Dynamic control of chromatin-associated m6A methylation regulates nascent RNA synthesis.

N6-methyladenosine (m6A) methylation is co-transcriptionally deposited on mRNA, but a possible role of m6A on transcription remains poorly understood. Here, we demonstrate that the METTL3/METTL14/WTAP m6A methyltransferase complex (MTC) is localized to many promoters and enhancers and deposits the m6A modification on nascent transcripts, including pre-mRNAs, promoter upstream transcripts (PROMPTs), and enhancer RNAs. PRO-seq analyses demonstrate that nascent RNAs originating from both promoters and enhancers are significantly decreased in the METTL3-depleted cells. Furthermore, genes targeted by the Integrator complex for premature termination are depleted of METTL3, suggesting a potential antagonistic relationship between METTL3 and Integrator. Consistently, we found the Integrator complex component INTS11 elevated at promoters and enhancers upon loss of MTC or nuclear m6A binders. Taken together, our findings suggest that MTC-mediated m6A modification protects nascent RNAs from Integrator-mediated termination and promotes productive transcription, thus unraveling an unexpected layer of gene regulation imposed by RNA m6A modification.

Enhancer variants on chromosome 2p14 regulating SPRED2 and ACTR2 act as a signal amplifier to protect against rheumatoid arthritis.

Genome-wide association studies (GWASs) have repeatedly reported multiple non-coding single-nucleotide polymorphisms (SNPs) at 2p14 associated with rheumatoid arthritis (RA), but their functional roles in the pathological mechanisms of RA remain to be explored. In this study, we integrated a series of bioinformatics and functional experiments and identified three intronic RA SNPs (rs1876518, rs268131, and rs2576923) within active enhancers that can regulate the expression of SPRED2 directly. At the same time, SPRED2 and ACTR2 influence each other as a positive feedback signal amplifier to strengthen the protective role in RA by inhibiting the migration and invasion of rheumatoid fibroblast-like synoviocytes (FLSs). In particular, the transcription factor CEBPB preferentially binds to the rs1876518-T allele to increase the expression of SPRED2 in FLSs. Our findings decipher the molecular mechanisms behind the GWAS signals at 2p14 for RA and emphasize SPRED2 as a potential candidate gene for RA, providing a potential target and direction for precise treatment of RA.

High-throughput functional dissection of noncoding SNPs with biased allelic enhancer activity for insulin resistance-relevant phenotypes.

Most of the single-nucleotide polymorphisms (SNPs) associated with insulin resistance (IR)-relevant phenotypes by genome-wide association studies (GWASs) are located in noncoding regions, complicating their functional interpretation. Here, we utilized an adapted STARR-seq to evaluate the regulatory activities of 5,987 noncoding SNPs associated with IR-relevant phenotypes. We identified 876 SNPs with biased allelic enhancer activity effects (baaSNPs) across 133 loci in three IR-relevant cell lines (HepG2, preadipocyte, and A673), which showed pervasive cell specificity and significant enrichment for cell-specific open chromatin regions or enhancer-indicative markers (H3K4me1, H3K27ac). Further functional characterization suggested several transcription factors (TFs) with preferential allelic binding to baaSNPs. We also incorporated multi-omics data to prioritize 102 candidate regulatory target genes for baaSNPs and revealed prevalent long-range regulatory effects and cell-specific IR-relevant biological functional enrichment on them. Specifically, we experimentally verified the distal regulatory mechanism at IRS1 locus, in which rs952227-A reinforces IRS1 expression by long-range chromatin interaction and preferential binding to the transcription factor HOXC6 to augment the enhancer activity. Finally, based on our STARR-seq screening data, we predicted the enhancer activity of 227,343 noncoding SNPs associated with IR-relevant phenotypes (fasting insulin adjusted for BMI, HDL cholesterol, and triglycerides) from the largest available GWAS summary statistics. We further provided an open resource (http://www.bigc.online/fnSNP-IR) for better understanding genetic regulatory mechanisms of IR-relevant phenotypes.

JMJD3 and SNAI2 synergistically protect against Parkinson's disease by mediating the YAP/HIF1α signaling pathway in a mouse model.

