The short peptide encoded by long non-coding RNA RNF217-AS1 inhibits stomach cancer tumorigenesis, macrophage recruitment, and pro-inflammatory responses.

Certain long non-coding RNAs (lncRNAs) have potential peptide-coding abilities. Here, the role and molecular basis of the RNF217-AS1-encoded peptide in stomach cancer (SC) tumorigenesis were explored. Here, lncRNAs associated with SC pathogenesis and macrophage infiltration and lncRNAs with peptide-coding potential were searched by bioinformatics analysis. The gene mRNA and protein levels were examined by RT-qPCR and western blot assays, respectively. Cell viability, migratory, and invasive abilities were measured by CCK-8, Transwell migration, and Transwell invasion assays, respectively. The potential biological processes related to lncRNA RNF217-AS1 were identified by single-gene GSEA analysis. The effect of RNF217-AS1-encoded peptide on SC tumorigenesis was examined by mouse xenograft experiments. The results showed that lncRNA NR2F1-AS1 and RNF217-AS1 were differentially expressed and associated with macrophage infiltration in SC, and they had the ability to translate into short peptides. The RNF217-AS1 ORF-encoded peptide could reduce SC cell viability, inhibit cell migration and invasion, as well as hinder the development of SC xenograft tumors. The RNF217-AS1 ORF-encoded peptide in human SC AGS cells suppressed THP-1 cell migration, triggered the differential expression of CXCL1/CXCL2/CXCL8/CXCL12, and inactivated the TLR4/NF-κB/STAT1 signaling pathways. As a conclusion, the RNF217-AS1 ORF-encoded peptide hindered SC progression in vitro and in vivo and suppressed macrophage recruitment and pro-inflammatory responses in SC.

Construction of a Spatial-Confined Self-Stacking Catalytic Circuit for Rapid and Sensitive Imaging of Piwi-Interacting RNA in Living Cells.

Piwi-interacting RNAs (piRNAs) are small noncoding RNAs that repress transposable elements to maintain genome integrity. The canonical catalytic hairpin assembly (CHA) circuit relies on random collisions of free-diffused reactant probes, which substantially slow down reaction efficiency and kinetics. Herein, we demonstrate the construction of a spatial-confined self-stacking catalytic circuit for rapid and sensitive imaging of piRNA in living cells based on intramolecular and intermolecular hybridization-accelerated CHA. We rationally design a 3WJ probe that not only accelerates the reaction kinetics by increasing the local concentration of reactant probes but also eliminates background signal leakage caused by cross-entanglement of preassembled probes. This strategy achieves high sensitivity and good specificity with shortened assay time. It can quantify intracellular piRNA expression at a single-cell level, discriminate piRNA expression in tissues of breast cancer patients and healthy persons, and in situ image piRNA in living cells, offering a new approach for early diagnosis and postoperative monitoring.

Questionnaire survey and analysis of drug clinical research implementation capabilities of breast cancer treatment departments in Chinese hospitals.

BACKGROUND: Clinical research competence determines the quality of clinical research and the reliability of research findings. We aimed to explore the clinical research implementation capabilities of breast cancer treatment departments in China. METHODS: This was a department-based cross-sectional study conducted in the form of electronic questionnaires on the Wenjuanxing platform from 7th August to 31st August 2023 among hospitals from the first batch of breast cancer standardized diagnosis and treatment quality control pilot centers in China. RESULTS: A total of 127 questionnaires from 122 hospitals were ultimately included in the analysis. Medical personnel involved in the clinical research of 118 (92.9 %) departments received good clinical practice (GCP) training. The steps of the approval process from research initiation to completion lasted 2-4 weeks or longer. The majority of departments initiated or participated in 2 or fewer clinical research projects over the past year. Among the differences between different departments, the Department of Medical Oncology had a better qualification profile and process and greater number of initiated and participated clinical studies than did the Department of Surgical Oncology. For needs and problems, most of the departments were strongly willing to undertake clinical research and receive professional training; the most common problem in the process of conducting studies was patient recruitment. CONCLUSIONS: Most departments generally exhibited complete capabilities for implementing clinical research. Improvements in implementation efficiency, quality of research and patient recruitment are still needed. Professional training and communication, as well as the recommendation of clinical research, are required in future development.

