Percutaneous coronary intervention leads to microplastics entering the blood: Interventional devices are a major source.

Microplastics (MPs) is an emerging pollutant potentially harmful to health. Medical practices using plastic devices, such as percutaneous coronary interventions (PCI), may result in MPs entering into the blood. The purpose of this study was to quantify the effect of PCI on microplastic levels in patients' blood. Laser direct infrared (LDIR) was used to detect MPs in the blood of 23 patients before and after PCI. MPs in the water in which devices used in PCI were washed were also examined. The concentration of MPs in the blood was significantly elevated (93.57 ± 35.95 vs. 4.96 ± 3.40 particles/10 mL of blood, P < 0.001) after PCI compared to before, and the increased MPs were polyamide (PA), polyethylene (PE), polyurethane (PU), and polyethylene terephthalate (PET), which was consistent with the types of MPs detected in the device washing water. The maximum diameter of MPs in blood before PCI was 50 µm, whereas after PCI it was 213 µm, and even 336 µm in device washing water. These findings indicated that PCI will cause MPs to enter the blood, and devices used during PCI were a major source, a range of medical practices that use plastic devices may be a new route for MPs to enter the human body.

Identification of NR3C2 as a functional diagnostic and prognostic biomarker and potential therapeutic target in non-small cell lung cancer.

Background: Non-small cell lung cancer (NSCLC), including the lung squamous cell carcinoma (LUSC) and lung adenocarcinoma (LUAD) subtypes, is a malignant tumor type with a poor 5-year survival rate. The identification of new powerful diagnostic biomarkers, prognostic biomarkers, and potential therapeutic targets in NSCLC is urgently required. Methods: The UCSC Xena, UALCAN, and GEO databases were used to screen and analyze differentially expressed genes, regulatory modes, and genetic/epigenetic alterations in NSCLC. The UCSC Xena database, GEO database, tissue microarray, and immunohistochemistry staining analyses were used to evaluate the diagnostic and prognostic values. Gain-of-function assays were performed to examine the roles. The ESTIMATE, TIMER, Linked Omics, STRING, and DAVID algorithms were used to analyze potential molecular mechanisms. Results: NR3C2 was identified as a potentially important molecule in NSCLC. NR3C2 is expressed at low levels in NSCLC, LUAD, and LUSC tissues, which is significantly related to the clinical indexes of these patients. Receiver operating characteristic curve analysis suggests that the altered NR3C2 expression patterns have diagnostic value in NSCLC, LUAD, and especially LUSC patients. Decreased NR3C2 expression levels can help predict poor prognosis in NSCLC and LUAD patients but not in LUSC patients. These results have been confirmed both with database analysis and real-world clinical samples on a tissue microarray. Copy number variation contributes to low NR3C2 expression levels in NSCLC and LUAD, while promoter DNA methylation is involved in its downregulation in LUSC. Two NR3C2 promoter methylation sites have high sensitivity and specificity for LUSC diagnosis with clinical application potential. NR3C2 may be a key participant in NSCLC development and progression and is closely associated with the tumor microenvironment and immune cell infiltration. NR3C2 co-expressed genes are involved in many cancer-related signaling pathways, further supporting a potentially significant role of NR3C2 in NSCLC. Conclusions: NR3C2 is a novel potential diagnostic and prognostic biomarker and therapeutic target in NSCLC.

Occurrence of Fusarium Crown Rot Caused by Fusarium culmorum on Winter Wheat in Xinjiang Uygur Autonomous Region, China.