This study aimed to characterize the functional relevance and mechanistic basis of the histone demethylase Jumonji domain-containing protein-3 (JMJD3) in preserving dopaminergic neuron survival in Parkinson's disease (PD). Mice with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced lesions and MN9D dopaminergic neuronal cell lines exposed to 6-OHDA, respectively, were used to simulate in vivo and in vitro PD-like environments. PD-related genes with differential expressions were identified using RNA sequencing of hippocampal tissues collected from MPTP-lesioned mice. A specific lentiviral shRNA vector was used to investigate the effects of JMJD3 on neuron activities in vitro and PD-like phenotypes in vivo. JMJD3 was found to up-regulate the expression of Snail family transcriptional repressor 2 (SNAI2) through the inhibition of H3 on lysine 27 (H3K27me3) enrichment in the SNAI2 promoter region. As a result, the viability of 6-OHDA-exposed MN9D cells was stimulated, and cell apoptosis was diminished. Knockdown of SNAI2 decreased the expression of yes-associated protein (YAP) and HIF1α while also reducing the viability of 6-OHDA-exposed MN9D cells and increasing cell apoptosis. The in vivo experiments demonstrated that JMJD3 activated the SNAI2/YAP/HIF1α signaling pathway, inhibiting PD-like phenotypes in MPTP-lesioned mice. Thus, the findings provide evidence that JMJD3 inhibits the enrichment of H3K27me3 at the SNAI2 promoter, leading to the upregulation of SNAI2 expression and activation of the YAP/HIF1α signaling pathway, ultimately exerting a protective effect on PD mice. This finding suggests that targeting the JMJD3-SNAI2 pathway could be a promising therapeutic strategy for PD. Further in-depth studies are needed to elucidate the underlying mechanisms and identify potential downstream targets of this pathway.

The human discs large protein 1 interacts with and maintains connexin 43 at the plasma membrane in keratinocytes.

Gap junction channels, composed of connexins, allow direct cell-to-cell communication. Connexin 43 (Cx43; also known as GJA1) is widely expressed in tissues, including the epidermis. In a previous study of human papillomavirus-positive cervical epithelial tumour cells, we identified Cx43 as a binding partner of the human homologue of Drosophila Discs large (Dlg1; also known as SAP97). Dlg1 is a member of the membrane associated-guanylate kinase (MAGUK) scaffolding protein family, which is known to control cell shape and polarity. Here, we show that Cx43 also interacts with Dlg1 in uninfected keratinocytes in vitro and in keratinocytes, dermal cells and adipocytes in normal human epidermis in vivo. Depletion of Dlg1 in keratinocytes did not alter Cx43 transcription but was associated with a reduction in Cx43 protein levels. Reduced Dlg1 levels in keratinocytes resulted in a reduction in Cx43 at the plasma membrane with a concomitant reduction in gap junctional intercellular communication and relocation of Cx43 to the Golgi compartment. Our data suggest a key role for Dlg1 in maintaining Cx43 at the plasma membrane in keratinocytes.

Age-associated cortical similarity networks correlate with cell type-specific transcriptional signatures.

Human brain structure shows heterogeneous patterns of change across adults aging and is associated with cognition. However, the relationship between cortical structural changes during aging and gene transcription signatures remains unclear. Here, using structural magnetic resonance imaging data of two separate cohorts of healthy participants from the Cambridge Centre for Aging and Neuroscience (n = 454, 18-87 years) and Dallas Lifespan Brain Study (n = 304, 20-89 years) and a transcriptome dataset, we investigated the link between cortical morphometric similarity network and brain-wide gene transcription. In two cohorts, we found reproducible morphometric similarity network change patterns of decreased morphological similarity with age in cognitive related areas (mainly located in superior frontal and temporal cortices), and increased morphological similarity in sensorimotor related areas (postcentral and lateral occipital cortices). Changes in morphometric similarity network showed significant spatial correlation with the expression of age-related genes that enriched to synaptic-related biological processes, synaptic abnormalities likely accounting for cognitive decline. Transcription changes in astrocytes, microglia, and neuronal cells interpreted most of the age-related morphometric similarity network changes, which suggest potential intervention and therapeutic targets for cognitive decline. Taken together, by linking gene transcription signatures to cortical morphometric similarity network, our findings might provide molecular and cellular substrates for cortical structural changes related to cognitive decline across adults aging.