Systematic evaluation of the meat qualities of free-range chicken (Xuan-Zhou) under different ages explored the optimal slaughter age.

Meat qualities of free-range chicken (Xuan-Zhou) (XZ-FRC) are closely associated with slaughter age and directly influence the economic benefits of supplier and consumer's preference. Understanding of the relationship between meat qualities and ages will be of prime important to explore a better slaughter age of XZ-FRC. In this study, the quality traits of breast and thigh muscles from XZ-FRCs at 9 to 14 wk were analyzed to establish a relatively reliable method for selecting a better slaughter age. The results showed that the effects of slaughter ages on color (CIE L*, a* and b* values), shear force, centrifugal loss, and flavor of XZ-FRCs were significant (P < 0.05). There were greater differences in meat qualities, whatever breast or thigh muscles, between same or different ages. Eleven feature indexes used for colligation evaluation of slaughter age were selected by combining the quality characteristics and data analysis. The score of colligation evaluation for XZ-FRCs at 12 wk was higher than that at 9 and 14 wk, suggesting that the 12 wk was an optimal slaughter age. This work would provide a reference method that helps the producers of livestock and poultry to select a better slaughter age.

Cognitive benefits of folic acid, docosahexaenoic acid and a combination of both nutrients in mild cognitive impairment; possible alterations though mitochondrial function and DNA damage.

INTRODUCTION: It is uncertain whether folic acid (FA) combined with docosahexaenoic acid (DHA) could improve cognitive performance. This study evaluated the effects of a 12-month FA and DHA supplementation, in combination or alone, on cognitive function, DNA oxidative damage, and mitochondrial function in participants with mild cognitive impairment (MCI). METHODS: This randomized, double-blind, placebo-controlled trial recruited MCI participants aged 60 years and older. Two hundred and eighty participants were randomly divided in equal proportion into four groups: FA+DHA (FA 800µg/d + DHA 800mg/d), FA (800µg/d), DHA (800mg/d), and placebo groups daily orally for 12 months. The primary outcome was cognitive function evaluated by the Wechsler Adult Intelligence Scale-Revised (WAIS-RC). Cognitive tests and blood mechanism-related biomarkers were determined at baseline and 12 months. RESULTS: During the 12-month follow, scores of full intelligence quotient (FIQ) (ßDHA: 1.302, 95%CI: 0.615, 1.990, p < 0.001; ßFA: 1.992, 95%CI: 1.304, 2.679, p < 0.001; ßFA+DHA: 2.777, 95%CI: 2.090, 3.465, p < 0.001), verbal intelligence quotient, and some subtests of the WAIS-RC were significantly improved in FA+DHA and single intervention groups compared to the placebo group. Moreover, the FA and DHA intervention combination was superior to either intervention alone (p < 0.001). Meanwhile, FA, DHA and their combined use significantly decreased 8-OHdG level and increased mitochondrial DNA copy number compared to the placebo (p < 0.05). CONCLUSIONS: Supplementation of FA and DHA, alone or combined, for 12 months can improve cognitive function in MCI participants, possibly through mitigating DNA oxidative damage and enhancing mitochondrial function. Combined supplementation may provide more cognitive benefit than supplementation alone. TRIAL REGISTRATION: Chinese Clinical Trial Registry, ChiCTR2000034351. Registered 3 July 2020 - Retrospectively registered, https://www.chictr.org.cn/showproj.html?proj=53345.

"Fertility-friendly hospitals": A key measure to promote long-term and balanced population development in China.

In response to the twin challenges of an aging population and declining birth rates, Zhejiang, China pioneered the concept of "fertility-friendly hospitals" in 2022 to support families and individuals in navigating the complexities of childbirth. Although fertility-friendly hospitals have not yet scaled up in number, their potential benefits and the challenges they face are evident. These facilities aim to provide comprehensive services from preconception to postnatal care, necessitating a high level of specialization and resource allocation, with an emphasis on patient education and participatory decision-making. Currently, there is an uneven distribution of resources across regions in China, with the density of maternal and child health care facilities in developed areas exceeding that of less developed regions by more than tenfold. The establishment of fertility-friendly hospitals will help to slow the pace of population aging and mitigate further declines in birth rates, thereby balancing the population composition and promoting long-term equitable social development. However, they also face challenges in balancing resources, improving the quality of services, and improving accessibility across different regions. As the concept is promoted and practiced, fertility-friendly hospitals are expected to become a significant force supporting Chinas population policy.

