Dectin-1 induces TRPV1 sensitization and contributes to visceral hypersensitivity of irritable bowel syndrome in male mice.

BACKGROUND: Visceral hypersensitivity is considered the core pathophysiological mechanism that causes abdominal pain in patients with irritable bowel syndrome (IBS). Fungal dysbiosis has been proved to contribute to visceral hypersensitivity in IBS patients. However, the underlying mechanisms for Dectin-1, a major fungal recognition receptor, in visceral hypersensitivity are poorly understood. This study aimed to explore the role of Dectin-1 in visceral hypersensitivity and elucidate the impact of Dectin-1 activity on the function of transient receptor potential vanilloid type 1 (TRPV1). METHODS: Visceral hypersensitivity model was established by the intracolonic administration of 0.1 mL TNBS (130 µg/mL in 30% ethanol) in the male mice. Fluconazole and nystatin were used as fungicides. Laminarin, a Dectin-1 antagonist and gene knockout (Clec7a-/-) mice were used to interrupt the function of Dectin-1. Colorectal distension-electromyogram recording was performed to assess visceral sensitivity. Immunostaining experiment was performed to determine the localization of Dectin-1 in dorsal root ganglion (DRG) neurons. Calcium imaging study was performed to assay TRPV1-mediated calcium influx in acutely dissociated DRG neurons. RESULTS: Pretreatment with fungicides, administration of laminarin or genetic deletion of Clec7a alleviated TNBS-induced visceral hypersensitivity in male mice. The expression of Dectin-1 was upregulated in the DRG and colon of TNBS-treated mice. Colocalization of Dectin-1 and TRPV1 was observed in DRG neurons. Importantly, pretreatment with curdlan, a Dectin-1 agonist, increased TRPV1-mediated calcium influx. CONCLUSIONS: Dectin-1 contributes to visceral hypersensitivity in IBS or in inflammatory bowel disease in remission and activation of Dectin-1 induces TRPV1 sensitization. SIGNIFICANCE STATEMENT: This work provides direct evidence for the functional regulation of TRPV1 channel by Dectin-1 activity, proposing a new mechanism underlying TRPV1 sensitization. Control of intestinal fungi might be beneficial for the treatment of refractory abdominal pain in patients with IBS or IBD in remission.

Distribution, risk evaluation, and source allocation of cesium and strontium in surface soil in a mining city.

Radioactive nuclides cesium (Cs) and strontium (Sr) possess long half-lives, with 135Cs at approximately 2.3 million years and 87Sr at about 49 billion years. Their persistent accumulation can result in long-lasting radioactive contamination of soil ecosystems. This study employed geo-accumulation index (Igeo), pollution load index (PLI), potential ecological risk index (PEPI), health risk assessment model (HRA), and Monte Carlo simulation to evaluate the pollution and health risks of Cs and Sr in the surface soil of different functional areas in a typical mining city in China. Positive matrix factorization (PMF) model was used to elucidate the potential sources of Cs and Sr and the respective contribution rates of natural and anthropogenic sources. The findings indicate that soils in the mining area exhibited significantly higher levels of Cs and Sr pollution compared to smelting factory area, agricultural area, and urban residential area. Strontium did not pose a potential ecological risk in any studied functional area. The non-carcinogenic health risk of Sr to the human body in the study area was relatively low. Because of the lack of parameters for Cs, the potential ecological and human health risks of Cs was not calculated. The primary source of Cs in the soil was identified as the parent material from which the soil developed, while Sr mainly originated from associated contamination caused by mining activities. This research provides data for the control of Cs and Sr pollution in the surface soil of mining city.

Identification of DNase I hypersensitive sites in the human genome by multiple sequence descriptors.

DNase I hypersensitive sites (DHSs) are chromatin regions highly sensitive to DNase I enzymes. Studying DHSs is crucial for understanding complex transcriptional regulation mechanisms and localizing cis-regulatory elements (CREs). Numerous studies have indicated that disease-related loci are often enriched in DHSs regions, underscoring the importance of identifying DHSs. Although wet experiments exist for DHSs identification, they are often labor-intensive. Therefore, there is a strong need to develop computational methods for this purpose. In this study, we used experimental data to construct a benchmark dataset. Seven feature extraction methods were employed to capture information about human DHSs. The F-score was applied to filter the features. By comparing the prediction performance of various classification algorithms through five-fold cross-validation, random forest was proposed to perform the final model construction. The model could produce an overall prediction accuracy of 0.859 with an AUC value of 0.837. We hope that this model can assist scholars conducting DNase research in identifying these sites.