The co-activation pattern between the DMN and other brain networks affects the cognition of older adults: evidence from naturalistic stimulation fMRI data.

Brain function changes affect cognitive functions in older adults, yet the relationship between cognition and the dynamic changes of brain networks during naturalistic stimulation is not clear. Here, we recruited the young, middle-aged and older groups from the Cambridge Center for Aging and Neuroscience to investigate the relationship between dynamic metrics of brain networks and cognition using functional magnetic resonance imaging data during movie-watching. We found six reliable co-activation pattern (CAP) states of brain networks grouped into three pairs with opposite activation patterns in three age groups. Compared with young and middle-aged adults, older adults dwelled shorter time in CAP state 4 with deactivated default mode network (DMN) and activated salience, frontoparietal and dorsal-attention networks (DAN), and longer time in state 6 with deactivated DMN and activated DAN and visual network, suggesting altered dynamic interaction between DMN and other brain networks might contribute to cognitive decline in older adults. Meanwhile, older adults showed easier transfer from state 6 to state 3 (activated DMN and deactivated sensorimotor network), suggesting that the fragile antagonism between DMN and other cognitive networks might contribute to cognitive decline in older adults. Our findings provided novel insights into aberrant brain network dynamics associated with cognitive decline.

PTEN Deficiency Facilitates Exosome Secretion and Metastasis in Cholangiocarcinoma by Impairing TFEB-mediated Lysosome Biogenesis.

BACKGROUND & AIMS: In eukaryotes, the ubiquitin-proteasome system and the autophagy-lysosome pathway are essential for maintaining cellular proteostasis and associated with cancer progression. Our previous studies have demonstrated that phosphatase and tensin homolog (PTEN), one of the most frequently mutated genes in human cancers, limits proteasome abundance and determines chemosensitivity to proteasome inhibitors in cholangiocarcinoma (CCA). However, whether PTEN regulates the lysosome pathway remains unclear. METHODS: We tested the effects of PTEN on lysosome biogenesis and exosome secretion using loss- and gain-of-function strategies in CCA cell lines. Using in vitro dephosphorylation assays, we explored the regulatory mechanism between PTEN and the key regulator of lysosome biogenesis, transcription factor EB (TFEB). Using the migration assays, invasion assays, and trans-splenic liver metastasis mouse models, we evaluated the function of PTEN deficiency, TFEB-mediated lysosome biogenesis, and exosome secretion on tumor metastasis. Moreover, we investigated the clinical significance of PTEN expression and exosome secretion by retrospective analysis. RESULTS: PTEN facilitated lysosome biogenesis and acidification through its protein phosphatase activity to dephosphorylate TFEB at Ser211. Notably, PTEN deficiency increased exosome secretion by reducing lysosome-mediated degradation of multi-vesicular bodies, which further facilitated the proliferation and invasion of CCA. TFEB agonist curcumin analog C1 restrained the metastatic phenotype caused by PTEN deficiency in mouse models, and we highlighted the correlation between PTEN deficiency and exosome secretion in clinical cohorts. CONCLUSIONS: In CCA, PTEN deficiency impairs lysosome biogenesis to facilitate exosome secretion and cancer metastasis in a TFEB phosphorylation-dependent manner.

Comprehensive evaluation of morphological and physiological responses of seventeen Crassulaceae species to waterlogging and drainage under temperate monsoon climate.