Wheat (Triticum aestivum L.) is the predominant grain crop and plays a pivotal role in grain production in Xinjiang Uygur Autonomous Region (XUAR), China. Its cultivated area constitutes approximately half of the total sown area of grain crops in XUAR, with 1.14 million hectares in 2021. Fusarium crown rot (FCR) of wheat, caused by Fusarium culmorum (W.G. Smith) Sacc., is one of the most devastating soil-borne diseases known to seriously reduce grain yield (Ma et al. 2024; Saad et al. 2023). In 2016, FCR of wheat, caused by F. culmorum, was firstly identified in Henan Province, China (Li et al. 2016). In June 2023, during the investigation of FCR of wheat in Aksu Prefecture, XUAR, FCR on winter wheat (cv. Xindong 20) was found (82.761349°E, 41.612202°N). The grain-filling period for winter wheat in early June coincided with a period of high temperatures and water demand in Aksu Prefecture. Approximately 8% of the Xindong 20 wheat plants exhibited symptoms of white heads and browning at the stem base, with the disease present in 82% of the wheat fields surveyed. To identify the pathogens, 20 samples of diseased stem basal tissue, each 0.5 cm in length, were collected and sterilized with 75% alcohol for 30s and 5% NaOCl solution for 2 min, followed by three rinses with sterile water. These samples were then plated onto potato dextrose agar (PDA) medium at 25°C for 5 days. A total of 17 isolates with consistent morphological characteristics were obtained using single-spore technique, with an isolation rate of 85%. The isolated strains exhibited rapid growth on PDA, producing fluffy, pale-yellow hyphae, and accumulating a pale-yellow to dark red pigment on the bottom of the medium. On carnation leaf agar (CLA), these strains formed orange colonies due to the aggregation of a large number of macroconidia. The macroconidia were short and thick, with three to four septa and rounded apical cell, averaging 31.94 to 40.96 × 5.62 to 6.71 µm (Magnification of ×400). Microconidia were not observed. These morphological characters were consistent with those of F. culmorum (Leslie and Summerell. 2006). Two isolates (D-9 and D-11) were selected for molecular identification. The EF-1α gene fragment was amplified using primers EF1/EF2 (5'-ATGGGTAAGGARGACAAGAC-3'/5'-GGARGTACCAGTSATCATG-3') as previously described by O'Donnell et al. (1998). The two 665 bp PCR products were sequenced and submitted to GenBank (GenBank Accession No: PP763247 and PP763248) with 99. 7% identity to the published F. culmorum sequences (e.g., OP985478, OP985477, MG195126, KX702638). The molecular identification was further confirmed by F. culmorum species-specific PCR primers FcOIF/FcOIR (Nicholson et al. 1998). The expected PCR products of 553 bp were produced only in F. culmorum. Strains D-9 and D-11 were used to conduct the pathogenicity experiment on 7-day-old winter wheat (cv. Xindong 20) using drip in the lower stem inoculation method with a 10-µl of 106 macroconidia ml-1 suspension, and the control 7-day-old winter wheat were treated with sterile water (Xu et al. 2017). The experiments were replicated five times in a greenhouse at temperatures ranging from 20℃ to 25℃. After 4 weeks, all inoculated wheat seedlings showed stem base browning or even death. No symptoms were observed on the control plants. The fungus was reisolated from all inoculated wheat plants by the method described above and identified by morphological and PCR amplification using F. culmorum species-specific primers FcOIF/FcOIR. No F. culmorum was isolated from the control wheat plants, fulfilling Koch's postulates. To the best of our knowledge, this is the first report of F.culmorum causing FCR on winter wheat in XUAR, China. Considering wheat is the predominant grain crop and plays a pivotal role in grain production in China, necessary measures should be taken to prevent the spread of F. culmorum to other regions.

Discovery of Fusarium pseudograminearum Causing Crown Rot of Winter Wheat in Xinjiang Uygur Autonomous Region, China.