Assessment of the influence of levees along Yangtze River on Oncomelania hupensis, the intermediate host of Schistosoma japonicum.

BACKGROUND: Oncomelania hupensis is the exclusive intermediate host of Schistosoma japonicum in China. Snail control is an essential component of schistosomiasis elimination programme. With 70 years of continuous efforts, the range of O. hupensis had reduced significantly, but slowed down in last decades. A large number of levees against flooding were constructed along Yangtze River and its affiliated lakes in the middle and lower reaches, which influenced the hydrology and ecology in the alluvial plains. The purpose of this study was to assess the impact of levees on the distribution of O. hupensis in the middle and lower reaches of the Yangtze River. METHODS: The snail habitats were digitalised by hand-held GPS system. The years for discovery and elimination of snail habitats were extracted from historical records. The accumulated snail-infested range for each habitat was calculated on the basis of annual reports. The current distribution of O. hupensis was determined by systematic and environmental sampling. The geographical distribution of levees was obtained from satellite imagery. To assess the impact of levees, the data pertaining to O. hupensis were divided into two parts: inside and outside the Yangtze River. Joinpoint regression was utilised to divide the study time span and further characterise the regression in each period. The 5-year-period moving averages of eliminated area infested by snails were calculated for the habitats inside and outside Yangtze River. The moving routes of corresponding geographical median centres were simulated in ArcGIS. Hotspot analysis was used to determine the areas with statistical significance clustering of O. hupensis density. RESULTS: Three periods were identified according to Joinpoint regression both inside and outside Yangtze River. The area infested by O. hupensis increased in the first two periods. It decreased rapidly outside Yangtze River year over year after 1970, while that inside the Yangtze River did not change significantly. Furthermore, the latter was significantly higher than the former. It was observed that the present density of O. hupensis inside Yangtze River was lower than outside the Yangtze River. The median centre for eliminated ranges inside Yangtze River wavered between the east (lower reach) and the west (middle reach). In contrast, the median centre for eliminated ranges continuously moved from the east to the west. CONCLUSIONS: Our findings indicated that the levees had a considerable negative impact on the distribution of O. hupensis outside Yangtze River. Some hotspots observed in the irrigation areas need a sluice system at the inlet of branch for snail control. The major distribution of O. hupensis located in Hubei might be caused by severe waterlogging. The intensive surveillance should be implemented there. The biggest two freshwater lakes, the major endemic regions historically, were identified as cold spots. The long-term impact of Three Gorges Dam on the distribution of O. hupensis in the lakes should be monitored and evaluated.

Anlotinib destabilizes PAX3-FOXO1 to induce rhabdomyosarcoma cell death via upregulating NEK2.

BACKGROUND: Rhabdomyosarcoma (RMS) is one of the most common soft tissue sarcomas in children and adolescents, in which PAX3-FOXO1 fusion gene positive patients have very poor prognosis. PAX3-FOXO1 has been identified as an independent prognostic predictor in RMS, with no currently available targeted therapeutic intervention. The novel tyrosine kinase inhibitor anlotinib exhibits a wide range of anticancer effects in multiple types of cancers; however, there have been no relevant studies regarding its application in RMS. MATERIALS AND METHODS: We investigated the effects of PAX3-FOXO1 on the therapeutic efficacy of anlotinib using the CCK-8 assay, flow cytometry, invasion assay, wound healing assay, western blotting, quantitative polymerase chain reaction(qPCR), and xenograft experiments. RNA-seq and co-immunoprecipitation assays were conducted to determine the specific mechanism by which anlotinib regulates PAX3-FOXO1 expression. RESULTS: Anlotinib effectively inhibited RMS cell proliferation and promoted apoptosis and G2/M phase arrest while impeding tumor growth in vivo. Downregulation of PAX3-FOXO1 enhances the antitumor effects of anlotinib. Anlotinib upregulates protein kinase NEK2 and increases the degradation of PAX3-FOXO1 via the ubiquitin-proteasome pathway, leading to a reduction in PAX3-FOXO1 protein levels. CONCLUSION: Anlotinib effectively inhibited the malignant progression of RMS and promoted degradation of the fusion protein PAX3-FOXO1. Anlotinib could be a targeted therapeutic approach to treat PAX3-FOXO1 fusion-positive RMS.