Unpredictable rainfall frequently results in excess moisture, which is detrimental to the landscape because it interferes with the genetic, morphological, and physiological processes of plants, even though the majority of urban landscapes frequently experience moisture shortages. A study was conducted to analyze the effects of a 36-day waterlogging phase and a subsequent 12-day recovery period on the morpho-physiological responses of 17 Crassulaceae species with the goal of identifying those which were more tolerant of the conditions. Results revealed that waterlogging stress has an impact on all morpho-physiological parameters. Sensitive materials (S7, Hylotelephium telephium 'Purple Emperor' and S15, S. sexangulare) showed severe ornamental quality damage, mortality, decreases in total dry biomass, root-shoot ratio, and chlorophyll content, as well as higher MDA concentrations. Lower reductions in these parameters, along with improved antioxidant enzyme activities and greater recovery capabilities after drainage, were observed in the most tolerant materials S2 (H. spectabile 'Brilliant'), S3 (H. spectabile 'Carl'), and S5 (H. telephium 'Autumn Joy'). Furthermore, with the exception of early death materials (S7 and S15), all materials showed varying intensities of adventitious root formation in response to waterlogging. The 17 species were divided into 4 clusters based on the comprehensive evaluation value. The first group included S1-S3, S5-S6, S8-S12, which were waterlogged tolerant with the highest values (0.63-0.82). S14 belongs to the intermediate waterlogging tolerant. S4, S13, S16, and S17 were clustered into the low waterlogging-tolerant group. S7 and S15 were the most susceptible to waterlogging. The survival and success of Crassulaceae species (especially, the first and second cluster), throughout this prolonged period of waterlogging (36 days) and recovery were attributed to a combination of physiological and morphological responses, indicating that they are an appealing species for the creation of rain gardens or obstructed drainage locations.

Circulating exosomal mir-16-2-3p is associated with coronary microvascular dysfunction in diabetes through regulating the fatty acid degradation of endothelial cells.

BACKGROUND: Coronary microvascular dysfunction (CMD) is a frequent complication of diabetes mellitus (DM) characterized by challenges in both diagnosis and intervention. Circulating levels of microRNAs are increasingly recognized as potential biomarkers for cardiovascular diseases. METHODS: Serum exosomes from patients with DM, DM with coronary microvascular dysfunction (DM-CMD) or DM with coronary artery disease (DM-CAD) were extracted for miRNA sequencing. The expression of miR-16-2-3p was assessed in high glucose-treated human aortic endothelial cells and human cardiac microvascular endothelial cells. Fluorescence in situ hybridization (FISH) was used to detect miR-16-2-3p within the myocardium of db/db mice. Intramyocardial injection of lentivirus overexpressing miR-16-2-3p was used to explore the function of the resulting gene in vivo. Bioinformatic analysis and in vitro assays were carried out to explore the downstream function and mechanism of miR-16-2-3p. Wound healing and tube formation assays were used to explore the effect of miR-16-2-3p on endothelial cell function. RESULTS: miR-16-2-3p was upregulated in circulating exosomes from DM-CMD, high glucose-treated human cardiac microvascular endothelial cells and the hearts of db/db mice. Cardiac miR-16-2-3p overexpression improved cardiac systolic and diastolic function and coronary microvascular reperfusion. In vitro experiments revealed that miR-16-2-3p could regulate fatty acid degradation in endothelial cells, and ACADM was identified as a potential downstream target. MiR-16-2-3p increased cell migration and tube formation in microvascular endothelial cells. CONCLUSIONS: Our findings suggest that circulating miR-16-2-3p may serve as a biomarker for individuals with DM-CMD. Additionally, miR-16-2-3p appears to alleviate coronary microvascular dysfunction in diabetes by modulating ACADM-mediated fatty acid degradation in endothelial cells.

High-fidelity single logical qubit encoding scheme assisted by single-sided quantum dot-cavity systems.

We present an encoding scheme of a single logical qubit with single-sided quantum dot (QD)-cavity systems, which is immune to the collective decoherence. By adjusting the Purcell factor to satisfy the balanced reflection condition, the detrimental effects of unbalanced reflection between the coupled and uncoupled QD-cavity systems can be effectively suppressed. Furthermore, the fidelity of each step can be increased to unity regardless of the strong coupling regime and the weak coupling regime of cavity quantum electrodynamics (QED) with the assistance of waveform correctors. The scheme requires QD-cavity systems and simple linear optical elements, which can be implemented with the currently experimental techniques.

Intraocular cetuximab: Safety and effect on axial elongation in young Guinea pigs with lens-induced myopization.

