conserved across various plant species. Furthermore, our meta-analysis showed that the increase in global UV radiation over the last forty years may reduce crop P-utilization efficiency worldwide. Our findings provide insights for optimizing P fertilizer management and breeding smart crops resilient to fluctuations in UV radiation and soil P levels.

PFDN5 plays a dual role in breast cancer and regulates tumor immune microenvironment: Insights from integrated bioinformatics analysis and experimental validation.

BACKGROUND: Although the prognosis for patients with breast cancer has improved, breast cancer remains the leading cause of death for women worldwide. Prefoldin 5 (PFDN5), as a subunit of the prefoldin complex, plays a vital role in aiding the correct folding of newly synthesized proteins. However, the exact impact of PFDN5 on breast cancer development and its prognostic implications remain unclear. METHODS: We conducted bioinformatics analysis to investigate the correlation between PFDN5 and patient survival, as well as various clinicopathological characteristics in breast cancer. Additionally, various assays were employed to validate the biological functions of PFDN5 in breast cancer. Finally, RNA sequencing (RNA-seq) was utilized to investigate the molecular mechanisms associated with PFDN5. RESULTS: Compared to normal tissues, PFDN5 exhibited lower expression levels in breast cancer tissues, and lower expression of PFDN5 is associated with poorer prognosis. PFDN5 led to G2/M phase arrest in the cell cycle and reduced proliferative potential in breast cancer cells. However, PFDN5 also promoted migration and invasion of breast cancer cells. Also, RNA-seq analysis revealed an involvement of PFDN5 in the cell cycle and TGF-ß signaling pathway. Furthermore, PFDN5 had a significant impact on tumor immune microenvironment by promoting macrophage polarization towards the M1 phenotype and exhibited a positive correlation with CD8+ T cell infiltration levels. CONCLUSIONS: PFDN5 plays a dual role in breast cancer and serves as a key factor in tumor immune microenvironment. Therefore, PFDN5 holds promise as a valuable biomarker for predicting both metastatic and prognosis in breast cancer.

Development and validation of a nomogram for predicting pulmonary complications in elderly patients undergoing thoracic surgery.

BACKGROUND: Postoperative pulmonary complications (PPCs) remain a prevalent concern among elderly patients undergoing surgery, with a notably higher incidence observed in elderly patients undergoing thoracic surgery. This study aimed to develop a nomogram to predict the risk of PPCs in this population. METHODS: A total of 2963 elderly patients who underwent thoracic surgery were enrolled and randomly divided into a training cohort (80%, n = 2369) or a validation cohort (20%, n = 593). Univariate and multivariate logistic regression analyses were conducted to identify risk factors for PPCs, and a nomogram was developed based on the findings from the training cohort. The validation cohort was used to validate the model. The predictive accuracy of the model was evaluated by receiver operating characteristic (ROC) curve, area under ROC (AUC), calibration curve, and decision curve analysis (DCA). RESULTS: A total of 918 (31.0%) patients reported PPCs. Nine independent risk factors for PPCs were identified: preoperative presence of chronic obstructive pulmonary disease (COPD), elevated leukocyte count, higher partial pressure of arterial carbon dioxide (PaCO2) level, surgical site, thoracotomy, intraoperative hypotension, blood loss > 100 mL, surgery duration > 180 min, and malignant tumor. The AUC value for the training cohort was 0.739 (95% CI: 0.719-0.762), and it was 0.703 for the validation cohort (95% CI: 0.657-0.749). The P-values for the Hosmer-Lemeshow test were 0.633 and 0.144 for the training and validation cohorts, respectively, indicating a notable calibration curve fit. The DCA curve indicated that the nomogram could be applied clinically if the risk threshold was between 12% and 84%, which was found to be between 8% and 82% in the validation cohort. CONCLUSION: This study highlighted the pressing need for early detection of PPCs in elderly patients undergoing thoracic surgery. The nomogram exhibited promising predictive efficacy for PPCs in elderly patients undergoing thoracic surgery, enabling the identification of high-risk patients and consequently aiding in the implementation of preventive interventions.

Regulated cleavage and translocation of FERONIA control immunity in Arabidopsis roots.