A Novel Hydrated Iron Vanadate Cathode Material for Advanced Aqueous Nickel-Ion Batteries.

Aqueous nickel-ion batteries (ANIBs) as an emerging energy storage device attracted much attention owing to their multielectron redox reaction and dendrite-free Ni anode, yet their development is hindered by the divalent properties of Ni2+ and the lack of suitable cathode materials. Herein, a hydrated iron vanadate (Fe2V3O10.5∙1.5H2O, FOH) with a preferred orientation along the (200) plane is innovatively proposed and used as cathode material for ANIBs. The FOH cathode exhibits a remarkable capacity of 129.3 mAh g-1 at 50 mA g-1 and a super-high capacity retention of 95% at 500 mA g-1 after 700 cycles. The desirable Ni2+ storage capacity of FOH can be attributed to the preferentially oriented and tunnel structures, which offer abundant reaction active planes and a broad Ni2+ diffusion path, the abundant vacancies and high specific surface area further increase ion storage sites and accelerate ion diffusion in the FOH lattice. Furthermore, the Ni2+ storage mechanism and structural evolution in the FOH cathode are explored through ex situ XRD, ex situ Raman, ex situ XPS and other ex situ characteristics. This work opens a new way for designing novel cathode materials to promote the development of ANIBs.

Is conventional functional liver remnant volume higher than 40% still sufficient to prevent post-hepatectomy liver failure in jaundiced patients with hilar cholangiocarcinoma? A single-center experience in China.

OBJECTIVE: Our study aims to evaluate the predictive accuracy of functional liver remnant volume (FLRV) in post-hepatectomy liver failure (PHLF) among surgically-treated jaundiced patients with hilar cholangiocarcinoma (HCCA). METHODS: We retrospectively reviewed surgically-treated jaundiced patients with HCCA between June, 2000 and June, 2018. The correlation between FRLV and PHLF were analyzed. The optimal cut off value of FLRV in jaundiced HCCA patients was also identified and its impact was furtherly evaluated. RESULTS: A total of 224 jaundiced HCCA patients who received a standard curative resection (43 patients developed PHLF) were identified. Patients with PHLF shared more aggressive clinic-pathological features and were generally in a more advanced stage than those without PHLF. An obvious inconsistent distribution of FLRV in patients with PHLF and those without PHLF were detected. FLRV (continuous data) had a high predictive accuracy in PHLF. The newly-acquired cut off value (FLRV = 53.5%, sensitivity = 81.22%, specificity = 81.4%) showed a significantly higher predictive accuracy than conventional FLRV cut off value (AUC: 0.81 vs. 0.60, p < 0.05). Moreover, patients with FLRV lower than 53.5% also shared a significantly higher major morbidity rate as well as a worse prognosis, which were not detected for FLRV of 40%. CONCLUSION: For jaundiced patients with HCCA, a modified FLRV of 53.5% is recommended due to its great impact on PHLF, as well as its correlation with postoperative major morbidities as well as overall prognosis, which might help clinicians to stratify patients with different therapeutic regimes and outcomes. Future multi-center studies for training and validation are required for further validation.

A bibliometric analysis from 2013 to 2023 reveals research hotspots and trends in the connection between sport and regenerative medicine.

The field of regenerative medicine for sports injuries has grown significantly in the 21st century. This study attempted to provide an overview of the current state of research and key findings regarding the relationship between sport and regenerative medicine in general, identifying trends and hotspots in research topics. We gathered the literature from the Web of Science (WOS) database covering the last 10 years (2013-2023) pertaining to regenerative medicine for sporter and applied Citespace to assess the knowledge mapping. The findings demonstrated that there were 572, with a faster increase after 2018. The country, institution, and author with the most publications are the USA, Harvard University, and Maffulli Nicola. In addition, the most co-cited reference is J Acad Nutr Diet (2016) (199). Adipose tissue, high tibial osteotomy, and bone marrow are the hot spots in this field in the next few years.

