Determining toxicity of europium oxide nanoparticles in immune cell components and hematopoiesis in dominant organs in mice: Role of lysosomal fluid interaction.

Extensive application of rare earth element oxide nanoparticles (REE NPs) has raised a concern over the possible toxic health effects after human exposure. Once entering the body, REE NPs are primarily processed by phagocytes in particular macrophages and undergo biotic phosphate complexation in lysosomal compartment. Such biotransformation affects the target organs and in vivo fate of REE NPs after escaping the lysosomes. However, the immunomodulatory effects of intraphagolysosomal dissolved REE NPs remains insufficient. Here, europium oxide (Eu2O3) NPs were pre-incubated with phagolysosomal simulant fluid (PSF) to mimic the biotransformation of europium oxide (p-Eu2O3) NPs under acid phagolysosome conditions. We investigated the alteration in immune cell components and the hematopoiesis disturbance on adult mice after intravenous administration of Eu2O3 NPs and p-Eu2O3 NPs. Our results indicated that the liver and spleen were the main target organs for Eu2O3 NPs and p-Eu2O3 NPs. Eu2O3 NPs had a much higher accumulative potential in organs than p-Eu2O3 NPs. Eu2O3 NPs induced more alterations in immune cells in the spleen, while p-Eu2O3 NPs caused stronger response in the liver. Regarding hematopoietic disruption, Eu2O3 NPs reduced platelets (PLTs) in peripheral blood, which might be related to the inhibited erythrocyte differentiation in the spleen. By contrast, p-Eu2O3 NPs did not cause significant disturbance in peripheral PLTs. Our study demonstrated that the preincubation with PSF led to a distinct response in the immune system compared to the pristine REE NPs, suggesting that the potentially toxic effects induced by the release of NPs after phagocytosis should not be neglected, especially when evaluating the safety of NPs application in vivo.

Human molybdenum exposure risk in industrial regions of China: New critical effect indicators and reference dose.

Evidence increasingly suggests molybdenum exposure at environmental levels is still associated with adverse human health, emphasizing the necessity to establish a more protective reference dose (RfD). Herein, we conducted a study measuring 15 urinary metals and 30 clinical health indicators in 2267 participants residing near chemical enterprises across 11 Chinese provinces to investigate their relationships. The kidney and cystatin-C emerged as the most sensitive organ and critical effect indicator of molybdenum exposure, respectively. Odds of cystatin-C-defined chronic kidney disease (CKD) in the highest quantile of molybdenum exposure significantly increased by 133.5% (odds ratio [OR]: 2.34, 95% CI: 1.78, 3.11) and 75.8% (OR: 1.76, 95% CI: 1.24, 2.49) before and after adjusting for urinary 14 metals, respectively. Intriguingly, cystatin-C significantly mediated 15.9-89.5% of molybdenum's impacts on liver and lung function, suggesting nephrotoxicity from molybdenum exposure may trigger hepatotoxicity and pulmonary toxicity. We derived a new RfD for molybdenum exposure (0.87 µg/kg-day) based on cystatin-C-defined estimated glomerular filtration rate by employing Bayesian Benchmark Dose modeling analysis. This RfD is significantly lower than current exposure guidance values (5-30 µg/kg-day). Remarkably, >90% of participants exceeded the new RfD, underscoring the significant health impacts of environmental molybdenum exposure on populations in industrial regions of China.

Human papillomavirus infection and the risk of cancer at specific sites other than anogenital tract and oropharyngeal region: an umbrella review.