This study aimed to examine the intraocular tolerability of the epidermal growth factor receptor antibody cetuximab, when applied intravitreally, and its effect on axial elongation. Guinea pigs aged 2-3 weeks were subjected to bilateral plano glasses and bilateral lens-induced myopization (LIM) as a single procedure for group I (n = 8) and group II (n = 8), respectively. In the animals of group III (n = 8), group IV (n = 8), and group V (n = 8), the right eyes of the animals, in addition to LIM, received four weekly intravitreal injections of cetuximab (Erbitux®) in doses of 6.25 µg, 12.5 µg, and 25 µg, respectively. As controls, the left eyes, in addition to LIM, received corresponding intraocular injections of phosphate-buffered saline. The animals underwent regular ophthalmoscopic examinations and biometry for axial length measurements. With increasing doses of cetuximab, the inter-eye difference in axial elongation (at study end, left eyes minus right eyes) were significantly the smallest in group I (0.00 ± 0.02 mm) and group II (-0.01 ± 0.02 mm), they were larger in group III (0.04 ± 0.04 mm) and group IV (0.10 ± 0.03 mm), and they were the largest in group V (0.11 ± 0.01 mm). The inter-eye difference in axial elongation enlarged (P < 0.001) with the number of injections applied. Retinal thickness at the posterior pole (right eyes) was significantly thicker in group V than in group II (P < 0.01). The density of apoptotic cells (visualized by TUNEL-staining) did not vary significantly between any of the groups (all P > 0.05). The results suggest that intravitreal injections of cetuximab in young guinea pigs with LIM resulted in a reduction in axial elongation in a dose-dependent and number of treatment-dependent manner. Intraocular toxic effects, such as intraocular inflammation, retinal thinning, or an increased density of apoptotic cells in the retina, were not observed in association with the intravitreally applied cetuximab.

Genetic linkage map construction and QTL analysis for plant height in proso millet (Panicum miliaceum L.).

KEY MESSAGE: A genetic linkage map representing proso millet genome was constructed with SSR markers, and a major QTL corresponding to plant height was mapped on chromosome 14 of this map. Proso millet (Panicum miliaceum L.) has the lowest water requirements of all cultivated cereal crops. However, the lack of a genetic map and the paucity of genomic resources for this species have limited the utility of proso millet for detailed genetic studies and hampered genetic improvement programs. In this study, 97,317 simple sequence repeat (SSR) markers were developed based on the genome sequence of the proso millet landrace Longmi 4. Using some of these markers in conjunction with previously identified SSRs, an SSR-based linkage map for proso millet was successfully constructed using a large mapping population (316 F2 offspring). In total, 186 SSR markers were assigned to 18 linkage groups corresponding to the haploid chromosomes. The constructed map had a total length of 3033.42 centimorgan (cM) covering 78.17% of the assembled reference genome. The length of the 18 linkage groups ranged from 88.89 cM (Chr. 15) to 274.82 cM (Chr. 16), with an average size of 168.17 cM. To our knowledge, this is the first genetic linkage map for proso millet based on SSR markers. Plant height is one of the most important traits in crop improvement. A major QTL was repeatedly detected in different environments, explaining 8.70-24.50% of the plant height variations. A candidate gene affecting auxin biosynthesis and transport, and ROS homeostasis regulation was predicted. Thus, the linkage map and QTL analysis provided herein will promote the development of gene mining and molecular breeding in proso millet.

Inhibition of P21-activated kinases 1 and 4 synergistically suppresses the growth of pancreatic cancer by stimulating anti-tumour immunity.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDA) is one of the most lethal types of cancer, and KRAS oncogene occurs in over 90% of cases. P21-activated kinases (PAK), containing six members (PAK1 to 6), function downstream of KRAS. PAK1 and PAK4 play important roles in carcinogenesis, but their combinational effect remains unknown. In this study, we have determined the effect of dual inhibition of PAK1 and PAK4 in PDA progression using knockout (KO) cancer cell lines. METHODS: Murine wild-type (WT) and PAK1KO pancreatic cancer cell lines were isolated from PAK1+/+ and PAK1-/- KPC (LSL-KrasG12D/+; LSL-Trp53 R172H/+; Pdx-1-Cre) mice. KPC PAK4KO and KPC PAK1&4 KO cell lines were generated from KPC WT and KPC PAK1KO cell lines respectively using the CRISPR-CAS9 gene knockout technique. PAK WT and KO cell lines were used in mouse models of pancreatic tumours. Cells and tumour tissue were also used in flow cytometry and proteomic studies. A human PDA tissue microarray was stained by immunohistochemistry. RESULTS: Double knock out of PAK1 and PAK4 caused complete regression of tumour in a syngeneic mouse model. PAK4KO inhibited tumour growth by stimulating a rapid increase of cytotoxic CD8+ T cell infiltration. PAK1KO synergistically with PAK4KO increased cytotoxic CD8+ T cell infiltration and stimulated a sustained infiltration of CD8+ T cells at a later phase to overcome the immune evasion in the PAK4KO tumour. The human PDA tissue microarray study showed the important role of PAK1 and PAK4 in intra-tumoral T-cell function. CONCLUSION: Our results demonstrated that dual inhibition of PAK1 and PAK4 synergistically suppressed PDA progression by stimulating cytotoxic CD8 + T cell response.