Fusarium pseudograminearum is an important plant pathogen that invades many crops (Zhang et al. 2018). Since it was first discovered in Australia in 1951, F. pseudograminearum has been reported in many countries and regions and caused huge economic losses (Burgess et al. 2001). In 2012, crown rot of wheat caused by F. pseudograminearum was discovered for the first time in Henan Province, China (Li et al. 2012). Wheat (Triticum aestivum L.) is one of the most important food crops in Xinjiang Uygur Autonomous Region (XUAR), with 1.07 million hectares cultivated in 2020. In June 2023, a survey of crown rot disease was carried out in winter wheat cv. Xindong 20 in Hotan area, XUAR, China (80.148907°E, 37.051474°N). About 5% of wheat plants showed symptoms of crown rot such as browning of the stem base and white head. The disease was observed in 85% of wheat fields. In order to identify the pathogens, 36 pieces of diseased stem basal tissue, 0.5 cm in length, were collected and sterilized with 75% alcohol for 30s and 5% NaOCl solution for 2 min, then rinsed three times with sterile water and placed on potato dextrose agar (PDA) medium at 25°C. A total of 27 isolates with consistent morphological characteristics were obtained using single-spore technique (Leslie and Summerell. 2006), and the isolation rate was 75%. The isolates grew rapidly on PDA, produced large numbers of fluffy white hyphae, and pink pigment accumulated in the medium. The isolates were grown on 2% mung bean flour medium and identified by morphological and molecular methods. Macroconidia were abundant, relatively slender, curved to almost straight, commonly two to seven septate, and averaged 22 to 72 × 1.8 to 4.9 µm. Microconidia were not observed. The morphological characters are consistent with Fusarium (Aoki and O'Donnell. 1999). Two isolates (LP-1 and LP-3) were selected for molecular identification. Primers EF1/EF2 (5'-ATGGGTAAGGARGACAAGAC-3'/5'-GGARGTACCAGTSATCATG-3') were used to amplify a portion of the EF-1α gene (O'Donnell et al. 1998). The two 696 bp PCR products were sequenced and submitted to GenBank. The EF-1α gene sequences (GenBank Accession No: PP062794 and PP062795) shared 99.9% identity (695/696) with published F.pseudograminearum sequences (e.g., OP105187, OP105184, OP105179, OP105173). The identification was further confirmed by F. pseudograminearum species-specific PCR primers Fp1-1/Fp1-2 (Aoki and O'Donnell. 1999). The expected PCR products of 518 bp were produced only in F. pseudograminearum. Pathogenicity tests of LP-1 and LP-3 isolates were performed on 7-day-old seedlings of winter wheat cv. Xindong 20 using the drip inoculation method with a 10-µl of a 106 macroconidia ml-1 suspension near the stem base (Xu et al. 2017). The experiment was repeated five times in a 20 to 25°C greenhouse. Control seedlings were treated with sterile water. After 4 weeks, wheat seedling death and crown browning occurred in the inoculated plants with over 90% incidence. No symptoms were observed in the control plants. The pathogen was reisolated from the inoculated plants by the method described above and identified by morphological and PCR amplification using F. pseudograminearum species-specific primers Fp1-1/Fp1-2. No F. pseudograminearum was isolated from the control plants, fulfilling Koch's postulates. To our knowledge, this is the first report of F. pseudograminearum causing crown rot of winter wheat in XUAR of China. Since F. pseudograminearum can cause great damage to wheat, one of the most important food crops in China, necessary measures should be taken to prevent the spread of F. pseudograminearum to other regions.

Design of Machine Learning Algorithms and Internal Validation of a Kidney Risk Prediction Model for Type 2 Diabetes Mellitus.

Objective: This study aimed to explore specific biochemical indicators and construct a risk prediction model for diabetic kidney disease (DKD) in patients with type 2 diabetes (T2D). Methods: This study included 234 T2D patients, of whom 166 had DKD, at the First Hospital of Jilin University from January 2021 to July 2022. Clinical characteristics, such as age, gender, and typical hematological parameters, were collected and used for modeling. Five machine learning algorithms [Extreme Gradient Boosting (XGBoost), Gradient Boosting Machine (GBM), Support Vector Machine (SVM), Logistic Regression (LR), and Random Forest (RF)] were used to identify critical clinical and pathological features and to build a risk prediction model for DKD. Additionally, clinical data from 70 patients (nT2D = 20, nDKD = 50) were collected for external validation from the Third Hospital of Jilin University. Results: The RF algorithm demonstrated the best performance in predicting progression to DKD, identifying five major indicators: estimated glomerular filtration rate (eGFR), glycated albumin (GA), Uric acid, HbA1c, and Zinc (Zn). The prediction model showed sufficient predictive accuracy with area under the curve (AUC) values of 0.960 (95% CI: 0.936-0.984) and 0.9326 (95% CI: 0.8747-0.9885) in the internal validation set and external validation set, respectively. The diagnostic efficacy of the RF model (AUC = 0.960) was significantly higher than each of the five features screened with the highest feature importance in the RF model. Conclusion: The online DKD risk prediction model constructed using the RF algorithm was selected based on its strong performance in the internal validation.

S100A8/A9 as a prognostic biomarker with causal effects for post-acute myocardial infarction heart failure.