BACKGROUND: Despite numerous studies having evaluated the associations between human papillomavirus (HPV) infection and risk of specific cancers other than anogenital tract and oropharyngeal, the findings are inconsistent and the quality of evidence has not been systematically quantified. We aimed to summarise the existing evidence as well as to evaluate the strength and credibility of these associations. METHODS: We conducted an umbrella review of systematic reviews and meta-analyses of observational studies. PubMed, EMBASE, and Web of Science were searched from inception to March 2024. Studies with systematic reviews and meta-analyses that examined associations between HPV or HPV-associated genotypes infection and specific cancers were eligible for this review. The quality of the methodology was evaluated using A Measurement Tool to Assess systematic Reviews (AMSTAR). The credibility of the evidence was assessed using GRADE. The protocol was preregistered with PROSPERO (CRD42023439070). FINDINGS: The umbrella review identified 31 eligible studies reporting 87 associations with meta-analytic estimates, including 1191 individual studies with 336,195 participants. Of those, 29 (93.5%) studies were rated as over moderate quality by AMSTAR. Only one association indicating HPV-18 infection associated with an increased risk of breast cancer (odds ratio [OR] = 3.48, 95% confidence interval [CI] = 2.24-5.41) was graded as convincing evidence. There were five unique outcomes identified as highly suggestive evidence, including HPV infection increased the risk of oral squamous cell carcinoma (OR = 7.03, 95% CI = 3.87-12.76), oesophageal cancer (OR = 3.32, 95% CI = 2.54-4.34), oesophageal squamous cell carcinoma (OR = 2.69, 95% CI = 2.05-3.54), lung cancer (OR = 3.60, 95% CI = 2.59-5.01), and breast cancer (OR = 6.26, 95% CI = 4.35-9.00). According to GRADE, one association was classified as high, indicating that compared with the controls in normal tissues, HPV infection was associated with an increased risk of breast cancer. INTERPRETATION: The umbrella review synthesised up-to-date observational evidence on HPV infection with the risk of breast cancer, oral squamous cell carcinoma, oesophageal cancer, oesophageal squamous cell carcinoma, and lung cancer. Further larger prospective cohort studies are needed to verify the associations, providing public health recommendations for prevention of disease. FUNDING: National Key Research and Development Program of China, Natural Science Foundation of China, Outstanding Scientific Fund of Shengjing Hospital of China Medical University, and 345 Talent Project of Shengjing Hospital of China Medical University.

Optical enhancement mode 2 improves the detection rate of gastric neoplastic lesion in high-risk populations: A multicenter randomized controlled clinical study.

OBJECTIVES: Detection of early neoplastic lesions is crucial for improving the survival rates of patients with gastric cancer. Optical enhancement mode 2 is a new image-enhanced endoscopic technique that offers bright images and can improve the visibility of neoplastic lesions. This study aimed to compare the detection of neoplastic lesions with optical enhancement mode 2 and white-light imaging (WLI) in a high-risk population. METHODS: In this prospective multicenter randomized controlled trial, patients were randomly assigned to optical enhancement mode 2 or WLI groups. Detection of suspicious neoplastic lesions during the examinations was recorded, and pathological diagnoses served as the gold standard. RESULTS: A total of 1211 and 1219 individuals were included in the optical enhancement mode 2 and WLI groups, respectively. The detection rate of neoplastic lesions was significantly higher in the optical enhancement mode 2 group (5.1% vs. 1.9%; risk ratio, 2.656 [95% confidence interval, 1.630-4.330]; p < 0.001). The detection rate of neoplastic lesions with an atrophic gastritis background was significantly higher in the optical enhancement mode 2 group (8.6% vs. 2.6%, p < 0.001). The optical enhancement mode 2 group also had a higher detection rate among endoscopists with different experiences. CONCLUSIONS: Optical enhancement mode 2 was more effective than WLI for detecting neoplastic lesions in the stomach, and can serve as a new method for screening early gastric cancer in clinical practice. CLINICAL REGISTRY: United States National Library of Medicine (https://www. CLINICALTRIALS: gov), ID: NCT040720521.

Triglyceride-glucose index and health outcomes: an umbrella review of systematic reviews with meta-analyses of observational studies.

BACKGROUND: Numerous meta-analyses have explored the association between the triglyceride-glucose (TyG) index and diverse health outcomes, yet the comprehensive assessment of the scope, validity, and quality of this evidence remains incomplete. Our aim was to systematically review and synthesise existing meta-analyses of TyG index and health outcomes and to assess the quality of the evidence. METHODS: A thorough search of PubMed, EMBASE, and Web of Science databases was conducted from their inception through to 8 April 2024. We assessed the quality of reviews using A Measurement Tool to Assess Systematic Reviews (AMSTAR) and the certainty of the evidence using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) system. This study was registered with PROSPERO (CRD: 42024518587). RESULTS: Overall, a total of 95 associations from 29 meta-analyses were included, investigating associations between TyG index and 30 health outcomes. Of these, 83 (87.4%) associations were statistically significant (P < 0.05) according to the random effects model. Based on the AMSTAR tool, 16 (55.2%) meta-analyses were high quality and none was low quality. The certainty of the evidence, assessed by the GRADE framework, showed that 6 (6.3%) associations were supported by moderate-quality evidence. When compared with the lowest category of the TyG index, the risk of contrast-induced nephropathy (CIN) [relative risk (RR) = 2.25, 95%CI 1.82, 2.77], the risk of stroke in patients with diabetes mellitus (RR = 1.26, 95%CI 1.18, 1.33) or with acute coronary syndrome disease (RR = 1.56, 95%CI 1.06, 2.28), the prognosis of coronary artery disease (CAD)-non-fatal MI (RR = 2.02, 95%CI 1.32, 3.10), and the severity of CAD including coronary artery stenosis (RR = 3.49, 95%CI 1.71, 7.12) and multi-vessel CAD (RR = 2.33, 95%CI 1.59, 3.42) increased with high TyG index. CONCLUSION: We found that the TyG index was positively associated with many diseases including the risk of CIN and stroke, the prognosis of CAD, and the severity of CAD which were supported by moderate-quality evidence. TyG index might be useful to identify people at high-risk for developing these diseases.