Plant roots exhibit localized immunity (LI) mainly in the transition zone (TZ) and elongation zone (EZ). Plasma membrane-localized receptor-like kinases (RLKs) can mediate the plant's response to rhizosphere bacteria. However, how RLKs are involved in triggering LI in roots remains unclear. Here we identified dual actions for the RLK FERONIA (FER) in the LI response of Arabidopsis (Arabidopsis thaliana). The FER cytoplasmic domain is cleaved and translocated to the nucleus (FERN) to activate LI in the TZ and EZ in response to colonization by beneficial and pathogenic bacteria. In the absence or cessation of bacterial infection, full-length FER is plasma membrane-localized to maintain growth. Upon colonization and invasion by a high titre of bacteria, mature RAPID ALKALINIZATION FACTOR23 peptide accumulates and activates the matrix metalloproteinase At2-MMP, which triggers FER cytoplasmic domain cleavage specifically in the TZ and EZ to activate LI. This work demonstrates that two molecular forms of a single RLK balance growth and immunity via LI activation in Arabidopsis roots.

A phase I clinical trial of sonodynamic therapy combined with radiotherapy for brainstem gliomas.

Brainstem gliomas (BSGs) are a class of clinically refractory malignant tumors for which there is no uniform and effective treatment protocol. Ultrasound and radiation can activate hematoporphyrin and produce sonodynamic and radiodynamic effects to kill cancer cells. Therefore, we conducted the first phase I clinical trial of sonodynamic therapy (SDT) combined with radiotherapy (RT) for the treatment of BSGs to verify its safety and efficacy. We conducted a study of SDT combined with RT in 11 patients with BSGs who received SDT and RT after hematoporphyrin administration. Magnetic resonance imaging was performed during this period to assess the tumor, and adverse events were recorded. All adverse events recorded were grade 1-2; no grade 3 or more serious adverse events were observed. Treatment was well tolerated, and no dose-limiting toxicities were observed. There were no treatment-related deaths during the course of treatment. 8 of 11 patients (72.7%) maintained stable disease, 2 (18.2%) achieved partial response, and the tumors were still shrinking as of the last follow-up date. The median progression-free survival (PFS) for patients was 9.2 (95% confidence interval [CI] 6.2-12.2) months, and the median overall survival (OS) was 11.7 (95% CI 9.6-13.8) months. Therefore, SDT combined with RT has a favorable safety and feasibility and shows a preliminary high therapeutic potential.

[Clinical Validation Study of Deep Learning-Generated Magnetic Resonance Images].

This research utilizes a deep learning-based image generation algorithm to generate pseudo-sagittal STIR sequences from sagittal T1WI and T2WI MR images. The evaluations include both subjective assessments by two physicians and objective analyses, measuring image quality through SNR and CNR in ROIs of five different tissues. Further analyses, including MAE, PSNR, SSIM, and COR, establish a strong correlation between the generated STIR sequences and the gold standard, with Bland-Altman analysis indicating pixel consistency. The findings indicate that the deep learning-generated STIR sequences not only align with but potentially surpass the gold standard in terms of image quality and clinical diagnostic capabilities. Moreover, the approach demonstrates promise for clinical implementation, offering reduced scan time and enhanced imaging efficiency.

Global, Regional, and National Burden of Intracerebral Hemorrhage in Young Adults From 1990 to 2021: A Population-Based Study.

BACKGROUND: Intracerebral hemorrhage (ICH) in young adults demands greater attention, given its poor prognosis; however, there has been a paucity of epidemiological data. The objective of this study is to estimate the temporal trends and distribution characteristics of the disease burden in 204 countries or territories between 1990 and 2021. METHODS AND RESULTS: The data, including incidence, mortality, prevalence, and disability-adjusted life year (DALY) rates were sourced from the Global Burden of Diseases Study 2021. From 1990 to 2021, there was a significant decline in the global incidence (estimated annual percentage change=-1.05), mortality (estimated annual percentage change=-0.92), and DALY (estimated annual percentage change=-1.00) rates of ICH in young adults. In 2021, the highest incidence, mortality, and DALY rates were observed in Southeast Asia, East Asia, and Oceania. Globally, high systolic blood pressure, smoking, and ambient particulate matter pollution were identified as the primary contributors to the largest proportion of DALYs associated with ICH in young adults. The health inequality of ICH in young adults has been reduced over the past 3 decades. CONCLUSIONS: There is a considerable degree of heterogeneity in the global burden of ICH in young adults. A decline in the incidence, mortality, prevalence, and DALY rates has been observed from 1990 to 2021, however, the number of absolute cases has increased. These results will enable health care professionals, policymakers, and researchers to refine the implementation of cost-effective policies, the allocation of health care resources, and the management of patients to further mitigate the burden of ICH in young adults.