Heart failure is the prevalent complication of acute myocardial infarction. We aim to identify a biomarker for heart failure post-acute myocardial infarction. This observational study includes 1062 and 1043 patients with acute myocardial infarction in the discovery and validation cohorts, respectively. The outcomes are in-hospital and long-term heart failure events. S100A8/A9 is screened out through proteomic analysis, and elevated circulating S100A8/A9 is independently associated with heart failure in discovery and validation cohorts. Furthermore, the predictive value of S100A8/A9 is superior to the traditional biomarkers, and the addition of S100A8/A9 improves the risk estimation using traditional risk factors. We finally report causal effect of S100A8/A9 on heart failure in three independent cohorts using Mendelian randomization approach. Here, we show that S100A8/A9 is a predictor and potentially causal medicator for heart failure post-acute myocardial infarction.

Ameliorative effects of zinc and vitamin E against phthalates-induced reproductive toxicity in male rats.

OBJECTIVE: Phthalates (PEs) could cause reproductive harm to males. A mixture of three widely used PEs (MPEs) was used to investigate the ameliorative effects of zinc (Zn) and vitamin E (VE) against male reproductive toxicity. METHODS: Fifty male SD rats were randomly divided into five groups (n = 10). Rats in MPEs group were orally treated with 160 mg/kg/d MPEs, while rats in MPEs combined Zn and/or VE groups were treated with 160 mg/kg/d MPEs plus 25 mg/kg/d Zn and/or 25 mg/kg/d VE. After intervention for 70 days, it's was measured of male reproductive organs' weight, histopathological observation of sperms and testes, serum hormones, PIWI proteins and steroidogenic proteins. RESULTS: Compared with control, anogenital distance, testes weight, epididymides weight, and sex hormones were significantly decreased, while the sperm malformation rate was markedly increased in MPEs group (p < .05); the testicular tissues were injured in MPEs group with disordered and decreased spermatids, and arrested spermatogenesis. PIWIL1, PIWIL2, StAR, CYP11A1 and CYP19A1 were down-regulated in MPEs group (p < .05). However, the alterations of these parameters were restored in MPEs combined Zn and/or VE groups (p < .05). CONCLUSION: Zn and/or VE improved steroid hormone metabolism, and inhibited MPEs' male reproductive toxicity.

Ionic liquid post-modified carboxylate-rich MOFs for efficient catalytic CO2 cycloaddition under solvent-free conditions.

The synthesis of cyclic carbonates through cycloaddition reactions between epoxides and carbon dioxide (CO2) is an important industrial process. Metal-Organic Frameworks (MOFs) have functional and ordered pore structures, making them attractive catalysts for converting gas molecules into valuable products. One approach to enhance the catalytic activity of MOFs in CO2 cycloaddition reactions is to create open metal sites within MOFs. In this study, the amino-functionalized rare earth Gd-MOF (Gd-TPTC-NH2) and its ionic liquid composite catalysts (Gd-TPTC-NH-[BMIM]Br) were synthesized using 2'-amino-[1,1':4',1''-terphenyl]-3,3'',5,5''-tetracarboxylic acid (H4TPTC-NH2) as the ligand. The catalytic performance of these two catalysts was observed in the cycloaddition reaction of CO2 and epoxides. Under the optimized reaction conditions, Gd-TPTC-NH-[BMIM]Br can effectively catalyze the cycloaddition reaction of a variety of epoxide substrates with good to excellent yields of cyclic carbonate products. Comparatively, epichlorohydrin and epibromohydrin, which possess halogen substituents, promote higher yields of cyclic carbonates due to the electron-withdrawing nature of Cl and Br substituents. Additionally, the Gd-TPTC-NH-[BMIM]Br catalyst demonstrated good recyclability and reproducibility, maintaining its catalytic activity without any changes in its structure or properties after five reuse cycles.

Improvement of the nutritional support management system for patients in intensive care units.