Combining multimodal diffusion-weighted imaging and morphological parameters for detecting lymph node metastasis in cervical cancer.

BACKGROUND: Accurate detection of lymph node metastasis (LNM) is crucial for determining the tumor stage, selecting optimal treatment, and estimating the prognosis for cervical cancer. This study aimed to assess the diagnostic efficacy of multimodal diffusion-weighted imaging (DWI) and morphological parameters alone or in combination, for detecting LNM in cervical cancer. METHODS: In this prospective study, we enrolled consecutive cervical cancer patients who received multimodal DWI (conventional DWI, intravoxel incoherent motion DWI, and diffusion kurtosis imaging) before treatment from June 2022 to June 2023. The largest lymph node (LN) observed on each side on imaging was matched with that detected on pathology to improve the accuracy of LN matching. Comparison of the diffusion and morphological parameters of LNs and the primary tumor between the positive and negative LN groups. A combined diagnostic model was constructed using multivariate logistic regression, and the diagnostic performance was evaluated using receiver operating characteristic curves. RESULTS: A total of 93 cervical cancer patients were enrolled: 35 with LNM (48 positive LNs were collected), and 58 without LNM (116 negative LNs were collected). The area under the curve (AUC) values for the apparent diffusion coefficient, diffusion coefficient, mean diffusivity, mean kurtosis, long-axis diameter, short-axis diameter of LNs, and the largest primary tumor diameter were 0.716, 0.720, 0.716, 0.723, 0.726, 0.798, and 0.744, respectively. Independent risk factors included the diffusion coefficient, mean kurtosis, short-axis diameter of LNs, and the largest primary tumor diameter. The AUC value of the combined model based on the independent risk factors was 0.920, superior to the AUC values of all the parameters mentioned above. CONCLUSION: Combining multimodal DWI and morphological parameters improved the diagnostic efficacy for detecting cervical cancer LNM than using either alone.

Phthalate exposure and markers of biological aging: The mediating role of inflammation and moderating role of dietary nutrient intake.

Limited evidence has suggested a relationship between phthalate exposure and biological aging. This study investigated the association between phthalate exposure and biological aging, focusing on the mediating role of inflammation and the interaction with dietary nutrient intake. Data were analyzed from a nationwide cross-sectional survey comprising 12,994 participants aged 18 and above. Eight phthalate metabolites were detected in spot urine samples. Biological aging was assessed using the Klemera-Doubal method-biological age (KDM-BA) acceleration, phenotypic age (PA) acceleration, and homeostatic dysregulation (HD). The systemic immune-inflammation index (SII) evaluated systemic inflammation. The individual and combined associations between phthalate exposure and biological aging were assessed using linear regression, weighted quantile sum (WQS) regression, and quantile g-computation (qgcomp). The participants had a mean age of 47 years, with 50.7 % male and 44.8 % non-Hispanic white. Most phthalate metabolites were positively correlated with KDM-BA acceleration (ß = 0.306-0.584), PA acceleration (ß = 0.081-0.281), and HD (ß = 0.016-0.026). Subgroup analysis indicated that men, older individuals, and non-Hispanic whites are particularly sensitive populations. WQS regression and qgcomp analyses consistently indicated a positive association between mixed phthalate exposure and HD, highlighting MEHHP as the most significant contributing metabolite. Mediation analyses showed inflammation partially mediated the association between phthalate metabolites and biological aging. Significant interactions regarding biological aging were found between specific phthalate metabolites and dietary nutrients (carotenoids, vitamins A, B1, B2, B6, B12, niacin, and selenium) intake. These findings indicated that the association between phthalate exposure and biological aging was mediated by inflammation, with nutrient intake mitigating this effect.

Fluoranthene slow down sulfamethazine migration in soil via π-π interaction to increase the abundance of antibiotic resistance genes.