Contribution to energy conservation and quality improvement of frozen pork via contact/contactless immersion freezing in NaCl solution.

High energy consumption and quality deterioration are major challenges in the meat freezing process. In this study, the energy consumption and qualities of frozen pork were investigated using three freezing methods: nonpackaged pork air freezing (NAF), contactless immersion freezing (PIF) and contact immersion freezing (NIF) with NaCl solution as a refrigerant. The results indicated that NIF could improve the energy conservation and freezing efficiency in >4 freezing treatment-times by increasing the unfrozen water content, decreasing the frozen heat load, shortening the freezing time and reducing evaporation loss. NIF could also increase the a* value of the pork and improve the water-holding capacity by facilitating the conversion of free water to immobilized-water. The two immersion freezing methods could reduce freezing-thawing loss and protein loss by alleviating muscle tissue freezing damage. These results provide a suitable application of immersion freezing with energy conservation, high efficiency and good quality of frozen-pork.

Inhibition of autophagy via 3-methyladenine alleviates the progression of preeclampsia.

Autophagy is a cellular mechanism for self-renewal that involves the breakdown of cytoplasmic proteins or organelles within lysosomes. Although preeclampsia (PE) exhibits several characteristics that could imply disrupted autophagy, there is limited evidence supporting the notion that impaired placental autophagy directly causes PE, as indicated by differential expression profiling of whole placental tissue. In this study, we aim to explore the significance of autophagy in maintaining pregnancy and its association with PE. First, the RNA-seq results show that 218 genes are differentially expressed in placentas from preeclamptic pregnancies. Notably, KEGG pathway analysis reveals significant enrichment of genes related to autophagy-related signaling pathways, including the PI3K-Akt signaling pathway, the AMPK signaling pathway, and the mTOR signaling pathway. Additionally, our findings indicate an increase in autophagy in placentas from pregnancies complicated by preeclampsia as well as in trophoblasts subjected to hypoxic conditions. Next, we examine the impact of 3-methyladenine (3-MA), a targeted inhibitor of autophagy, on the progression of PE. The administration of 3-MA profoundly alleviates the severity of PE-like symptoms in rats subjected to reduced uterine perfusion pressure (RUPP). The findings from our study suggest that inhibiting autophagy may serve as a promising approach for adjuvant chemotherapy for PE.

A circular microphone array with virtual microphones based on acoustics-informed neural networks.

Acoustic beamforming aims to focus acoustic signals to a specific direction and suppress undesirable interferences from other directions. Despite its flexibility and steerability, beamforming with circular microphone arrays suffers from significant performance degradation at frequencies corresponding to zeros of the Bessel functions. To conquer this constraint, baffled or concentric circular microphone arrays have been studied; however, the former need a bulky baffle that interferes with the original sound field, whereas the latter require more microphones that increase the complexity and cost, both of which are undesirable in practical applications. To tackle this challenge, this paper proposes a circular microphone array equipped with virtual microphones, which resolves the performance degradation commonly associated with circular microphone arrays without resorting to physical modifications. The sound pressures at the virtual microphones are predicted from those measured by the physical microphones based on an acoustics-informed neural network, and then the sound pressures measured by the physical microphones and those predicted at the virtual microphones are integrated to design the beamformer. Experimental results demonstrate that the proposed approach not only eliminates the performance degradation but also suppresses spatial aliasing at high frequencies, thereby underscoring its promising potential.

YY1-mediated enhancer-promoter communication in the immunoglobulin µ locus is regulated by MSL/MOF recruitment.