Design and Testing of a Seedling Pick-Up Device for a Facility Tomato Automatic Transplanting Machine.

At present, tomato transplanting in facility agriculture is mainly manual operation. In an attempt to resolve the problems of high labor intensity and low efficiency of manual operation, this paper designs a clip stem automatic transplanting and seedling picking device based on the yolov5 algorithm. First of all, through the study of the characteristics of tomato seedlings of different seedling ages, the age of tomato seedlings suitable for transplanting was obtained. Secondly, the improved yolov5 algorithm was used to determine the position and shape of tomato seedlings. By adding a lightweight upsampling operator (CARAFE) and an improved loss function, the feature extraction ability and detection speed of tomato seedling stems were improved. The accuracy of the improved yolov5 algorithm reached 92.6%, and mAP_0.5 reached 95.4%. Finally, the seedling verification test was carried out with tomato seedlings of about 40 days old. The test results show that the damage rate of the device is 7.2%, and the success rate is not less than 90.3%. This study can provide a reference for research into automatic transplanting machines.

Dearomative hydroamination of heteroarenes catalyzed by the phenolate photocatalyst.

Dearomative functionalization of heteroarenes offers an attractive and sustainable approach for the rapid construction of complex 3D heterocyclic scaffolds from planar structures. Despite progress in this field, dearomative amination of heteroarenes via a radical anion intermediate remains a challenge. Here, we report a photoredox-catalyzed dearomative hydroamination of heteroarenes with hydrazodiformates under mild and transition-metal-free reaction conditions. Various benzofurans and benzothiophenes can efficiently participate in this transformation. A series of mechanistic experiments revealed that heteroaryl radical anions are the crucial intermediates, generated through photo-induced electron transfer between the excited phenolate photocatalyst and heteroarenes.

PKM2-Driven Lactate Overproduction Triggers Endothelial-To-Mesenchymal Transition in Ischemic Flap via Mediating TWIST1 Lactylation.

The accumulation of lactate is a rising risk factor for patients after flap transplantation. Endothelial-to-mesenchymal transition (EndoMT) plays a critical role in skin fibrosis. Nevertheless, whether lactate overproduction directly contributes to flap necrosis and its mechanism remain unknown. The current study reveals that skin flap mice exhibit enhanced PKM2 and fibrotic response. Endothelial-specific deletion of PKM2 attenuates flap necrosis and ameliorates flap fibrosis in mice. Administration of lactate or overexpressing PKM2 promotes dysfunction of endothelial cells and stimulates mesenchymal-like phenotype following hypoxia. Mechanistically, glycolytic-lactate induces a correlation between Twist1 and p300/CBP, leading to lactylation of Twist1 lysine 150 (K150la). The increase in K150la promotes Twist1 phosphorylation and nuclear translocation and further regulates the transcription of TGFB1, hence inducing fibrosis phenotype. Genetically deletion of endothelial-specific PKM2 in mice diminishes lactate accumulation and Twist1 lactylation, then attenuates EndoMT-associated fibrosis following flap ischemia. The serum lactate levels of flap transplantation patients are elevated and exhibit predictive value for prognosis. This findings suggested a novel role of PKM2-derived lactate in mediating Twist1 lactylation and exacerbates flap fibrosis and ischemia. Inhibition of glycolytic-lactate and Twist1 lactylation reduces flap necrosis and fibrotic response might become a potential therapeutic strategy for flap ischemia.

Three new species of Talaromyces sect. Talaromyces discovered in China.

