Cation/Anion Doping Strategy for Na4MnV(PO4)3 with High Energy Density and Long Cycling Life through Construction by Aspergillus niger.

Na4MnV(PO4)3 (NMVP) has gained attention for its high redox potential, good cycling stability, and competitive price but suffers from poor intrinsic electronic conductivity and Jahn-Teller effect from Mn3+. In this work, cation/anion doping strategy was used for Aspergillus niger-bioderived carbon-coated NMVP (NMVP/AN) to improve the structural stability and electrochemical performance, where Al3+ doping inhibited the dissolution of Mn and enhanced the Mn3+/Mn2+ redox pair activity; besides, F- doping not only weakens the Na2-O bond but also endows the hierarchical and porous structure of NMVP/AN, which led to a more rapid and fluid transfer of Na+. The elaborately designed Na3.9Mn0.9Al0.1V(PO4)3/AN (NMAVP/AN) exhibits 105.9 mA h g-1 at 0.5 C, and the as-prepared Na3.1MnV(PO3.7F0.3)3/AN (NMVPF/AN) delivers 104.1 mA h g-1 at 5 C. Further demonstration of the hard carbon//NMAVP/AN full cell manifests the good potential of Al3+-doped NMVP/AN for practical applications (100.6 mA h g-1 at 1 C). These findings open up the possibility of unlocking the high-performance Na superionic conductor (NASICON).

Exploring the impacts of producer services agglomeration on manufacturing carbon emissions: Empirical evidence from China.

This study employs panel data from 30 provinces and cities in China from 2004 to 2019 to empirically estimate the relationship between producer services agglomeration (PSA) and manufacturing carbon emissions. The findings suggest that such agglomeration is beneficial for lowering carbon emissions in manufacturing, and this conclusion passes multiple robustness tests. Heterogeneity analysis results show that PSA in the east and west regions significantly lowers manufacturing carbon emissions, while its impact in the central region is not significant. High-end PSA is beneficial for cutting carbon emissions in manufacturing, but the inhibitory effect of middle- and low-end PSA is not significant. PSA significantly suppresses carbon emissions from capital- and technology-intensive manufacturing, while it has little impact on carbon emissions from labor-intensive manufacturing. Further analysis reveals that PSA has a dual-threshold impact based on absorptive capacity and a single-threshold effect based on infrastructure level on manufacturing carbon emissions. As the absorption capacity crosses the second threshold or the infrastructure level crosses the first threshold, the inhibition effect of PSA on manufacturing carbon emissions begins to become prominent and shows a trend of enhancement. Our research findings provide theoretical and empirical bases for lowering carbon emissions in the manufacturing sector and fostering its ascent to the highest position of the value chain.

[Molecular study of a case with variant of RHCE*ce allele in haplotype dce resulting in weakened e antigen].

OBJECTIVE: To explore the Rh genotype for a female with RhD(-) blood type and its molecular basis. METHODS: A 26-year-old female who had attended the outpatient clinic of the First Affiliated Hospital of Zhengzhou University in August 2019 was selected as the study subject. Peripheral blood samples were collected from the proband and her parents for Rh phenotyping with gel card method. PCR-sequence-based typing (PCR-SBT) and DNA sequencing were used to determine the RHD zygosity and Rh genotype of the proband and her parents. Homology modeling of Rh proteins was performed with bioinformatic software, and protein structural alterations caused by the variant was simulated by molecular dynamics. RESULTS: Serological tests showed that the proband and her father both had weakened e antigen of the Rh phenotype. PCR-SBT and DNA sequencing showed that the genotypes of the proband and her parents were dce/dCE, dce/DcE and dCE/DcE, respectively. And the genotypes of the RHD and RHCE of the proband were RHD*01N.01/RHD*01N.16, RHCE*01.01/RHCE*04, respectively. Protein simulation and molecular dynamics analysis revealed that the ce_16C variant resulted from RHCE*ce (c.48G>C) may alter the structure of intracellular and extracellular loops, mainly affecting the mobility of extracellular loops 2, 6 and intracellular loops 3, 4. CONCLUSION: Variant of the RHCE*ce allele c.48G>C probably underlay the weakened e antigen in this proband.

High salt condition alters LPS synthesis and induces the emergence of drug resistance mutations in Helicobacter pylori.