Sulfonamide antibiotics and polycyclic aromatic hydrocarbons (PAHs) often coexist in soil, leading to compound pollution through various pathways. This study focuses on sulfamethazine (SMZ) and PAHs (fluoranthene) as the subject for compound pollution research. Using a soil-groundwater simulation system, we investigated the migration characteristics of SMZ under coexistence with fluoranthene (Fla) and observed variations in the abundance of antibiotic resistance genes (ARGs). Through molecular docking simulations and isothermal adsorption experiments, we discovered that Fla bound with SMZ via π-π interactions, resulting in a 20.9% increase in the SMZ soil-water partition coefficient. Under compound conditions, the concentration of SMZ in surface soil could reach 1.4 times that of SMZ added alone, with an 13.4% extension in SMZ half-life. The deceleration of SMZ's vertical migration rate placed additional stress on surface soil microbiota, leading to a proliferation of ARGs by 66.3%-125.8%. Moreover, under compound pollution, certain potential hosts like Comamonadaceae and Gemmatimonas exhibited a significant positive correlation with resistance genes such as sul 1 and sul 2. These findings shed light on the impact of PAHs on sulfonamide antibiotic migration and the abundance of ARGs. They also provide theoretical insights for the development of technologies aimed at mitigating compound pollution in soil.

Reduction of Beany Flavor and Improvement of Nutritional Quality in Fermented Pea Milk: Based on Novel Bifidobacterium animalis subsp. lactis 80.

Peas (Pisum sativum L.) serve as a significant source of plant-based protein, garnering consumer attention due to their high nutritional value and non-GMO modified nature; however, the beany flavor limits its applicability. In this study, the effects of Bifidobacterium animalis subsp. Lactis 80 (Bla80) fermentation on the physicochemical characteristics, particle size distribution, rheological properties, and volatile flavor compounds of pea milk was investigated. After fermentation by Bla80, the pH of pea milk decreased from 6.64 ± 0.01 to 5.14 ± 0.01, and the (D4,3) distribution decreased from 142.4 ± 0.47 µm to 122.7 ± 0.55 µm. In addition, Lactic acid bacteria (LAB) fermentation significantly reduced the particle size distribution of pea milk, which was conducive to improving the taste of pea milk and also indicated that Bla80 had the probiotic potential of utilizing pea milk as a fermentation substrate. According to GC-MS analysis, 64 volatile compounds were identified in fermented pea milk and included aldehydes, alcohols, esters, ketones, acids, and furans. Specifically, aldehydes in treated samples decreased by 27.36% compared to untreated samples, while esters, ketones, and alcohols increased by 11.07%, 10.96%, and 5.19%, respectively. These results demonstrated that Bla80 fermentation can significantly decrease the unpleasant beany flavor, such as aldehydes and furans, and increase fruity or floral aromas in treated pea milk. Therefore, Bla80 fermentation provides a new method to improve physicochemical properties and consumer acceptance of fermented pea milk, eliminating undesirable aromas for the application of pea lactic acid bacteria beverage.

A mitochondria-related genes associated neuroblastoma signature - based on bulk and single-cell transcriptome sequencing data analysis, and experimental validation.

Background: Neuroblastoma (NB), characterized by its marked heterogeneity, is the most common extracranial solid tumor in children. The status and functionality of mitochondria are crucial in regulating NB cell behavior. While the significance of mitochondria-related genes (MRGs) in NB is still missing in key knowledge. Materials and methods: This study leverages consensus clustering and machine learning algorithms to construct and validate an MRGs-related signature in NB. Single-cell data analysis and experimental validation were employed to characterize the pivotal role of FEN1 within NB cells. Results: MRGs facilitated the classification of NB patients into 2 distinct clusters with considerable differences. The constructed MRGs-related signature and its quantitative indicators, mtScore and mtRisk, effectively characterize the MRGs-related patient clusters. Notably, the MRGs-related signature outperformed MYCN in predicting NB patient prognosis and was adept at representing the tumor microenvironment (TME), tumor cell stemness, and sensitivity to the chemotherapeutic agents Cisplatin, Topotecan, and Irinotecan. FEN1, identified as the most contributory gene within the MRGs-related signature, was found to play a crucial role in the communication between NB cells and the TME, and in the developmental trajectory of NB cells. Experimental validations confirmed FEN1's significant influence on NB cell proliferation, apoptosis, cell cycle, and invasiveness. Conclusion: The MRGs-related signature developed in this study offers a novel predictive tool for assessing NB patient prognosis, immune infiltration, stemness, and chemotherapeutic sensitivity. Our findings unveil the critical function of FEN1 in NB, suggesting its potential as a therapeutic target.