The rearrangement and expression of the immunoglobulin µ heavy chain (Igh) gene require communication of the intragenic Eµ and 3' regulatory region (RR) enhancers with the variable (VH) gene promoter. Eµ binding of the transcription factor YY1 has been implicated in enhancer-promoter communication, but the YY1 protein network remains obscure. By analyzing the comprehensive proteome of the 1-kb Eµ wild-type enhancer and that of Eµ lacking the YY1 binding site, we identified the male-specific lethal (MSL)/MOF complex as a component of the YY1 protein network. We found that MSL2 recruitment depends on YY1 and that gene knockout of Msl2 in primary pre-B cells reduces µ gene expression and chromatin looping of Eµ to the 3' RR enhancer and VH promoter. Moreover, Mof heterozygosity in mice impaired µ expression and early B cell differentiation. Together, these data suggest that the MSL/MOF complex regulates Igh gene expression by augmenting YY1-mediated enhancer-promoter communication.

Tumor suppressor FRMD3 controls mammary epithelial cell fate determination via notch signaling pathway.

The luminal-to-basal transition in mammary epithelial cells (MECs) is accompanied by changes in epithelial cell lineage plasticity; however, the underlying mechanism remains elusive. Here, we report that deficiency of Frmd3 inhibits mammary gland lineage development and induces stemness of MECs, subsequently leading to the occurrence of triple-negative breast cancer. Loss of Frmd3 in PyMT mice results in a luminal-to-basal transition phenotype. Single-cell RNA sequencing of MECs indicated that knockout of Frmd3 inhibits the Notch signaling pathway. Mechanistically, FERM domain-containing protein 3 (FRMD3) promotes the degradation of Disheveled-2 by disrupting its interaction with deubiquitinase USP9x. FRMD3 also interrupts the interaction of Disheveled-2 with CK1, FOXK1/2, and NICD and decreases Disheveled-2 phosphorylation and nuclear localization, thereby impairing Notch-dependent luminal epithelial lineage plasticity in MECs. A low level of FRMD3 predicts poor outcomes for breast cancer patients. Together, we demonstrated that FRMD3 is a tumor suppressor that functions as an endogenous activator of the Notch signaling pathway, facilitating the basal-to-luminal transformation in MECs.

Simultaneous removal of noise and correction of motion warping in neuron calcium imaging using a pipeline structure of self-supervised deep learning models.

Calcium imaging is susceptible to motion distortions and background noises, particularly for monitoring active animals under low-dose laser irradiation, and hence unavoidably hinder the critical analysis of neural functions. Current research efforts tend to focus on either denoising or dewarping and do not provide effective methods for videos distorted by both noises and motion artifacts simultaneously. We found that when a self-supervised denoising model of DeepCAD [Nat. Methods18, 1359 (2021)10.1038/s41592-021-01225-0] is used on the calcium imaging contaminated by noise and motion warping, it can remove the motion artifacts effectively but with regenerated noises. To address this issue, we develop a two-level deep-learning (DL) pipeline to dewarp and denoise the calcium imaging video sequentially. The pipeline consists of two 3D self-supervised DL models that do not require warp-free and high signal-to-noise ratio (SNR) observations for network optimization. Specifically, a high-frequency enhancement block is presented in the denoising network to restore more structure information in the denoising process; a hierarchical perception module and a multi-scale attention module are designed in the dewarping network to tackle distortions of various sizes. Experiments conducted on seven videos from two-photon and confocal imaging systems demonstrate that our two-level DL pipeline can restore high-clarity neuron images distorted by both motion warping and background noises. Compared to typical DeepCAD, our denoising model achieves a significant improvement of approximately 30% in image resolution and up to 28% in signal-to-noise ratio; compared to traditional dewarping and denoising methods, our proposed pipeline network recovers more neurons, enhancing signal fidelity and improving data correlation among frames by 35% and 60% respectively. This work may provide an attractive method for long-term neural activity monitoring in awake animals and also facilitate functional analysis of neural circuits.

Efficacy and safety of first-line regimens for advanced HER2-positive breast cancer: A Bayesian network meta-analysis.