Association between the systemic immune-inflammation index and sarcopenia: a systematic review and meta-analysis.

BACKGROUND: Sarcopenia is associated with increased morbidity and mortality. The systemic immune-inflammation index (SII) has been correlated to a variety of disorders. The present study conducted a systematic review and meta-analysis to investigate the relationship between SII and sarcopenia. METHODS: A literature search was performed in Web of Science, PubMed, Embase, Cochrane Library, CINAHL, China National Knowledge Infrastructure, Chinese Biomedical Literature Database, Wanfang Database, and VIP Chinese Science and Technology Database, from inception to March 2024. Then, the literature quality was assessed. After the heterogeneity test, a random effects or fixed effects model was applied to establish the forest plot, and investigate the relationship between SII and sarcopenia. Then, the sensitivity analysis and publication bias were examined. RESULTS: Nine articles, which included 18,634 adults, were analyzed. Sarcopenic adults had higher SII levels, when compared to non-sarcopenic adults (standardized mean difference [SMD] = 0.66, 95% confidence interval [CI] = 0.22 - 0.19, p = 0.003). The high SII level was associated to the increased risk of sarcopenia (odds ratio = 1.52, 95% CI = 1.09-2.13, p = 0.01). In addition, the subgroup analysis revealed that the SII levels were higher in the sarcopenic group, when compared to the non-sarcopenic group, in elderly adults, as well as in adults with or without gastrointestinal disorders. The analysis was robust with a low risk of publication bias. CONCLUSIONS: SII is closely associated to sarcopenia. Sarcopenic adults had elevated SII levels. The high SII level increased the risk of sarcopenia. Large scale multi-center prospective studies are required to validate these study findings.

Au/Doc/Quer@PDA/A10-3.2 Nanoparticles for targeted treatment of docetaxel-resistant prostate cancer.

Docetaxel (Doc), as a first-line chemotherapy drug for prostate cancer (PC), often loses its therapeutic efficacy due to acquired resistance and lack of targeting specificity. Therefore, there is a need to develop a novel drug that can overcome Doc resistance and enhance its targeting ability to inhibit PC progression. In this study, we prepared Au/Doc/Quer@PDA/A10-3.2 nanoparticles (NPs) composite drug by encapsulating Doc and quercetin (Quer) within polydopamine (PDA)-coated Au NPs and further modifying them with RNA oligonucleotide aptamer A10-3.2. A10-3.2 was used for specific targeting of prostate-specific membrane antigen (PSMA)-positive PC cells (LNCaP). Quer was employed to reverse the resistance of Doc-resistant cell line (LNCaP/R) to Doc. Physical characterization using ultraviolet-visible spectroscopy (UV-vis), transmission electron microscopy (TEM), dynamic light scattering (DLS), X-ray photoelectron spectroscopy (XPS), and Fourier-transform infrared spectroscopy (FTIR) confirmed the successful preparation of Au/Doc/Quer@PDA/A10-3.2 NPs. Fluorescence imaging and flow cytometry experiments demonstrated the targeting ability of Au/Doc/Quer@PDA/A10-3.2 NPs towards PSMA-positive LNCaP/R cells. Cell proliferation, apoptosis, invasion, and migration experiments revealed that Quer reversed the resistance of LNCaP/R cells to Doc. Immunoblotting experiments further confirmed the mechanism behind sensitization of chemotherapy by Quer. Finally, we evaluated the therapeutic efficacy of Au/Doc/Quer@PDA/A10-3.2 NPs in a mouse model of PC. In conclusion, this study synthesized and validated a novel nano-composite drug (Au/Doc/Quer@PDA/A10-3.2 NPs) for combating Doc-resistant PC, which could potentially be applied in clinical treatment of PC.

Fusobacterium nucleatum-induced imbalance in microbiome-derived butyric acid levels promotes the occurrence and development of colorectal cancer.