GPRC5A is a potential prognostic biomarker and correlates with immune cell infiltration in non-small cell lung cancer.

Background: The tumor microenvironment (TME) plays an important role in tumor progression and immunotherapy responses in non-small cell lung cancer (NSCLC). The programmed cell death 1 (PD-1)/ programmed cell death-ligand 1 (PD-L1) checkpoint is a central mediator of immunosuppression in the TME. However, there is still a need to identify additional biomarkers that could reflect the difference in TME and PD-L1 expression in NSCLC patients. To this end, we focused on the expression of G-protein-coupled receptor family C group 5 type A (GPRC5A) in NSCLC. GPRC5A, is a retinoic acid-inducible gene that plays multiple roles in NSCLC. However, little is known about the role of GPRC5A in regulating the TME and PD-L1. Our objective was to describe the critical role of GPRC5A expression in NSCLC in the setting of immune cell infiltration. Methods: We identified the relationship between GPRC5A expression and the clinicopathologic characteristics of NSCLC patients in the Fudan University Shanghai Cancer Center (FUSCC) cohort. Furthermore, we validated GPRC5A as a predictive biomarker by using public databases to reveal the relationship between GPRC5A expression and immune cell infiltration. To correlate the expression of GPRC5A with the spatial distribution of PD-L1 in NSCLC samples, we performed multiplex immunohistochemistry (mIHC). Results: Low GPRC5A expression is associated with earlier pathological stage (pStage). Analysis of immune cell infiltration indicates there is a relationship between low GPRC5A expression and increased infiltration of CD8+ T cells, activated CD4+ T cells, and M1 macrophages within the TME. Furthermore, low GPRC5A expression is associated with an increased immunophenotype score (IPS) in NSCLC. Additionally, analysis of mIHC reveals there is a correlation between low GPRC5A expression and spatial distribution of tumoral PD-L1 expression. Conclusions: Our study revealed the relationship between low expression of GPRC5A and earlier pStage in NSCLC. Furthermore, we observed that low expression of GPRC5A is associated with increased infiltration of immune cells, higher IPS, and spatial distribution of PD-L1-positive tumor cells. Therefore, we speculate that low expression of GPRC5A is associated with immunotherapy, but further validation is still required.

Study on regeneration mechanism of composite adsorbent by Mg-MOF-74-based modified biochar.

In this paper, composite adsorbent was prepared from biochar and Mg-MOF-74 by in-situ growth method to investigate regeneration mechanism. The effects of O2 and temperature on regeneration characteristics were investigated by CO2 adsorption properties and characterization techniques, and the optimal regeneration conditions were determined. Regeneration mechanism of adsorbent was revealed by adsorption kinetics and elemental valence analysis. The related wave function parameters were calculated based on DFT to reveal the repair mechanism of the failed oxidation sites from the microscopic level. The mechanism of CO2 adsorption by the repaired oxidation sites was explored based on the regenerated adsorption configuration. It was found that the regeneration performance of the adsorbent exhibited a trend of increasing and then decreasing with the increase of O2 concentration and temperature, and the optimal regeneration conditions were determined to be 5 % O2 concentration and 200 °C. At optimal regeneration conditions, a synergistic interaction between O2 and poly-metals was generated to enhance the adsorbent polarity. O2 also reacted with the adsorbent in a redox reaction to produce new oxygen-containing functional groups and cause pore expansion, the mass transfer and diffusion was enhanced. The oxidation site adsorbed O2 to undergo electron rearrangement and release the adsorbed CO2. Due to the nature of common orbital hybridization between metals, the metals underwent conjugation and synergistic effects with O2 to form tetrahedral co-coordination structures with lower energies. The electron density and electric field effects of the system were enhanced. The former enhanced interaction with CO2 to form carbonate. The latter increased the activity of the neighboring N atom, which in turn generated a stable ring structure with carbonate, and CO2 adsorption was enhanced.

Association of Life's essential 8 score with the risk of all-cause mortality and cardio-cerebrovascular mortality in patients with stroke.