Background: The current standard of care for advanced human epidermal growth factor receptor 2 (HER2)-positive breast cancer is pertuzumab plus trastuzumab and docetaxel as first-line therapy. However, with the development of newer treatment regimens, there is a lack of evidence regarding which is the optimal treatment strategy. The aim of this network meta-analysis was to evaluate the efficacy and safety of first-line regimens for advanced HER2-positive breast cancer by indirect comparisons. Methods: A systematic review and Bayesian network meta-analysis were conducted. The PubMed, EMBASE, and Cochrane Library databases were searched for relevant articles published through to December 2023. The hazard ratio (HR) and 95% credible interval (CrI) were used to compare progression-free survival (PFS) between treatments, and the odds ratio and 95% CrI were used to compare the objective response rate (ORR) and safety. Results: Twenty randomized clinical trials that included 15 regimens and 7094 patients were analyzed. Compared with the traditional trastuzumab and docetaxel regimen, PFS was longer on the pyrotinib and trastuzumab plus docetaxel regimen (HR: 0.41, 95% CrI: 0.22-0.75) and the pertuzumab and trastuzumab plus docetaxel regimen (HR: 0.65, 95% CrI: 0.43-0.98). Consistent with the results for PFS, the ORR was better on the pyrotinib and trastuzumab plus docetaxel regimen and the pertuzumab and trastuzumab plus docetaxel regimen than on the traditional trastuzumab and docetaxel regimen. The surface under the cumulative ranking curve indicated that the pyrotinib and trastuzumab plus docetaxel regimen was most likely to rank first in achieving the best PFS and ORR. Comparable results were found for grade ≥3 AE rates of ≥10%. Conclusions: Our results suggest that the pyrotinib and trastuzumab plus docetaxel regimen is most likely to be the optimal first-line therapy for patients with HER2-positive breast cancer.

Integrative analyses identified gap junction beta-2 as a prognostic biomarker and therapeutic target for breast cancer.

Background: Increasing evidence has shown that connexins are involved in the regulation of tumor development, immune escape, and drug resistance. This study investigated the gene expression patterns, prognostic values, and potential mechanisms of connexins in breast cancer. Methods: We conducted a comprehensive analysis of connexins using public gene and protein expression databases and clinical samples from our institution. Connexin mRNA expressions in breast cancer and matched normal tissues were compared, and multiomics studies were performed. Results: Gap junction beta-2 mRNA was overexpressed in breast cancers of different pathological types and molecular subtypes, and its high expression was associated with poor prognosis. The tumor membrane of the gap junction beta-2 mutated group was positive, and the corresponding protein was expressed. Somatic mutation and copy number variation of gap junction beta-2 are rare in breast cancer. The gap junction beta-2 transcription level in the p110α subunit of the phosphoinositide 3-kinase mutant subgroup was higher than that in the wild-type subgroup. Gap junction beta-2 was associated with the phosphoinositide 3-kinase-Akt signaling pathway, extracellular matrix-receptor interaction, focal adhesion, and proteoglycans in cancer. Furthermore, gap junction beta-2 overexpression may be associated with phosphoinositide 3-kinase and histone deacetylase inhibitor resistance, and its expression level correlated with infiltrating CD8+ T cells, macrophages, neutrophils, and dendritic cells. Conclusions: Gap junction beta-2 may be a promising therapeutic target for targeted therapy and immunotherapy and may be used to predict breast cancer prognosis.

Metronomic chemotherapy plus anti-PD-1 in metastatic breast cancer: a Bayesian adaptive randomized phase 2 trial.

It remains unclear whether metronomic chemotherapy is superior to conventional chemotherapy when combined with immune checkpoint blockade. Here we performed a phase 2 clinical trial of metronomic chemotherapy combined with PD-1 blockade to compare the efficacy of combined conventional chemotherapy and PD-1 blockade using Bayesian adaptive randomization and efficacy monitoring. Eligible patients had metastatic HER2-negative breast cancer and had not received more than one prior line of standard chemotherapy. Patients (total n = 97) were randomized to receive (1) metronomic vinorelbine (NVB) monotherapy (n = 11), (2) NVB plus anti-PD-1 toripalimab (n = 7), (3) anti-angiogenic bevacizumab, NVB and toripalimab (n = 27), (4) conventional cisplatin, NVB and toripalimab (n = 26), or (5) metronomic cyclophosphamide, capecitabine, NVB and toripalimab (the VEX cohort) (n = 26). The primary endpoint was disease control rate (DCR). Secondary objectives included progression-free survival (PFS) and safety. The study met the primary endpoint. The VEX (69.7%) and cisplatin (73.7%) cohorts had the highest DCR. The median PFS of patients in the VEX cohort was the longest, reaching 6.6 months, followed by the bevacizumab (4.0 months) and cisplatin (3.5 months) cohorts. In general, the five regimens were well tolerated, with nausea and neutropenia being the most common adverse events. An exploratory mass cytometry analysis indicated that metronomic VEX chemotherapy reprograms the systemic immune response. Together, the clinical and translational data of this study indicate that metronomic VEX chemotherapy combined with PD-1 blockade can be a treatment option in patients with breast cancer. ClinicalTrials.gov Identifier: NCT04389073 .