BACKGROUND: Colorectal cancer (CRC) ranks among the most prevalent malignant tumors globally. Recent reports suggest that Fusobacterium nucleatum (F. nucleatum) contributes to the initiation, progression, and prognosis of CRC. Butyrate, a short-chain fatty acid derived from the bacterial fermentation of soluble dietary fiber, is known to inhibit various cancers. This study is designed to explore whether F. nucleatum influences the onset and progression of CRC by impacting the intestinal metabolite butyric acid. AIM: To investigate the mechanism by which F. nucleatum affects CRC occurrence and development. METHODS: Alterations in the gut microbiota of BALB/c mice were observed following the oral administration of F. nucleatum. Additionally, DLD-1 and HCT116 cell lines were exposed to sodium butyrate (NaB) and F. nucleatum in vitro to examine the effects on proliferative proteins and mitochondrial function. RESULTS: Our research indicates that the prevalence of F. nucleatum in fecal samples from CRC patients is significantly greater than in healthy counterparts, while the prevalence of butyrate-producing bacteria is notably lower. In mice colonized with F. nucleatum, the population of butyrate-producing bacteria decreased, resulting in altered levels of butyric acid, a key intestinal metabolite of butyrate. Exposure to NaB can impair mitochondrial morphology and diminish mitochondrial membrane potential in DLD-1 and HCT116 CRC cells. Consequently, this leads to modulated production of adenosine triphosphate and reactive oxygen species, thereby inhibiting cancer cell proliferation. Additionally, NaB triggers the adenosine monophosphate-activated protein kinase (AMPK) signaling pathway, blocks the cell cycle in HCT116 and DLD-1 cells, and curtails the proliferation of CRC cells. The combined presence of F. nucleatum and NaB attenuated the effects of the latter. By employing small interfering RNA to suppress AMPK, it was demonstrated that AMPK is essential for NaB's inhibition of CRC cell proliferation. CONCLUSION: F. nucleatum can promote cancer progression through its inhibitory effect on butyric acid, via the AMPK signaling pathway.

SOD1-high fibroblasts derived exosomal miR-3960 promotes cisplatin resistance in triple-negative breast cancer by suppressing BRSK2-mediated phosphorylation of PIMREG.

Platinum-based neoadjuvant therapy represented by cisplatin is widely employed in treating Triple-Negative Breast Cancer (TNBC), a particularly aggressive subtype of breast cancer. Nevertheless, the emergence of cisplatin resistance presents a formidable challenge to clinical chemotherapy efficacy. Herein, we revealed the critical role of tumor microenvironment (TME) derived exosomal miR-3960 and phosphorylation at the S16 site of PIMREG in activating NF-κB signaling pathway and promoting cisplatin resistance of TNBC. Detailed regulatory mechanisms revealed that SOD1-upregulated fibroblasts secrete miR-3960 and are then transported into TNBC cells via exosomes. Within TNBC cells, miR-3960 targets and inhibits the expression of BRSK2, an AMPK protein kinase family member. Furthermore, we emphasized that BRSK2 contributes to ubiquitination degradation of PIMREG and modulates subsequent activation of the NF-κB signaling pathway by mediating PIMREG phosphorylation at the S16 site, ultimately affects the cisplatin resistance of TNBC. In conclusion, our research demonstrated the crucial role of SOD1high fibroblast, exosomal miR-3960 and S16 site phosphorylated PIMREG in regulating the NF-κB signaling pathway and cisplatin resistance of TNBC. These findings provided significant potential as biomarkers for accurately diagnosing cisplatin-resistant TNBC patients and guiding chemotherapy strategy selection.

Self-Assembled STING-Activating Coordination Nanoparticles for Cancer Immunotherapy and Vaccine Applications.

The cGAS-STING pathway plays a crucial role in innate immune activation against cancer and infections, and STING agonists based on cyclic dinucleotides (CDN) have garnered attention for their potential use in cancer immunotherapy and vaccines. However, the limited drug-like properties of CDN necessitate an efficient delivery system to the immune system. To address these challenges, we developed an immunostimulatory delivery system for STING agonists. Here, we have examined aqueous coordination interactions between CDN and metal ions and report that CDN mixed with Zn2+ and Mn2+ formed distinctive crystal structures. Further pharmaceutical engineering led to the development of a functional coordination nanoparticle, termed the Zinc-Mn-CDN Particle (ZMCP), produced by a simple aqueous one-pot synthesis. Local or systemic administration of ZMCP exerted robust antitumor efficacy in mice. Importantly, recombinant protein antigens from SARS-CoV-2 can be simply loaded during the aqueous one-pot synthesis. The resulting ZMCP antigens elicited strong cellular and humoral immune responses that neutralized SARS-CoV-2, highlighting ZMCP as a self-adjuvant vaccine platform against COVID-19 and other infectious pathogens. Overall, this work establishes a paradigm for developing translational coordination nanomedicine based on drug-metal ion coordination and broadens the applicability of coordination medicine for the delivery of proteins and other biologics.