The burgeoning emergence of drug-resistant Helicobacter pylori strains poses a significant challenge to the clinical success of eradication therapies and is primarily attributed to mutations within drug-targeting genes that lead to antibiotic resistance. This study investigated the effect of high salt conditions on the occurrence of drug-resistance mutations in H. pylori. We found that high salt condition significantly amplifies the frequency of drug resistance mutations in H. pylori. This can be chiefly attributed to our discovery indicating that high salt concentration results in elevated reactive oxygen species (ROS) levels, initiating DNA damage within H. pylori. Mechanistically, high salt condition suppresses lipopolysaccharide (LPS) synthesis gene expression, inducing alterations in the LPS structure and escalating outer membrane permeability. This disruption of LPS synthesis attenuates the expression and activity of SodB, facilitates increased ROS levels, and consequently increases the drug resistance mutation frequency. Impairing LPS synthesis engenders a reduction in intracellular iron levels, leading to diminished holo-Fur activity and increased apo-Fur activity, which represses the expression of SodB directly. Our findings suggest a correlation between high salt intake and the emergence of drug resistance in the human pathogen H. pylori, implying that dietary choices affect the risk of emergence of antimicrobial resistance.IMPORTANCEDrug resistance mutations mainly contribute to the emergence of clinical antibiotic-resistant Helicobacter pylori, a bacterium linked to stomach ulcers and cancer. In this study, we explored how elevated salt conditions influence the emergence of drug resistance in H. pylori. We demonstrate that H. pylori exhibits an increased antibiotic resistance mutation frequency when exposed to a high salt environment. We observed an increase in reactive oxygen species (ROS) under high salt conditions, which can cause DNA damage and potentially lead to mutations. Moreover, our results showed that high salt condition alters the bacterium's lipopolysaccharide (LPS) synthesis, leading to a reduced expression of SodB in a Fur-dependent manner. This reduction, in turn, elevates ROS levels, culminating in a higher frequency of drug-resistance mutations. Our research underscores the critical need to consider environmental influences, such as diet and lifestyle, in managing bacterial infections and combating the growing challenge of antibiotic resistance.

Inhibiting histone deacetylase 6 suppresses the proliferation of microvascular endothelial cells by epigenetically activating miR-375-3p, potentially contributing to bone loss during mechanical unloading.

BACKGROUND: Mechanical unloading-induced bone loss threatens prolonged spaceflight and human health. Recent studies have confirmed that osteoporosis is associated with a significant reduction in bone microvessels, but the relationship between them and the underlying mechanism under mechanical unloading are still unclear. METHODS: We established a 2D clinostat and hindlimb-unloaded (HLU) mouse model to simulate unloading in vitro and in vivo. Micro-CT scanning was performed to assess changes in the bone microstructure and mass of the tibia. The levels of CD31, Endomucin (EMCN) and histone deacetylase 6 (HDAC6) in tibial microvessels were detected by immunofluorescence (IF) staining. In addition, we established a coculture system of microvascular endothelial cells (MVECs) and osteoblasts, and qRT‒PCR or western blotting was used to detect RNA and protein expression; cell proliferation was detected by CCK‒8 and EdU assays. ChIP was used to detect whether HDAC6 binds to the miRNA promoter region. RESULTS: Bone mass and bone microvessels were simultaneously significantly reduced in HLU mice. Furthermore, MVECs effectively promoted the proliferation and differentiation of osteoblasts under coculture conditions in vitro. Mechanistically, we found that the HDAC6 content was significantly reduced in the bone microvessels of HLU mice and that HDAC6 inhibited the expression of miR-375-3p by reducing histone acetylation in the miR-375 promoter region in MVECs. miR-375-3p was upregulated under unloading and it could inhibit MVEC proliferation by directly targeting low-density lipoprotein-related receptor 5 (LRP5) expression. In addition, silencing HDAC6 promoted the miR-375-3p/LRP5 pathway to suppress MVEC proliferation under mechanical unloading, and regulation of HDAC6/miR-375-3p axis in MVECs could affect osteoblast proliferation under coculture conditions. CONCLUSION: Our study revealed that disuse-induced bone loss may be closely related to a reduction in the number of bone microvessels and that the modulation of MVEC function could improve bone loss induced by unloading. Mechanistically, the HDAC6/miR-375-3p/LRP5 pathway in MVECs might be a promising strategy for the clinical treatment of unloading-induced bone loss.