BACKGROUND: Nutritional support for patients hospitalized in the intensive care unit (ICU) is an important part of clinical treatment and care, but there are significant implementation difficulties. AIM: To introduce a modified nutritional support management system for ICU patients based on closed-loop information management and psychological counseling. METHODS: The division of functions, personnel training, system construction, development of an intelligent decision-making software system, quality control, and improvement of the whole process were carried out to systematically manage nutritional support for ICU patients. RESULTS: Following the implementation of the whole process management system, the scores of ICU medical staff's knowledge, attitudes/beliefs, and practices regarding nutritional support were comprehensively enhanced. The proportion of hospital bed-days of total enteral nutrition (EN) in ICU patients increased from 5.58% to 11.46%, and the proportion of EN plus parenteral nutrition increased from 42.71% to 47.07%. The rate of EN initiation within 48 h of ICU admission increased from 37.50% to 48.28%, and the EN compliance rate within 72 h elevated from 20.59% to 31.72%. After the implementation of the project, the Self-rating Anxiety Scale score decreased from 61.07 ± 9.91 points to 52.03 ± 9.02 points, the Self-rating Depression Scale score reduced from 62.47 ± 10.50 points to 56.34 ± 9.83 points, and the ICU stay decreased from 5.76 ± 2.77 d to 5.10 ± 2.12 d. CONCLUSION: The nutritional support management system based on closed-loop information management and psychological counseling achieved remarkable results in clinical applications in ICU patients.

Alleviative effect of quercetin against reproductive toxicity induced by chronic exposure to the mixture of phthalates in male rats.

Phthalates (PEs) are widely used plasticizers in polymer products, and humans are increasingly exposed to them. This study was designed to investigate the alleviative effect of phytochemicals quercetin (Que) against male reproductive toxicity caused by the mixture of three commonly used PEs (MPEs), and further to explore the underlying mechanism. Forty-eight male SD rats were randomly and evenly divided into control group, Que group, MPEs group and MPEs+Que group (n = 12); The oral exposure doses of MPEs and Que were 450 mg/kg/d and 50 mg/kg/d, respectively. After 91 days of continuous intervention, compared with control group, the testes weight, epididymis weight, serum sex hormones, and anogenital distance were significantly decreased in MPEs group (P < 0.05); Testicular histopathological observation showed that all seminiferous tubules were atrophy, leydig cells were hyperplasia, spermatogenic cells growth were arrested in MPEs group. Ultrastructural observation of testicular germ cells showed that the edges of the nuclear membranes were indistinct, and the mitochondria were severely damaged with the cristae disrupted, decreased or even disappeared in MPEs group. Immunohistochemistry and Western blot analysis showed that testicular CYP11A1, CYP17A1 and 17ß-HSD were up-regulated, while StAR, PIWIL1 and PIWIL2 were down-regulated in MPEs group (P < 0.05); However, the alterations of these parameters were restored in MPEs+Que group. The results indicated MPEs disturbed steroid hormone metabolism, and caused male reproductive injuries; whereas, Que could inhibit MPEs' male reproductive toxicity, which might relate to the restored regulation of steroid hormone metabolism.

Long-term exposure to the mixture of phthalates induced male reproductive toxicity in rats and the alleviative effects of quercetin.

Phthalates (PEs), such as di(2-ethylhexyl) phthalate (DEHP), dibutyl phthalate (DBP) and butyl benzyl phthalate (BBP) could cause reproductive and developmental toxicities, while human beings are increasingly exposed to them at low-doses. Phytochemical quercetin (Que) is a flavonoid that has estrogenic effect, anti-inflammatory and anti-oxidant effects. This study was conducted to assess the alleviative effect of Que. on male reproductive toxicity induced by the mixture of three commonly used PEs (MPEs) at low-dose in rats, and explore the underlying mechanism. Male rats were treated with MPEs (16 mg/kg/day) and/or Que. (50 mg/kg/d) for 91 days. The results showed that MPEs exposure caused male reproductive injuries, such as decreased serum sex hormones levels, abnormal testicular pathological structure, increased abnormal sperm rate and changed expressions of PIWIL1 and PIWIL2. Furthermore, MPEs also changed the expression of steroidogenic proteins in steroid hormone metabolism, including StAR, CYP11A1, CYP17A1, 17ß-HSD, CYP19A1. However, the alterations of these parameters were reversed by Que. MPEs caused male reproductive injuries in rats; Que. inhibited MPEs' male reproductive toxicity, which might relate to the improvement of testosterone biosynthesis.

NAC transcription factor SlNOR-like1 plays a dual regulatory role in tomato fruit cuticle formation.