Background: Talaromyces species play an important role in the nutrient cycle in natural ecosystems, degradation of vegetal biomass in industries and the implications in medicine. However, the species diversity of this genus is still far from fully understood. Methods: The polyphasic taxonomic approach integrating morphological comparisons and molecular phylogenetic analyses based on BenA, CaM, Rpb2 and ITS sequences was used to propose three new Talaromyces species. Results: Three new species of sect. Talaromyces isolated from soil are proposed, namely, T. disparis (ex-type AS3.26221), T. funiformis (ex-type AS3.26220) and T. jianfengicus (ex-type AS3.26253). T. disparis is unique in low growth rate, velvety texture, limited to moderate sporulation, biverticillate, monoverticillate and irregular penicilli bearing a portion of abnormally large globose conidia, it has no close relatives in phylogeny. Being a member of T. pinophilus complex, T. funiformis produces mycelial funicles on Czapek yeast autolysate agar (CYA), 5% malt extract agar (MEA) and yeast extract (YES), sparse sporulation on Czapek agar (Cz), CYA, MEA and YES while abundant on oatmeal agar (OA), bearing appressed biverticillate penicilli and globose to pyriform conida with smooth to finely rough walls. T. jianfengicus belongs to T. verruculosus complex, is characterized by velvety colony texture with moderate to abundant elm-green conidia en masse, producing biverticillate penicilli, globose conidia with verrucose walls. Conclusion: It is now a common practice in establishing new species of Aspergillus, Penicillium and Talaromyces based on morphological characters and phylogenetic analyses of BenA, CaM, Rpb2 and ITS sequences. The proposal of the three novelties of Talaromyces in this article is not only supported by their morphological distinctiveness, but also confirmed by the phylogenetic analyses of the concatenated BenA-CaM-Rpb2 and BenA-CaM-ITS, as well as the individual BenA, CaM, Rpb2 and ITS sequence matrices.

DeepCheck: multitask learning aids in assessing microbial genome quality.

Metagenomic analyses facilitate the exploration of the microbial world, advancing our understanding of microbial roles in ecological and biological processes. A pivotal aspect of metagenomic analysis involves assessing the quality of metagenome-assembled genomes (MAGs), crucial for accurate biological insights. Current machine learning-based methods often treat completeness and contamination prediction as separate tasks, overlooking their inherent relationship and limiting models' generalization. In this study, we present DeepCheck, a multitasking deep learning framework for simultaneous prediction of MAG completeness and contamination. DeepCheck consistently outperforms existing tools in accuracy across various experimental settings and demonstrates comparable speed while maintaining high predictive accuracy even for new lineages. Additionally, we employ interpretable machine learning techniques to identify specific genes and pathways that drive the model's predictions, enabling independent investigation and assessment of these biological elements for deeper insights.

Correlation study of multiple inflammatory indices and vertebral compression fracture: A cross-sectional study.

Background: Vertebral compression fractures (VCFs) are prevalent in patients with osteoporosis and pose significant health risks. Although chronic low-grade inflammation plays a crucial role in the pathogenesis of osteoporosis, the relationship between various inflammatory indices and the occurrence of fractures remains unclear. Objective: This study aims to evaluate the correlation between multiple inflammatory indices, neutrophil-to-lymphocyte ratio (NLR), monocyte-to-lymphocyte ratio (MLR), platelet-to-lymphocyte ratio (PLR), systemic immune-inflammatory index (SII), and systemic inflammatory response index (SIRI), and VCFs, to explore the significance of these indices in clinical application. Methods: Clinical data of 310 patients diagnosed with osteoporosis from November 2020 to June 2023 in the hospital were collected. The general conditions between fracture and non-fracture groups were described. Spearman analysis and binary logistic regression analysis were used to assess the relationship between inflammatory indices and VCFs. Receiver operating characteristic curve was used to evaluate the diagnostic efficacy of these inflammatory indices for VCFs. Results: VCFs were diagnosed in 43.55 % of patients with osteoporosis. NLR(ρ = 0.169, P=0.003), MLR(ρ = 0.293, P<0.001), SII(ρ = 0.126, P=0.027), and SIRI(ρ = 0.273, P<0.001) were positively correlated with the occurrence of VCFs. NLR(OR=1.480, 95 %CI 1.114 âˆ¼ 1.966, P=0.007), MLR(multiplied by 100, OR=1.048, 95 %CI 1.011 âˆ¼ 1.087, P=0.011), and SIRI(OR=3.327, 95 %CI 1.510 âˆ¼ 7.330, P=0.003) were independent risk factors for VCFs, hip bone mineral density (BMD) (OR=0.011, 95 %CI 0.001 âˆ¼ 0.151, P=0.001) was an independent protective factor for VCFs. MLR(AUC 0.671, 95 % CI=0.610 âˆ¼ 0.732, P <0.001) had relatively high clinical diagnostic efficacy. Conclusion: The neutrophil-to-lymphocyte ratio (NLR), monocyte-to-lymphocyte ratio (MLR), and systemic inflammatory response index (SIRI) are independent risk factors for vertebral compression fractures.