The chest CT perspective on sarcopenia: Exploring reference values for muscle mass quantity/quality and its application in old adults.

OBJECTIVE: To determine reference values for diagnosing sarcopenia through chest CT scans and evaluate their suitability for use among the Chinese old population. METHODS: Chest CT scans were obtained from 500 healthy individuals aged 19-39. Skeletal muscle mass was assessed on chest CT at the level of T4 by the skeletal muscle area (T4SMA), skeletal muscle index (T4SMI), T12 erector spinae muscle area (T12ESMA), and T12 skeletal muscle index (T12SMI), as well as skeletal muscle density (SMD) at T4 and T12 levels. The diagnostic threshold for sarcopenia was defined as a gender-specific value below 2 SD of the mean value in the young group. These cutoff values were then applied to a group of older adults aged 65 and over. RESULTS: Diagnostic thresholds for low skeletal muscle in men were 110.05 cm², 36.01 cm²/m², 29.56 cm², and 9.65 cm²/m² for T4SMA, T4SMI, T12ESMA, and T12SMI, respectively. For women, the thresholds were: 69.93 cm², 26.51 cm²/m², 17.84 cm²/m², and 6.87 cm²/m², respectively. Diagnostic thresholds for low SMD were 38.63HU in men, 34.74 HU for women at T4 level. At T12 level, the cutoff values were 40.94 HU for men and 36.63 HU for women. Sarcopenia prevalence in men, defined by T4SMA, T4SMI, T12ESMA, and T12SMI cutoffs, was 35.6%, 18.9%, 36.7%, and 23.7%, respectively. In women, sarcopenia prevalence was 5.1%, 3.2%, 3.2%, and 1.9%, respectively. CONCLUSION: This study established reference values for sarcopenia diagnosis through chest CT scans among the Chinese population, highlighting the importance of utilizing chest CT scans for sarcopenia detection and muscle health monitoring in older adults.

Prohibiting the electron-phonon coupling effect in tungsten trioxide nanosheet colloid with enhanced photocatalytic antibacterial capacity.

The serious combination of abundant electrons/holes in bulk primarily hinders the efficiency in the photocatalytic reaction. It is crucial to control the spatial charge dynamics through delicately designing the crystal configuration of photocatalyst. In this work, a modified tungsten trioxide nanosheet colloid (M-WO3) was synthesized by an ion exchange method. Compared to pristine WO3 (P-WO3), the crystal lattice vibration frequency of M-WO3 increases from 2.8 meV to 4.3 meV, which effectively prohibits electron-phonon coupling and powerfully accelerates the separation and transfer of photoinduced charge carriers. Irradiated by visible-light, M-WO3 shows much higher photocatalytic bacterial inactivation performance than P-WO3. In addition, this regulation method increases the surface charges of the WO3 colloid to improve its stability, which endows this colloid photocatalyst with broad prospects in practical photocatalytic antibacterial applications. This work offers guidance to construct efficiently separated photoinduced electron/hole pairs of the colloid photocatalyst by designing its crystal structure.

Natural Flavonoid-Derived Enzyme Mimics DHKNase Balance the Two-Edged Reactive Oxygen Species Function for Wound Healing and Inflammatory Bowel Disease Therapy.

Rational regulation of reactive oxygen species (ROS) plays a vital importance in maintaining homeostasis of living biological systems. For ROS-related pathologies, chemotherapy technology derived from metal nanomaterials currently occupies a pivotal position. However, they suffer from inherent issues such as complicated synthesis, batch-to-batch variability, high cost, and potential biological toxicity caused by metal elements. Here, we reported for the first time that dual-action 3,5-dihydroxy-1-ketonaphthalene-structured small-molecule enzyme imitator (DHKNase) exhibited 2-edged ROS regulation, catering to the execution of physiology-beneficial ROS destiny among diverse pathologies in living systems. Based on this, DHKNase is validated to enable remarkable therapeutic effects in 2 classic disease models, including the pathogen-infected wound-healing model and the dextran sulfate sodium (DSS)-caused inflammatory bowel disease (IBD). This work provides a guiding landmark for developing novel natural small-molecule enzyme imitator and significantly expands their application potential in the biomedical field.

Neoadjuvant Immunotherapy Alone for Patients With Locally Advanced and Resectable Metastatic Colorectal Cancer of dMMR/MSI-H Status.