The plant cuticle is an important protective barrier on the plant surface, constructed mainly by polymerized cutin matrix and a complex wax mixture. Although the pathway of plant cuticle biosynthesis has been clarified, knowledge of the transcriptional regulation network underlying fruit cuticle formation remains limited. In the present work, we discovered that tomato fruits of the NAC transcription factor SlNOR-like1 knockout mutants (nor-like1) produced by CRISPR/Cas9 [clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9] displayed reduced cutin deposition and cuticle thickness, with a microcracking phenotype, while wax accumulation was promoted. Further research revealed that SlNOR-like1 promotes cutin deposition by binding to the promoters of glycerol-3-phosphate acyltransferase6 (SlGPAT6; a key gene for cutin monomer formation) and CUTIN DEFICIENT2 (SlCD2; a positive regulator of cutin production) to activate their expression. Meanwhile, SlNOR-like1 inhibits wax accumulation, acting as a transcriptional repressor by targeting wax biosynthesis, and transport-related genes 3-ketoacyl-CoA synthase1 (SlKCS1), ECERIFERUM 1-2 (SlCER1-2), SlWAX2, and glycosylphosphatidylinositol-anchored lipid transfer protein 1-like (SlLTPG1-like). In conclusion, SlNOR-like1 executes a dual regulatory effect on tomato fruit cuticle development. Our results provide a new model for the transcriptional regulation of fruit cuticle formation.

Multi-omics reveals aging-related pathway in natural aging mouse liver.

Aging is associated with gradual changes in liver structure, altered metabolites and other physiological/pathological functions in hepatic cells. However, its characterized phenotypes based on altered metabolites and the underlying biological mechanism are unclear. Advancements in high-throughput omics technology provide new opportunities to understand the pathological process of aging. Here, in our present study, both metabolomics and phosphoproteomics were applied to identify the altered metabolites and phosphorylated proteins in liver of young (the WTY group) and naturally aged (the WTA group) mice, to find novel biomarkers and pathways, and uncover the biological mechanism. Analysis showed that the body weights, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) increased in the WTA group. The grips decreased with age, while the triglyceride (TG) and cholesterol (TC) did not change significantly. The increase of fibrosis, accumulation of inflammatory cells, hepatocytes degeneration, the deposition of lipid droplets and glycogen, the damaged mitochondria, and deduction of endoplasmic reticulum were observed in the aging liver under optical and electron microscopes. In addition, a network of metabolites and phosphorylated proteomes of the aging liver was established. Metabolomics detected 970 metabolites in the positive ion mode and 778 metabolites in the negative ion mode. A total of 150 pathways were pooled. Phosphoproteomics identified 2618 proteins which contained 16621 phosphosites. A total of 164 pathways were detected. 65 common pathways were detected in two omics. Phosphorylated protein heat shock protein HSP 90-alpha (HSP90A) and v-raf murine viral oncogene homolog B1(BRAF), related to cancer pathway, were significantly upregulated in aged mice liver. Western blot verified that protein expression of MEK and ERK, downstream of BRAF pathway were elevated in the liver of aging mice. However, the protein expression of BRAF was not a significant difference. Overall, these findings revealed a close link between aging and cancer and contributed to our understanding of the multi-omics changes in natural aging.

Phase I study of a non-S2P SARS-CoV-2 mRNA vaccine LVRNA009 in Chinese adults.

BACKGROUND: COVID-19 caused by SARS-CoV-2 is a great threat to public health. We present the safety and immunogenicity data from a phase I trial in China of an mRNA vaccine (LVRNA009). METHODS: In the single-centre, double-blind, placebo-controlled and dose-escalation study, 72 healthy unvaccinated adults aged 18-59 years were randomized (3:1) to receive LVRNA009 with one of three vaccine dosage (25, 50 and 100 µg) or placebo, to evaluate for the safety, tolerability and immunogenicity of LVRNA009. RESULTS: All these participants received two injections 28 days apart. No adverse events higher than grade 2 were reported during the study. A total of 30 participants (42 %) reported solicited adverse reactions during the first 14 days after vaccinations. Of the events reported, fever (n = 11, 15 %) was the most common systemic adverse reaction, and pain at the injection site (n = 17, 24 %) was the most frequent solicited local adverse reaction. Anti-S-protein IgG and neutralising antibodies were observed to have been induced 14 days after the first dose, significantly increased 7 days after the second dose, and remained at a high level 28 days after the second dose. Specific T-cell responses peaked 7 days and persisted 28 days after second vaccination. CONCLUSION: LVRNA009 has demonstrated promising results in safety and tolerability at all three dose levels among Chinese adults. LVRNA009 at three dose levels could rapidly induce strong humoral and cellular immune responses, including binding and neutralising antibody production and IFN- γ secretion, which showed good immunogenicity. CLINICAL TRIAL REGISTRATION NUMBER: Clinicaltrials.gov NCT05364047; Chictr.org.cn ChiCTR2100049349.