Cost-effectiveness of first-line enfortumab vedotin in addition to pembrolizumab for metastatic urothelial carcinoma in the United States.

Background and objective: The EV-302 trial found that the combination of enfortumab vedotin (EV) with pembrolizumab significantly improved survival for patients with metastatic urothelial carcinoma (mUC). However, given the high cost of the drugs, there is a need to assess its value by considering both efficacy and cost. This study assessed the cost-effectiveness of EV plus pembrolizumab as a first-line treatment for patients with mUC from the perspective of U.S. payers. Methods: A Markov model was developed to compare the lifetime costs and effectiveness of EV in combination with pembrolizumab with chemotherapy in the treatment of mUC patients from U.S. payer perspective. Life-years (LYs), quality-adjusted LYs (QALYs), and lifetime costs were estimated. One-way, two-way and probabilistic sensitivity analyses were conducted to evaluate model uncertainty. Additionally, subgroup analyses were performed. Results: Compared to chemotherapy, the combination of EV and pembrolizumab provided an additional 2.10 LYs and 1.72 QALYs, at an incremental cost of $962,240.8 per patient. The incremental cost-effectiveness ratio (ICER) is $558,973 per QALY. Subgroup analysis indicated that patients ineligible for cisplatin treatment had a lower ICER compared to those who were eligible for cisplatin. Conclusions: From the perspective of US payers, at a willingness-to-pay threshold of $150,000 per QALY, the combination of EV and pembrolizumab is estimated to not be cost-effective compared to traditional chemotherapy in the first-line treatment of mUC patients.

Tryptophan-rich diet and its effects on Htr7+ Tregs in alleviating neuroinflammation and cognitive impairment induced by lipopolysaccharide.

BACKGROUND: Neuroinflammation is a vital pathogenic mechanism for neurodegenerative diseases such as Alzheimer's, schizophrenia, and age-related cognitive decline. Regulatory T cells (Tregs) exhibit potent anti-inflammatory properties and can modulate neurodegenerative diseases arising from central nervous system inflammatory responses. However, the role of Tregs in neuroinflammation-related cognitive dysfunction remains unclear. It is highly plausible that Htr7+ Tregs expressing unique genes associated with the nervous system, including the Htr7 gene encoding the serotonin receptor 5-HT7, play a pivotal role. METHODS: Mice were given a tryptophan-rich diet (with a tryptophan content of 0.6%) or a normal diet (with a tryptophan content of 0.16%). The neuroinflammation-mediated cognitive dysfunction model was established by intracerebroventricular injection of lipopolysaccharide (LPS) in 8-week-old C57BL/6J mice. The activation and infiltration of Tregs were measured using flow cytometry. Primary Tregs were cocultured separately with primary CD8+ T cells and primary microglia for in vitro validation of the impact of 5-HT and 5-HT7 receptor on Tregs. Prior to their transfer into recombination activating gene 1 (Rag1-/-) mice, Tregs were ex vivo transfected with lentivirus to knock down the expression of Htr7. RESULTS: In this study, the tryptophan-rich diet was found to reverse LPS-induced cognitive impairment and reduce the levels of 5-HT in peripheral blood. The tryptophan-rich diet led to increased levels of 5-HT in peripheral blood, which in turn promoted the proliferation and activation of Htr7+ Tregs. Additionally, the tryptophan-rich diet was also shown to attenuate LPS-mediated neuroinflammation by activating Htr7+ Tregs. Furthermore, 5-HT and 5-HT7 receptor were found to enhance the immunosuppressive effect of Tregs on CD8+ T cells and microglia. In Rag1-/- mice, Htr7+ Tregs were shown to alleviate LPS-induced neuroinflammation and cognitive impairment. CONCLUSIONS: Our research revealed the ability of Htr7+ Tregs to mitigate neuroinflammation and prevent neuronal damage by suppressing the infiltration of CD8+ T cells into the brain and excessive activation of microglia, thereby ameliorating LPS-induced cognitive impairment. These insights may offer novel therapeutic targets involving Tregs for neuroinflammation and cognitive impairment.