BACKGROUND: A higher Life's Essential 8 (LE8)-based cardiovascular health (CVH) has been reported to be associated with a lower risk of both all-cause mortality and cardio-cerebrovascular diseases (CCVDs) related mortality in adults in the United States. At the same time, multiple studies have shown a significant negative association of CVH with the risk of stroke and CCVDs. Since no research has investigated the applicability of the LE8 in stroke patients, this study aimed to explore the association of LE8 with all-cause mortality and cardio-cerebrovascular mortality in stroke patients. METHODS: Data of patients were extracted from the National Health and Nutrition Examination Surveys (NHANES) database in 2007-2018 in this retrospective cohort study. Weighted univariate and multivariate COX regression analyses were utilized to investigate the associations of LE8 with all-cause mortality and cardio-cerebrovascular mortality. We further explored these relationships in subgroups of age, gender, body mass index (BMI), cancer, congestive heart failure (CHF), and coronary heart disease (CHD). The evaluation indexes were hazard ratios (HRs) and 95% confidence intervals (CIs). RESULTS: Among the eligible patients, 278 died from all-cause and 89 (8.38%) of them died due to CCVDs. After adjusting for covariates, patients with LE8 score ≥ 58.75 seemed to have both lower risk of all-cause mortality (HR = 0.46, 95%CI: 0.31-0.69) and cardio-cerebrovascular mortality (HR = 0.51, 95%CI: 0.26-0.98), comparing to those with LE8 score < 48.123. Higher LE8 scores were associated with lower risk of all-cause mortality in patients aged < 65 years old, without cancer, and whatever the gender, BMI, CHF or CHD conditions (all P < 0.05). The relationships between high LE8 scores and low cardio-cerebrovascular mortality risk were only found in age < 65 years old and non-cancer subgroups (all P < 0.05). CONCLUSION: A higher LE8 score was associated with lower risk of both all-cause mortality and cardio-cerebrovascular mortality in patients with stroke, which may provide some reference for risk management and prognosis improvement in stoke. However, more evidences are needed to verify this beneficial role of high LE8 score in stroke prognosis.

Organ-specific Toxocara canis larvae migration and host immune response in experimentally infected mice.

We investigated organ specific Toxocara canis larval migration in mice infected with T. canis larvae. We observed the worm burden and systemic immune responses. Three groups of BALB/c mice (n=5 each) were orally administered 1,000 T. canis 2nd stage larvae to induce larva migrans. Mice were sacrificed at 1, 3, and 5 weeks post-infection. Liver, lung, brain, and eye tissues were collected. Tissue from 2 mice per group was digested for larval count, while the remaining 3 mice underwent histological analysis. Blood hematology and serology were evaluated and compared to that in a control uninfected group (n=5) to assess the immune response. Cytokine levels in bronchoalveolar lavage (BAL) fluid were also analyzed. We found that, 1 week post-infection, the mean parasite load in the liver (72±7.1), brain (31±4.2), lungs (20±5.7), and eyes (2±0) peaked and stayed constant until the 3 weeks. By 5-week post-infection, the worm burden in the liver and lungs significantly decreased to 10±4.2 and 9±5.7, respectively, while they remained relatively stable in the brain and eyes (18±4.2 and 1±0, respectively). Interestingly, ocular larvae resided in all retinal layers, without notable inflammation in outer retina. Mice infected with T. canis exhibited elevated levels of neutrophils, monocytes, eosinophils, and immunoglobulin E. At 5 weeks post-infection, interleukin (IL)-5 and IL-13 levels were elevated in BAL fluid. Whereas IL-4, IL-10, IL-17, and interferon-γ levels in BAL fluid were similar to that in controls. Our findings demonstrate that a small portion of T. canis larvae migrate to the eyes and brain within the first week of infection. Minimal tissue inflammation was observed, probably due to increase of anti-inflammatory cytokines. This study contributes to our understanding of the histological and immunological responses to T. canis infection in mice, which may have implications to further understand human toxocariasis.

A novel antioxidant iron-chelating peptide from yak skin: analysis of the chelating mechanism and digestion stability in vitro.