Mapping 18F-FDG Kinetics Together with Patient-Specific Bootstrap Assessment of Uncertainties: An Illustration with Data from a PET/CT Scanner with a Long Axial Field of View.

The purpose of this study was to examine a nonparametric approach to mapping kinetic parameters and their uncertainties with data from the emerging generation of dynamic whole-body PET/CT scanners. Methods: Dynamic PET 18F-FDG data from a set of 24 cancer patients studied on a long-axial-field-of-view PET/CT scanner were considered. Kinetics were mapped using a nonparametric residue mapping (NPRM) technique. Uncertainties were evaluated using an image-based bootstrapping methodology. Kinetics and bootstrap-derived uncertainties are reported for voxels, maximum-intensity projections, and volumes of interest (VOIs) corresponding to several key organs and lesions. Comparisons between NPRM and standard 2-compartment (2C) modeling of VOI kinetics are carefully examined. Results: NPRM-generated kinetic maps were of good quality and well aligned with vascular and metabolic 18F-FDG patterns, reasonable for the range of VOIs considered. On a single 3.2-GHz processor, the specification of the bootstrapping model took 140 min; individual bootstrap replicates required 80 min each. VOI time-course data were much more accurately represented, particularly in the early time course, by NPRM than by 2C modeling constructs, and improvements in fit were statistically highly significant. Although 18F-FDG flux values evaluated by NPRM and 2C modeling were generally similar, significant deviations between vascular blood and distribution volume estimates were found. The bootstrap enables the assessment of quite complex summaries of mapped kinetics. This is illustrated with maximum-intensity maps of kinetics and their uncertainties. Conclusion: NPRM kinetics combined with image-domain bootstrapping is practical with large whole-body dynamic 18F-FDG datasets. The information provided by bootstrapping could support more sophisticated uses of PET biomarkers used in clinical decision-making for the individual patient.

USP26 promotes colorectal cancer tumorigenesis by restraining PRKN-mediated mitophagy.

Deubiquitinating enzymes (DUBs) are promising targets for cancer therapy because of their pivotal roles in various physiological and pathological processes. Among these, ubiquitin-specific peptidase 26 (USP26) is a protease with crucial regulatory functions. Our study sheds light on the upregulation of USP26 in colorectal cancer (CRC), in which its increased expression correlates with an unfavorable prognosis. Herein, we evidenced the role of USP26 in promoting CRC tumorigenesis in a parkin RBR E3 ubiquitin-protein ligase (PRKN) protein-dependent manner. Our investigation revealed that USP26 directly interacted with PRKN protein, facilitating its deubiquitination, and subsequently reducing its activity. Additionally, we identified the K129 site on PRKN as a specific target for USP26-mediated deubiquitination. Our research highlights that a K-to-R mutation at the site on PRKN diminishes its potential for activation and ability to mediate mitophagy. In summary, our findings underscore the significance of USP26-mediated deubiquitination in restraining the activation of the PRKN-mediated mitophagy pathway, ultimately driving CRC tumorigenesis. This study not only elucidated the multifaceted role of USP26 in CRC but also introduced a promising avenue for therapeutic exploration through the development of small molecule inhibitors targeting USP26. This strategy holds promise as a novel therapeutic approach for CRC.

Influence of Microbiota on Tumor Immunotherapy.

The role of the microbiome in immunotherapy has recently garnered substantial attention, with molecular studies and clinical trials providing emerging evidence on the pivotal influence of the microbiota in enhancing therapeutic outcomes via immune response modulation. However, the impact of microbial communities can considerably vary across individuals and different immunotherapeutic approaches, posing prominent challenges in harnessing their potential. In this comprehensive review, we outline the current research applications in tumor immunotherapy and delve into the possible mechanisms through which immune function is influenced by microbial communities in various body sites, encompassing those in the gut, extraintestinal barrier, and intratumoral environment. Furthermore, we discuss the effects of diverse microbiome-based strategies, including probiotics, prebiotics, fecal microbiota transplantation, and the targeted modulation of specific microbial taxa, and antibiotic treatments on cancer immunotherapy. All these strategies potentially have a profound impact on immunotherapy and pave the way for personalized therapeutic approaches and predictive biomarkers.