Identification of cuproptosis-related gene SLC31A1 and upstream LncRNA-miRNA regulatory axis in breast cancer.

Mounting evidence indicate that cuproptosis, a novel form of programmed cell death, contributes to cancer development and progression. However, a comprehensive analysis regarding the expressions, functions, and regulatory network of cuproptosis-related genes is still lacking. In the present work, cuproptosis-related genes, upstream miRNAs and lncRNAs, and clinical data of breast cancer from TCGA database were analyzed by R language including Cox regression analysis, correlation calculation, ROC curve construction, and survival evaluation, and were further verified by public-available databases. Chemosensitivity and immune infiltration were also evaluated by online tools. SLC31A1 was significantly increased in breast cancer samples than those in normal tissues. SLC31A1 was negatively related to a favorable outcome in breast cancer, and the AUC value increased with the prolongation of follow-up time. LINC01614 and miR-204-5p were potential upstream regulators of SLC31A1. Moreover, SLC31A1 was significantly positively correlated with different immune cells infiltration, immune cell biomarkers, and immune checkpoints in breast cancer. SLC31A1 was a potential cuproptosis-related gene in breast cancer, which was significantly upregulated and was able to predict diagnosis, prognosis, chemosensitivity, and immune infiltration. LINC01640/miR-204-5p/SLC31A1 might be a significant and promising axis during cuproptosis in breast cancer.

STING activation in TET2-mutated hematopoietic stem/progenitor cells contributes to the increased self-renewal and neoplastic transformation.

Somatic loss-of-function mutations of the dioxygenase Ten-eleven translocation-2 (TET2) occur frequently in individuals with clonal hematopoiesis (CH) and acute myeloid leukemia (AML). These common hematopoietic disorders can be recapitulated in mouse models. However, the underlying mechanisms by which the deficiency in TET2 promotes these disorders remain unclear. Here we show that the cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS)-stimulator of interferon genes (STING) pathway is activated to mediate the effect of TET2 deficiency in dysregulated hematopoiesis in mouse models. DNA damage arising in Tet2-deficient hematopoietic stem/progenitor cells (HSPCs) leads to activation of the cGAS-STING pathway which in turn promotes the enhanced self-renewal and development of CH. Notably, both pharmacological inhibition and genetic deletion of STING suppresses Tet2 mutation-induced aberrant hematopoiesis. In patient-derived xenograft (PDX) models, STING inhibition specifically attenuates the proliferation of leukemia cells from TET2-mutated individuals. These observations suggest that the development of CH associated with TET2 mutations is powered through chronic inflammation dependent on the activated cGAS-STING pathway and that STING may represent a potential target for intervention of relevant hematopoietic diseases.

CDK13 promotes lipid deposition and prostate cancer progression by stimulating NSUN5-mediated m5C modification of ACC1 mRNA.

Cyclin-dependent kinases (CDKs) regulate cell cycle progression and the transcription of a number of genes, including lipid metabolism-related genes, and aberrant lipid metabolism is involved in prostate carcinogenesis. Previous studies have shown that CDK13 expression is upregulated and fatty acid synthesis is increased in prostate cancer (PCa). However, the molecular mechanisms linking CDK13 upregulation and aberrant lipid metabolism in PCa cells remain largely unknown. Here, we showed that upregulation of CDK13 in PCa cells increases the fatty acyl chains and lipid classes, leading to lipid deposition in the cells, which is positively correlated with the expression of acetyl-CoA carboxylase (ACC1), the first rate-limiting enzyme in fatty acid synthesis. Gain- and loss-of-function studies showed that ACC1 mediates CDK13-induced lipid accumulation and PCa progression by enhancing lipid synthesis. Mechanistically, CDK13 interacts with RNA-methyltransferase NSUN5 to promote its phosphorylation at Ser327. In turn, phosphorylated NSUN5 catalyzes the m5C modification of ACC1 mRNA, and then the m5C-modified ACC1 mRNA binds to ALYREF to enhance its stability and nuclear export, thereby contributing to an increase in ACC1 expression and lipid deposition in PCa cells. Overall, our results disclose a novel function of CDK13 in regulating the ACC1 expression and identify a previously unrecognized CDK13/NSUN5/ACC1 pathway that mediates fatty acid synthesis and lipid accumulation in PCa cells, and targeting this newly identified pathway may be a novel therapeutic option for the treatment of PCa.