BACKGROUND: The global prevalence of iron deficiency has posed significant public health risks. Animal-derived collagen peptides have been recognized for their potent metal ion-chelating capabilities, which can greatly enhance the bioavailability of iron. Yak skins, typically discarded during production and processing, serve as a valuable resource. Based on yak skin collagen peptide (YSP), we have developed a novel iron-chelating peptide: yak skin collagen iron-chelating peptide (YSP-Fe). RESULTS: The maximum level of iron chelation of YSP-Fe achieved was 42.72 ± 0.65 mg g-1. Structural analysis indicated that YSP-Fe was primarily formed from amino, carboxyl and carbonyl groups combined with ferrous ions. Through examination of the amino acid composition, molecular docking and peptide sequence identification, it was determined that Gly, Asp and Arg played crucial roles in the chelation of ferrous ions by YSP. Furthermore, YSP-Fe was more stable in simulated gastrointestinal digestion compared to FeSO4. CONCLUSION: YSP-Fe demonstrated dual benefits of iron supplementation and antioxidant effects. These significant findings provide a foundation for the development of novel iron supplements and the effective utilization of yak skin as a valuable resource. © 2024 Society of Chemical Industry.

Odontogenesis-Empowered Extracellular Vesicles Safeguard Donor-Recipient Stem Cell Interplay to Support Tooth Regeneration.

Harnessing the developmental events of mesenchymal condensation to direct postnatal dental stem cell aggregation represents a cutting-edge and promising approach to tooth regeneration. Tooth avulsion is among the most prevalent and serious dental injuries, and odontogenic aggregates assembled by stem cells from human exfoliated deciduous teeth (SHED) have proven effective in revitalizing avulsed teeth after replantation in the clinical trial. However, whether and how SHED aggregates (SA) communicate with recipient components and promote synergistic tissue regeneration to support replanted teeth remains elusive. Here, it is shown that SA-mediated avulsed tooth regeneration involves periodontal restoration and recovery of recipient Gli1+ stem cells, which are mobilized and necessarily contribute to the reestablishment of the tooth-periodontal ligament-bone interface. Mechanistically, the release of extracellular vesicles (EVs) is revealed indispensable for the implanted SA to mobilize recipient Gli1+ cells and regenerate avulsed teeth. Furthermore, SHED aggregates-released EVs (SA-EVs) are featured with odontogenic properties linked to tissue regeneration, which enhance migration, proliferation, and differentiation of Gli1+ cells. Importantly, local application of SA-EVs per se empowers recipient Gli1+ cells and safeguards regeneration of avulsed teeth. Collectively, the findings establish a paradigm in which odontogenesis-featured EVs govern donor-recipient stem cell interplay to achieve tooth regeneration, inspiring cell-free translational regenerative strategies.

Identification of a Safe and Tolerable Carbamazepine Dosing Paradigm that Facilitates Effective Evaluation of CYP3A4 Induction.

Carbamazepine (CBZ) is the recommended alternative to rifampicin as a CYP3A4 inducer in drug-drug interaction studies. However, the traditional CBZ dosing paradigm can lead to several adverse events (AEs). This study tested a shorter CBZ dosing regimen using the CYP3A4-sensitive index substrate midazolam (MDZ). This was a fixed-sequence arm of an open-label, phase I study (NCT04840888). Healthy participants (n = 15) aged 18-63 years received oral doses of 1.2 mg MDZ alone (Day 1), CBZ b.i.d. alone (100 mg Days 2-4; 200 mg Days 5-7; 300 mg Days 8-10 and 12-13), and 300 mg CBZ b.i.d. plus 1.2 mg MDZ (Days 11 and 14). One participant (6.7%) experienced constipation due to treatment with CBZ plus MDZ on Day 11. One participant (6.7%) experienced urticaria (Days 12-13), and two participants (13.3%) experienced somnolence (Days 8-10) due to treatment with 300 mg CBZ b.i.d. alone. All AEs were mild. For MDZ, the geometric mean (90% CI) ratio (vs. Day 1) of the area under the curve (AUC 0-∞) was 0.28 (0.24-0.31) on Day 11 and 0.26 (0.23-0.29) on Day 14. The AUC (0-12 hours) of CBZ was 114,000 ng∙h/mL on Day 11 and 105,000 ng∙h/mL on Day 14. Steady-state concentrations of CBZ and induction of CYP3A4 were achieved on Day 11. The data are consistent with predictions of physiologically-based pharmacokinetic models in Simcyp. The 9-day dosing regimen for CBZ induction was well-tolerated by healthy participants, supporting the use of a shorter CBZ regimen for CYP3A4 induction studies.