Repression of YEATS2 induces cellular senescence in hepatocellular carcinoma and inhibits tumor growth.

Hepatocellular carcinoma (HCC) stands as the third leading cause of cancer-related fatalities globally. In this study, we observed a significant increase in the expression level of the YEATS2 gene in HCC patients, and it is negatively correlated with the patients' survival rate. While we have previously identified the association between YEATS2 and the survival of pancreatic cancer cells, the regulatory mechanisms and significance in HCC are still to be fully elucidated. Our study shows that knockdown (KD) of YEATS2 expression leads to DNA damage, which in turn results in an upregulation of γ-H2A.X expression and activation of the canonical senescence-related pathway p53/p21Cip1. Moreover, our transcriptomic analysis reveals that YEATS2 KD cells can enhance the expression of p21Cip1 via the c-Myc/miR-93-5p pathway, consequently fostering the senescence of HCC cells. The initiation of cellular senescence through dual-channel activation suggests that YEATS2 plays a pivotal regulatory role in the process of cell proliferation. Ultimately, our in vivo research utilizing a nude mouse tumor model revealed a notable decrease in both tumor volume and weight after the suppression of YEATS2 expression. This phenomenon is likely attributable to the attenuation of proliferative cell activity, coupled with a concurrent augmentation in the population of natural killer (NK) cells. In summary, our research results have supplemented the understanding of the regulatory mechanisms of HCC cell proliferation and indicated that targeting YEATS2 may potentially inhibit liver tumor growth.

Uptake and 4-week quit rates from an opt-out co-located smoking cessation service delivered alongside community-based low-dose computed tomography screening within the Yorkshire Lung Screening Trial.

BACKGROUND: Up to 50% of those attending for low-dose computed tomography screening for lung cancer continue to smoke and co-delivery of smoking cessation services alongside screening may maximise clinical benefit. Here we present data from an opt-out co-located smoking cessation service delivered alongside the Yorkshire Lung Screening Trial (YLST). METHODS: Eligible YLST participants were offered an immediate consultation with a smoking cessation practitioner (SCP) at their screening visit with ongoing smoking cessation support over subsequent weeks. RESULTS: Of 2150 eligible participants, 1905 (89%) accepted the offer of an SCP consultation during their initial visit, with 1609 (75%) receiving ongoing smoking cessation support over subsequent weeks. Uptake of ongoing support was not associated with age, ethnicity, deprivation or educational level in multivariable analyses, although men were less likely to engage (adjusted OR (ORadj) 0.71, 95% CI 0.56-0.89). Uptake was higher in those with higher nicotine dependency, motivation to stop smoking and self-efficacy for quitting. Overall, 323 participants self-reported quitting at 4 weeks (15.0% of the eligible population); 266 were validated by exhaled carbon monoxide (12.4%). Multivariable analyses of eligible smokers suggested 4-week quitting was more likely in men (ORadj 1.43, 95% CI 1.11-1.84), those with higher motivation to quit and previous quit attempts, while those with a stronger smoking habit in terms of cigarettes per day were less likely to quit. CONCLUSIONS: There was high uptake for co-located opt-out smoking cessation support across a wide range of participant demographics. Protected funding for integrated smoking cessation services should be considered to maximise programme equity and benefit.

Genome-wide identification, subcellular localization, and expression analysis of the phosphatidyl ethanolamine-binding protein family reveals the candidates involved in flowering and yield regulation of Tartary buckwheat (Fagopyrum tataricum).