Risk of cardiac rupture among elderly patients with diabetes presenting with first acute myocardial infarction.

Objective: We aimed to analyze the risk of cardiac rupture (CR) in aged diabetic patients with acute ST-segment elevated myocardial infarction (STEMI) who were followed up for one month, and analyze its independent risk factors. Methods: A total of 3063 aged patients with first onset STEMI admitted to Beijing Anzhen Hospital from January 2001 to December 2020 were retrospectively included. There were 2020 patients without diabetes mellitus (DM) and 1043 patients with DM. We used propensity scores matching (PSM) method to balance baseline exposure factors between patients with or without DM, and all were divided the DM group (1043 cases) and the non-DM group (1043 cases) after the PSM. The primary outcome was CR (the composite rate of papillary muscle rupture, ventricular septum perforation, free wall rupture), which was diagnosed based on clinical manifestations and/or echocardiographic findings. Kaplan-meier survival analyses and log-rank test was used to evaluate the risk of CR between the two groups, and Cox regression analysis was used to evaluate the independent risk factors for CR. Results: After PSM, the baseline clinical data were similar between the DM and non-DM group (all P>0.05). However, level of glycated hemoglobin was significantly higher in the DM group (P<0.05). During 1 month of follow-up, there were 55 (2.64%) cases of CR, most occurred within 48h after admission (40 cases). Among the 55 cases, 11(0.53%) had papillary muscle rupture, 18(0.86%) had ventricular septum perforation, and 26(1.25%) had free wall rupture. Kaplan-meier survival analyses detected that the DM group was associated with significantly increased risk of CR (3.36% vs. 1.92%, HR=1.532, 95% CI: 1.054-2.346, P=0.030), ventricular septum perforation (1.05% vs. 0.67%, HR=1.464, 95% CI: 1.021-2.099, P=0.038) and free wall rupture (1.63% vs. 0.86%, HR=1.861, 95% CI: 1.074-3.225, P=0.027) than those in the non-DM group. Among the 2031 aged STEMI patients without CR, 144 cases (6.90%, 144/2086) died; and among the 55 patients with CR, 37 cases (1.77%, 37/2086) died due to CR. Therefore, twenty percent (20.44%, 37/181) of death was due to CR. Multivariate Cox regression analysis indicated that DM (HR=1.532, 95%CI: 1.054-2.346), age (HR=1.390, 95%CI: 1.079-1.791), female (HR=1.183, 95%CI: 1.049-1.334), troponin I (HR=1.364, 95%CI: 1.108-1.679), brain natriuretic peptide (HR=1.512, 95%CI: 1.069-2.139), revascularization (HR=0.827, 95%CI: 0.731-0.936) and ß-receptor blocker (HR=0.849, 95%CI: 0.760-0.948) were independent risk factors of CR (all P<0.05). Conclusion: DM as well as a few other factors, are independent determinants of CR. CR is not a rare event among the aged STEMI patients and twenty percent of deaths are due to CR. However, large sample-sized studies are warranted to confirm these findings.

Stereoselective Photoredox Catalyzed (3+3) Dipolar Cycloaddition of Nitrone with Aryl Cyclopropane.

By resorting to the principle of remote activation, we herein demonstrate the first photoredox catalyzed (3+3) dipolar cycloaddition of nitrones with aryl cyclopropanes. Key to the fidelity of the reaction resides in a facile manner of substrate activation by single-electron transfer (SET) oxidation with photoredox catalysis, and the reaction takes place through a stepwise cascade encompassing a three-electron-type nucleophilic substitution triggered cyclopropane ring-opening and a diastereoselective 6-endo-trig radical cyclization manifold. The reaction proceeds under mild conditions with excellent regio- and stereoselectivity, nicely complementing the well-developed Lewis acid catalyzed cycloaddition of donor-acceptor cyclopropanes. Other merits of the protocol include wide scope of aryl cyclopropanes with diversified substitution patterns and good functional-group compatibility. A mechanism involving an aryl radical cation promoted remote activation mode was also proposed and supported by mechanistic experiments.