Validation and update of a clinical score model to predict technical difficulty of colorectal endoscopic submucosal dissection: a multicenter prospective cohort study.

BACKGROUND AND AIMS: The Zhongshan colorectal endoscopic submucosal dissection (CR-ESD) score model was proposed to grade the technical difficulty of CR-ESD. The objective of this study was to prospectively validate and update the score model. METHODS: A multicenter prospective cohort analysis of CR-ESD was conducted. Individual data on patients, lesions, and outcomes of CR-ESD were used to validate the original model and further refine the difficulty of the prediction model. Data were randomly divided into discovery and internal validation cohorts. A multivariate Cox regression analysis was conducted on the discovery cohort to develop an updated risk-scoring system, which was then validated. RESULTS: Five hundred forty-eight patients with 565 colorectal lesions treated by ESD from 4 hospitals were included. In the prospective validation cohort, the area under the receiver-operating characteristic (ROC) curve for the original model was .707. Six risk factors were identified and assigned point values: tumor size (2 points for 30-50 mm, 3 points for ≥50 mm), at least two-thirds circumference of the lesion (3 points), tumor location in the cecum (2 points) or flexure (2 points), laterally spreading tumor-nongranular lesions (1 point), preceding biopsy sampling (1 point), and NBI International Colorectal Endoscopic type 3 (3 points). The updated model had an area under the ROC curve of .738 in the discovery cohort and of .782 in the validation cohort. Cases were categorized into easy (score = 0-1), intermediate (score = 2-3), difficult (score = 4-6), and very difficult (score ≥7) groups. Satisfactory discrimination and calibration were observed. CONCLUSIONS: The original model achieved an acceptable level of prediction in the prospective cohort. The updated model exhibited superior performance and can be used in place of the previous version. (Clinical trial registration number: ChiCTR2100047087.).

Severity Identification of Graves Orbitopathy via Random Forest Algorithm.

This study aims to establish a random forest model for detecting the severity of Graves Orbitopathy (GO) and identify significant classification factors. This is a hospital-based study of 199 patients with GO that were collected between December 2019 and February 2022. Clinical information was collected from medical records. The severity of GO can be categorized as mild, moderate-to-severe, and sight-threatening GO based on guidelines of the European Group on Graves' orbitopathy. A random forest model was constructed according to the risk factors of GO and the main ocular symptoms of patients to differentiate mild GO from severe GO and finally was compared with logistic regression analysis, Support Vector Machine (SVM), and Naive Bayes. A random forest model with 15 variables was constructed. Blurred vision, disease course, thyroid-stimulating hormone receptor antibodies, and age ranked high both in mini-decreased gini and mini decrease accuracy. The accuracy, positive predictive value, negative predictive value, and the F1 Score of the random forest model are 0.83, 0.82, 0.86, and 0.82, respectively. Compared to the three other models, our random forest model showed a more reliable performance based on AUC (0.85 vs. 0.83 vs. 0.80 vs. 0.76) and accuracy (0.83 vs. 0.78 vs. 0.77 vs. 0.70). In conclusion, this study shows the potential for applying a random forest model as a complementary tool to differentiate GO severity.

Evaluation and Prediction Analysis of 3- and 5-Year Relative Survival Rates of Patients with Cervical Cancer: A Model-Based Period Analysis.