Background: PEBP (phosphatidyl ethanolamine-binding protein) is widely found in eukaryotes including plants, animals and microorganisms. In plants, the PEBP family plays vital roles in regulating flowering time and morphogenesis and is highly associated to agronomic traits and yields of crops, which has been identified and characterized in many plant species but not well studied in Tartary buckwheat (Fagopyrum tataricum Gaertn.), an important coarse food grain with medicinal value. Methods: Genome-wide analysis of FtPEBP gene family members in Tartary buckwheat was performed using bioinformatic tools. Subcellular localization analysis was performed by confocal microscopy. The expression levels of these genes in leaf and inflorescence samples were analyzed using qRT-PCR. Results: Fourteen Fagopyrum tataricum PEBP (FtPEBP) genes were identified and divided into three sub-clades according to their phylogenetic relationships. Subcellular localization analysis of the FtPEBP proteins in tobacco leaves indicated that FT- and TFL-GFP fusion proteins were localized in both the nucleus and cytoplasm. Gene structure analysis showed that most FtPEBP genes contain four exons and three introns. FtPEBP genes are unevenly distributed in Tartary buckwheat chromosomes. Three tandem repeats were found among FtFT5/FtFT6, FtMFT1/FtMFT2 and FtTFL4/FtTFL5. Five orthologous gene pairs were detected between F. tataricum and F. esculentum. Seven light-responsive, nine hormone-related and four stress-responsive elements were detected in FtPEBPs promoters. We used real-time PCR to investigate the expression levels of FtPEBPs among two flowering-type cultivars at floral transition time. We found FtFT1/FtFT3 were highly expressed in leaf and young inflorescence of early-flowering type, whereas they were expressed at very low levels in late-flowering type cultivars. Thus, we deduced that FtFT1/FtFT3 may be positive regulators for flowering and yield of Tartary buckwheat. These results lay an important foundation for further studies on the functions of FtPEBP genes which may be utilized for yield improvement.

Methane gas sensor based on direct absorption spectroscopy and the laser self-heating effect.

In this paper, a methane detection sensor based on direct absorption spectroscopy and the self-heating effect of lasers is proposed, which abandons the traditional method of relying on a thermoelectric cooler (TEC) to ensure stable gas concentration detection. The sensor can achieve stable concentration measurement in the temperature range of -10∘ to 40°C without the need for a TEC, which greatly simplifies the structure of the sensor and reduces the cost. The results of gas concentration calibration experiments show that the sensor has a good linear correlation (R 2=0.9993). Long-term continuous detection experiments show that the sensor maintains a relative detection error between -2.667% and 4.3% over the full test temperature range. In addition, signal-to-noise ratio analysis experiments further determine that the minimum detection limit of the sensor for methane gas is 27.33p p m⋅m (1σ). Given its advantages of simple structure, low cost, high accuracy, and stability, this methane detection sensor is well suited for natural gas leakage monitoring in home environments and can also be widely used in industrial safety detection and environmental monitoring applications. This technology provides a cost-effective solution for domestic and industrial methane detection.

MicroRNA-630 alleviates inflammatory reactions in rats with diabetic kidney disease by targeting toll-like receptor 4.

BACKGROUND: Diabetic kidney disease (DKD) is a major complication of diabetes mellitus. Renal tubular epithelial cell (TEC) damage, which is strongly associated with the inflammatory response and mesenchymal trans-differentiation, plays a significant role in DKD; However, the precise molecular mechanism is unknown. The recently identified microRNA-630 (miR-630) has been hypothesized to be closely associated with cell migration, apoptosis, and autophagy. However, the association between miR-630 and DKD and the underlying mechanism remain unknown. AIM: To investigate how miR-630 affects TEC injury and the inflammatory response in DKD rats. METHODS: Streptozotocin was administered to six-week-old male rats to create a hyperglycemic diabetic model. In the second week of modeling, the rats were divided into control, DKD, negative control of lentivirus, and miR-630 overexpression groups. After 8 wk, urine and blood samples were collected for the kidney injury assays, and renal tissues were removed for further molecular assays. The target gene for miR-630 was predicted using bioinformatics, and the association between miR-630 and toll-like receptor 4 (TLR4) was confirmed using in vitro investigations and double luciferase reporter gene assays. Overexpression of miR-630 in DKD rats led to changes in body weight, renal weight index, basic blood parameters and histopathological changes. RESULTS: The expression level of miR-630 was reduced in the kidney tissue of rats with DKD (P < 0.05). The miR-630 and TLR4 expressions in rat renal TECs (NRK-52E) were measured using quantitative reverse transcription polymerase chain reaction. The mRNA expression level of miR-630 was significantly lower in the high-glucose (HG) and HG + mimic negative control (NC) groups than in the normal glucose (NG) group (P < 0.05). In contrast, the mRNA expression level of TLR4 was significantly higher in these groups (P < 0.05). However, miR-630 mRNA expression increased and TLR4 mRNA expression significantly decreased in the HG + miR-630 mimic group than in the HG + mimic NC group (P < 0.05). Furthermore, the levels of tumor necrosis factor-alpha (TNF-α), interleukin-1ß (IL-1ß), and IL-6 were significantly higher in the HG and HG + mimic NC groups than in NG group (P < 0.05). However, the levels of these cytokines were significantly lower in the HG + miR-630 mimic group than in the HG + mimic NC group (P < 0.05). Notably, changes in protein expression were observed. The HG and HG + mimic NC groups showed a significant decrease in E-cadherin protein expression, whereas TLR4, α-smooth muscle actin (SMA), and collagen IV protein expression increased (P < 0.05). Conversely, the HG + miR-630 mimic group exhibited a significant increase in E-cadherin protein expression and a notable decrease in TLR4, α-SMA, and collagen IV protein expression than in the HG + mimic NC group (P < 0.05). The miR-630 targets TLR4 gene expression. In vivo experiments demonstrated that DKD rats treated with miR-630 agomir exhibited significantly higher miR-630 mRNA expression than DKD rats injected with agomir NC. Additionally, rats treated with miR-630 agomir showed significant reductions in urinary albumin, blood glucose, TLR4, and proinflammatory markers (TNF-α, IL-1ß, and IL-6) expression levels (P < 0.05). Moreover, these rats exhibited fewer kidney lesions and reduced infiltration of inflammatory cells. CONCLUSION: MiR-630 may inhibit the inflammatory reaction of DKD by targeting TLR4, and has a protective effect on DKD.