ATN-Res2Unet: an advanced deep learning network for the elimination of saturation artifacts in endoscopy optical coherence tomography.

Endoscopic optical coherence tomography (OCT) possesses the capability to non-invasively image internal lumens; however, it is susceptible to saturation artifacts arising from robust reflective structures. In this study, we introduce an innovative deep learning network, ATN-Res2Unet, designed to mitigate saturation artifacts in endoscopic OCT images. This is achieved through the integration of multi-scale perception, multi-attention mechanisms, and frequency domain filters. To address the challenge of obtaining ground truth in endoscopic OCT, we propose a method for constructing training data pairs. Experimental in vivo data substantiates the effectiveness of ATN-Res2Unet in reducing diverse artifacts while preserving structural information. Comparative analysis with prior studies reveals a notable enhancement, with average quantitative indicators increasing by 45.4-83.8%. Significantly, this study marks the inaugural exploration of leveraging deep learning to eradicate artifacts from endoscopic OCT images, presenting considerable potential for clinical applications.

The Myopia Prevalence and Association With Physical Activity Among Primary School Students Aged 6-12 Years: A Cross-Sectional Study in Tianjin, China.

Purpose: This study aimed to investigate the prevalence of myopia and determine the association between physical activity and risk of myopia among primary school students in Tianjin, China. Methods: A cross-sectional study was conducted among subjects from nine primary schools. All of the subjects underwent visual acuity and spherical equivalent (SE) with noncycloplegic autorefraction measurement. Myopia was defined as an SE refraction ≤-0.50D and an uncorrected visual acuity <5.0 in either eye. Physical activity was measured via the Physical Activity Questionnaire for Children. Data were analyzed using the Pearson χ2 test and binary logistic regression. Stratification analysis by sex was also performed. Results: A total of 2976 participants (1408 boys and 1568 girls) aged six to 12 years (mean age 8.82 years) were included in this study. The overall prevalence of myopia was 52.92%. When stratified according to physical activity, myopia prevalence significantly decreased with increasing physical activity levels (χ2 trend test = 127.63, P < 0.001). In the binary logistic regression analysis, after adjusting for age, sex, and school region, the odds ratio for the association between physical activity and myopia was 0.762 (95% confidence interval, 0.675-0.862, P < 0.001). When stratified by sex, the significant statistical association between physical activity and myopia both can be found in two groups (P < 0.05). Conclusions: Higher levels of physical activity were independently associated with decreased risk of myopia. The significant reverse statistical association between physical activity and myopia can be found in male or female groups. Translational Relevance: Taking part in physical activities may be an effective way to reduce the prevalence of myopia.

Optimization of QuEChERS cleanup for quantification of γ-oryzanol in vegetable oils by UHPLC-MS/MS.

This study was based on QuEChERS cleanup coupled with UHPLC-MS/MS for the determination of γ-oryzanol compounds in vegetable oils. Several parameters of QuEChERS and UHPLC-MS/MS were studied for purification and detection of γ-oryzanol compounds in oil samples. Under the optimized conditions, the whole pretreatment procedure could be accomplished within 10 min without tedious procedure, larger volume of organic solvent and complicated apparatus. The limit of detections and the limit of quantifications for γ-oryzanol compounds were ranging from 0.1-0.3 µg kg-1 and 0.4-1.0 µg kg-1, respectively. Satisfactory recoveries of all analyts were ranging from 72.2 % to 101.3 %, and the intra-day and inter-day precision were less than 10.6 %. The validation indicated that rice band oil and corn oil were rich in 24-mCAF, CAF, ß-SIF, CMF and STF. The QuEChERS-UHPLC-MS/MS simultaneously quantified five γ-oryzanol compounds in lipid matrices and assessed the nutritional and functional substances of vegetable oils.