BACKGROUND: Cervical cancer remains a threat to female health due to high mortality. Clarification of the long-term trend of survival rate over time and the associated risk factors would be greatly informative to improve the prognosis of cervical cancer patients. METHODS: This retrospective study was based on data extracted from the Surveillance, Epidemiology, and End Results (SEER) database of the United States. The 3-year and 5-year overall survival rates of patients with cervical cancer during 2002-2006, 2007-2011, and 2012-2016 were analyzed. Period analysis was used to assess the variation in survival rate stratified by age, race, and socioeconomic status during the 15-year study period and then predicted the relative survival rate in the following period from 2017 to 2021. RESULTS: During 2002-2016, the 3-year relative survival rate of cervical cancer patients increased from 73.1% to 73.5% with a high jump between 2007 and 2011. This upward trend is expected to continue to 74.3% between 2017 and 2021. Patients older than 60 years, black ethnicity, or medium and high poverty status were likely to have a lower relative survival rate. CONCLUSION: This study confirmed the increased relative survival rate of cervical cancer patients over years and identified relevant risk factors. Targeted initiatives for elderly and socially underprivileged individuals may be able to mitigate inequality.

Why was the study conducted? Cervical cancer is one of the most common cancers endangering global women's health. Although there are currently relevant screening methods and vaccines, cervical cancer still leads to a higher risk of death in infected women and poses a serious threat to women's health. Therefore, it would be informative for future policy making if the risk factors affecting prognosis were assessed and the trend of long-term survival rate of patients with cervical cancer over time was predicted.What did the researchers do? We extracted data on cervical cancer patients from the Surveillance, Epidemiology, and End Results (SEER) database between 2002 and 2016 and used a model-based period analysis to assess the characteristics of the 3- and 5-year relative survival rates of cervical cancer patients stratified by age, race, and socioeconomic status. The relative survival rate for the period from 2017 to 2021 was projected.What did the researchers find? Our study found that the 3-year relative survival rate for cervical cancer patients increased from 73.1% to 73.5% between 2002 and 2016, with a jump between 2007 and 2011. Patients older than 60 years, those of black ethnicity, or those with medium and high poverty status were more likely to have a low relative survival rate.What do the findings mean? Our study confirms that the relative survival rate of cervical cancer patients has increased in recent years and has maintained an overall upward trend. Our findings suggest that age, race, and socioeconomic status are relevant risk factors. These findings would help us to predict future trends, better allocate medical resources, and optimize health policies to improve the prognosis of cervical cancer, such as targeting the elderly and other vulnerable groups.

Effect of heart rate on poor outcome in stroke patients treated with intra-arterial thrombectomy.

BACKGROUND AND PURPOSE: The relationship between heart rate and the prognosis of patients with large vessel occlusion strokes treated with mechanical thrombectomy (MT) is not well established. This study aimed to evaluate the association of mean heart rate and heart rate variability (HRV) with the clinical outcomes after MT therapy. METHODS: Acute ischemic stroke patients undergoing MT therapy were prospectively recruited from March 2020 to November 2022. Their heart rate was collected every hour for the initial 72 h after MT procedure, and the variability of heart rate was measured by standard deviation (SD) and coefficient of variation (CV). All-cause mortality and worsening of functional outcome (change in modified Rankin Scale (mRS) score) at 3-month were captured. Binary logistic regression was used to evaluate the association between heart rate indicators and all-cause mortality. Ordinal logistic regression was used to evaluate the association between heart rate indicators and worsening of functional outcome. RESULTS: Among 191 MT-treated patients, 51(26.7%) patients died at 3-month after stroke. Increased mean heart rate per 10-bpm, heart rate SD and CV per 5-unit were all associated with the increased risk of mortality (adjusted hazard ratio [aHR] with 95% CI: 1.29 [1.09-1.51], 1.19 [1.07-1.32], 1.14 [1.03-1.27]; respectively). Patients in the highest tertile of heart rate SD had an increased risk of mortality (4.62, 1.70-12.52). After using mRS as a continuous variable, we found increased mean heart rate per 10-bpm, heart rate SD and CV per 5-unit were associated with the worsening of functional outcome (adjusted odds ratio [aOR] with 95% CI: 1.35 [1.11-1.64], 1.27 [1.05-1.53], 1.19 [1.02-1.40]; respectively). A linear relationship was observed between mean heart rate or heart rate SD and mortality; while all of the heart rate measures in this study showed a linear relationship with the worsening of functional outcome. CONCLUSIONS: Higher mean heart rate and HRV were associated with the increased risk of 3-month all-cause mortality and worse functional outcome after MT therapy for AIS patients.