Prevalence and related factors of sleep quality among Chinese undergraduates in Jiangsu Province: multiple models' analysis.

Background and aims: In China, a significant number of undergraduates are experiencing poor sleep quality. This study was designed to investigate the prevalence of poor sleep quality and identify associated factors among undergraduates in Jiangsu Province, China. Methods: A total of 8,457 participants were collected in 2022 using whole-group convenience sampling. The factors studied included basic demographics, family and social support, personal lifestyles, physical and mental health, mobile phone addiction index (MPAI), and the Connor-Davidson resilience scale (CD-RISC). The Pittsburgh Sleep Quality Index (PSQI) was used to assess sleep quality. Four models, including weighted multiple linear regression, binary logistic regression, weighted linear mixed model, and logistic regression with random effects, were applied to identify associated factors for sleep quality. Results: Of the 8,457 participants analyzed, 26.64% (2,253) were classified into the poor sleep quality group with a PSQI score >7. No significant relationship was found between sleep quality and gender, native place, economic level of family, physical exercise, dormitory light, dormitory hygiene, and amativeness matter. Risk factors for sleep quality identified by the four models included lower CD-RISC, higher MPAI, fourth grade or above, smoking, drinking, greater academic pressure, greater employment pressure, roommate sleeping late, noisy dormitory, poorer physical health status, poorer mental health status, and psychological counseling. Conclusions: These findings provide valuable insights for university administrators, enabling them to better understand the risk factors associated with poor sleep quality in undergraduates. By identifying these factors, administrators can provide targeted intervention measures and counseling programs to improve students' sleep quality.

Siponimod Attenuates Neuronal Cell Death Triggered by Neuroinflammation via NFκB and Mitochondrial Pathways.

Multiple sclerosis (MS) is the most common autoimmune demyelinating disease of the central nervous system (CNS), consisting of heterogeneous clinical courses varying from relapsing-remitting MS (RRMS), in which disability is linked to bouts of inflammation, to progressive disease such as primary progressive MS (PPMS) and secondary progressive MS (SPMS), in which neurological disability is thought to be linked to neurodegeneration. As a result, successful therapeutics for progressive MS likely need to have both anti-inflammatory and direct neuroprotective properties. The modulation of sphingosine-1-phosphate (S1P) receptors has been implicated in neuroprotection in preclinical animal models. Siponimod/BAF312, the first oral treatment approved for SPMS, may have direct neuroprotective benefits mediated by its activity as a selective (S1P receptor 1) S1P1 and (S1P receptor 5) S1P5 modulator. We showed that S1P1 was mainly present in cortical neurons in lesioned areas of the MS brain. To gain a better understanding of the neuroprotective effects of siponimod in MS, we used both rat neurons and human-induced pluripotent stem cell (iPSC)-derived neurons treated with the neuroinflammatory cytokine tumor necrosis factor-alpha (TNF-α). Cell survival/apoptotic assays using flow cytometry and IncuCyte live cell analyses showed that siponimod decreased TNF-α induced neuronal cell apoptosis in both rat and human iPSCs. Importantly, a transcriptomic analysis revealed that mitochondrial oxidative phosphorylation, NFκB and cytokine signaling pathways contributed to siponimod's neuroprotective effects. Our data suggest that the neuroprotection of siponimod/BAF312 likely involves the relief of oxidative stress in neuronal cells. Further studies are needed to explore the molecular mechanisms of such interactions to determine the relationship between mitochondrial dysfunction and neuroinflammation/neurodegeneration.