Insights into the synergistic toxicity mechanisms caused by nano- and microplastics with triclosan using a dose-dependent functional genomics approach in Saccharomyces cerevisiae.

The emergence of polystyrene (PS) nano- and microplastics (NMPs) and triclosan (TCS) as environmental contaminants has raised concerns about their combined toxicities to organisms, but the complex toxicity arising from their interactions and the underlying molecular mechanisms remain obscure to us. In this study, we comprehensively detected the combined toxicity of PS-NMPs and TCS via the dose-dependent yeast functional genomics profiling. Firstly, our findings demonstrated that the combined exposure to PS-NMPs and TCS elicited a synergistic toxic effect in which the toxicity depended on the size of the PS-NMPs. Secondly, we found that TCS exposure, either alone or in combination with PS-NMPs, influenced lipid biosynthetic processes and ATP export pathways, while the unique responsive genes triggered by combined exposure to TCS and PS-NMPs are significantly enriched in mitochondrial translation, ribosomal small subunit assembly, and tRNA wobble uridine modification. Thirdly, our results demonstrated that point of departure (POD) at the pathway level was positively correlated with IC50, and POD was a more sensitive predictor of toxicity than the apical toxicity endpoints. More importantly, our findings suggested that the combined exposure of PS-NMPs in a size-dependent manner not only alleviated the harmful effects of TCS on glycerophospholipid metabolism, but also exacerbated its negative impact on oxidative phosphorylation. Collectively, our study not only provides new insights into the intricate molecular mechanisms that control the combined toxicity of PS-NMPs and TCS, but also confirms the effectiveness of the dose-dependent functional genomics approach in elucidating the molecular mechanisms of the combined toxicity of pollutants.

Development and validation of a predictive model for severe white matter hyperintensity with obesity.

Purpose: The purpose of the present study was to identify predictors of severe white matter hyperintensity (WMH) with obesity (SWO), and to build a prediction model for screening obese people with severe WMH without Nuclear Magnetic Resonance Imaging (MRI) examination. Patients subjects and methods: From September 2020 to October 2021, 650 patients with WMH were recruited consecutively. The subjects were divided into two groups, SWO group and non-SWO group. Univariate and Logistic regression analysis were was applied to explore the potential predictors of SWO. The Youden index method was adopted to determine the best cut-off value in the establishment of the prediction model of SWO. Each parameter had two options, low and high. The score table of the prediction model and nomogram based on the logistic regression were constructed. Of the 650 subjects, 487 subjects (75%) were randomly assigned to the training group and 163 subjects (25%) to the validation group. By resampling the area under the curve (AUC) of the subject's operating characteristics and calibration curves 1,000 times, nomogram performance was verified. A decision curve analysis (DCA) was used to evaluate the nomogram's clinical usefulness. By resampling the area under the curve (AUC) of the subject's operating characteristics and calibration curves 1,000 times, nomogram performance was verified. A decision curve analysis (DCA) was used to evaluate the nomogram's clinical usefulness. Results: Logistic regression demonstrated that hypertension, uric acid (UA), complement 3 (C3) and Interleukin 8 (IL-8) were independent risk factors for SWO. Hypertension, UA, C3, IL-8, folic acid (FA), fasting C-peptide (FCP) and eosinophil could be used to predict the occurrence of SWO in the prediction models, with a good diagnostic performance, Areas Under Curves (AUC) of Total score was 0.823 (95% CI: 0.760-0.885, p < 0.001), sensitivity of 60.0%, specificity of 91.4%. In the development group, the nomogram's AUC (C statistic) was 0.829 (95% CI: 0.760-0.899), while in the validation group, it was 0.835 (95% CI: 0.696, 0.975). In both the development and validation groups, the calibration curves following 1,000 bootstraps showed a satisfactory fit between the observed and predicted probabilities. DCA showed that the nomogram had great clinical utility. Conclusion: Hypertension, UA, C3, IL-8, FA, FCP and eosinophil models had the potential to predict the incidence of SWO. When the total score of the model exceeded 9 points, the risk of SWO would increase significantly, and the nomogram enabled visualization of the patient's WMH risk. The application prospect of our models mainly lied in the convenient screening of SWO without MRI examination in order to detect SWO and control the WMH hazards early.