Dietary cholesterol intervention could alleviate the intestinal injury of Oreochromis niloticus induced by plant-based diet via the intestinal barriers.

This study aims to explore the effects of supplementing cholesterol in plant-based feed on intestinal barriers (including physical barrier, chemical barrier, immune barrier, biological barrier) of GIFT strain tilapia (Oreochromis niloticus). Four isonitrogenous and isolipidic diets were prepared as follows: plant-based protein diet (Con group) containing corn protein powder, soybean meal, cottonseed meal, and rapeseed meal, with the addition of cholesterol at a level of 0.6 % (C0.6 % group), 1.2 % (C1.2 % group), and 1.8 % (C1.8 % group), respectively. A total of 360 fish (mean initial weight of (6.08 ± 0.12) g) were divided into 12 tanks with 30 fish per tank, each treatment was set with three tanks and the feeding period lasted 9 weeks. Histological analysis revealed that both the C0.6 % and C1.2 % groups exhibited a more organized intestinal structure, with significantly increased muscle layer thickness compared to the Con group (P < 0.05). Furthermore, in the C1.2 % group, there was a significant up-regulation of tight junction-related genes (claudin-14, occludin, zo-1) compared to the Con group (P < 0.05). 5-ethynyl-2'-deoxyuridine staining results also demonstrated a notable enhancement in intestinal cell proliferation within the C1.2 % group (P < 0.05). Regarding the intestinal chemical barrier, trypsin and lipase activities were significantly elevated in the C1.2 % group (P < 0.05), while hepcidin gene expression was considerably down-regulated in this group but up-regulated in the C1.8 % group (P < 0.05). In terms of the intestinal immune barrier, inflammation-related gene expression levels (tnf-α, il-1ß, caspase 9, ire1, perk, atf6) were markedly reduced in the C1.2 % group (P < 0.05). Regarding the intestinal biological barrier, the composition of the intestinal microbiota indicated that compared to the Con group, both the 0.6 % and 1.2 % groups showed a significant increase in Shannon index (P < 0.05). Additionally, there was a significant increase in the abundance of Firmicutes and Clostridium in the C1.2 % group (P < 0.05). In summary, supplementation of 1.2 % cholesterol in the plant-based diet exhibits the potential to enhance intestinal tight junction function and improve the composition of intestinal microbiota, thereby significantly promoting tilapia's intestinal health.

Photocatalysis Meets Piezoelectricity in a Type-I Oxygen Vacancy-Rich BaTiO3/BiOBr Heterojunction: Mechanism Insights from Characterizations to DFT Calculations.

It is a challenging task to design a piezoelectric photocatalyst with excellent performance under mechanical agitation instead of ultrasonic irradiation. Integrating vacancy defects into a heterojunction seems to be an effective strategy for synergistically increasing its piezo-photocatalytic performance. For this goal, a two-step hydrothermal method was adopted to architect a type-I oxygen-vacancy-rich BaTiO3/BiOBr heterojunction to surge the degradation of Rhodamine B (RhB) under the combined action of simulated sunlight irradiation and mechanical agitation. Various instrumental techniques demonstrated the formation of a BaTiO3/BiOBr heterojunction with high crystallinity. The existence of surface oxygen vacancies was confirmed by XPS and EPR tests. PFM results manifested that this heterojunction had excellent piezoelectric properties, with a piezoelectric response value of 30.31 pm V-1. Comparative experiments indicated that RhB degradation efficiency under piezo-photocatalysis over this heterojunction largely exceeded the total sum of those under piezocatalysis and photocatalysis. h+, ·O2-, and 1O2 were the dominant reactive species for RhB degradation. The improved separation efficiency of photogenerated charges was verified by electrochemical measurements. DFT calculations indicated that the polarization of BaTiO3 could affect the electronic band structure of BiOBr. This work will provide comprehensive insights into piezo-photocatalytic mechanism at a microcosmic level and help to develop new-styled piezoelectric photocatalysts.