BACKGROUND: The use of programmed death-1 blockade has a significant therapeutic effect in patients with Mismatch Repair-Deficient/Microsatellite Instability-High metastatic colorectal cancer. However, data on preoperative single-agent programmed death-1 blockade are rare. OBJECTIVE: This study aims to evaluate the effectiveness and safety of preoperative programmed death-1 blockade as a conversion strategy in patients with locally advanced and resectable metastatic Mismatch Repair-Deficient/Microsatellite Instability-High colorectal cancer. DESIGN: This is a retrospective observational study. SETTINGS: This study was conducted at a high-volume tertiary referral cancer center in China. PATIENTS: Twenty-four patients of consecutive cases since 2020-2022 with Mismatch Repair-Deficient/Microsatellite Instability-High colorectal cancer who received preoperative single-agent programmed death-1 blockade were retrospectively reviewed. These patients had either bulking tumor scheduled for multivisceral resection, a strong desire for organ preservation, or potentially resectable metastatic lesions. MAIN OUTCOME MEASURES: Pathological complete response, clinical complete response, toxicity, R0 resection rate, and complications were evaluated. RESULTS: Patients tolerated preoperative immunotherapy well. The R0 resection rate was 95.2% and the pathological complete response rate was 47.6%. Three patients (12.5%) were evaluated as clinical complete response and then underwent "watch and wait". One half of the cT4b patients were spared multivisceral resection, while 60% (3/5) achieved pathological complete response. All three patients with liver metastases obtained CR of all liver lesions after programmed death-1 blockade treatment. Grade III postoperative complications occurred in two patients. LIMITATIONS: The limitations of this study are as follows: retrospective study, small sample size, and short follow-up. CONCLUSIONS: Preoperative anti-programmed death-1 therapy alone as a conversion strategy in initially resected difficult dMMR/MSI-H colorectal cancer can achieve a high tumor complete response. The use of immuno-preoperative therapy in patients with T4b colon cancer or low rectal cancer can reduce multivisceral resection and achieve high organ function preservation. See Video Abstract.

Effort-reward imbalance and well-being among psychiatric nurses: the mediating role of burnout and decent work.

BACKGROUND: Psychiatric nurses face additional challenges due to negative perceptions, workplace violence, and a lack of respect, impacting their well-being and job satisfaction, which are crucial for improving psychiatric care and patient outcomes. OBJECTIVES: This study aims to examine the relationship between effort-reward imbalance, well-being, burnout, and decent work among psychiatric nurses. METHODS: This study used a cross-sectional design. Data were collected using a convenience sampling method in February 2024 from 397 psychiatric nurses at two psychiatric hospitals in Hangzhou and Huzhou, Zhejiang Province. The Effort-Reward Imbalance Scale, Decent Work Perception Scale, Maslach Burnout Inventory-General Survey, and General Well-Being Schedule Scale were used for data collection. Data analysis was conducted using SPSS 26.0 and the PROCESS macro. RESULTS: The study found that effort-reward imbalance among psychiatric nurses was negatively correlated with decent work (r = -0.564, p < 0.001) and well-being (r = -0.541, p < 0.001), and positively correlated with burnout (r = 0.603, p < 0.001). Burnout mediated the relationship between effort-reward imbalance and well-being (95% CI [-0.386, -0.257]), while decent work also served as a mediator (95% CI [-0.100, -0.012]). Additionally, burnout and decent work were found to mediate the relationship between effort-reward imbalance and well-being (95% CI [-0.050, -0.006]). CONCLUSION: This study highlights the impact of effort-reward imbalance on well-being, confirming that burnout and decent work serve as mediators. Enhancing support, fair compensation, reasonable work schedules, and professional development can promote psychiatric nurses' perception of decent work and improve their well-being.

Metabolomics combined with network pharmacology reveals the protective effect of astragaloside IV on alcoholic liver disease.

BACKGROUND: Alcoholic liver disease (ALD) is a significant contributor to liver damage. However, the clinical options for the treatment of ALD are limited. Astragaloside IV (AST-IV) is a saponin isolated from Astragalus membranaceus (AM). This study aimed to explore the underlying mechanisms of action of AST-IV in ALD by integrating metabolomics and network pharmacology. METHODS: Sprague-Dawley (SD) rats were used to establish a rat model of ALD. AST-IV and polyene phosphatidyl choline (PPC; a positive control drug) were administered to rats with ALD for 4 weeks. We measured the body weight, liver index, ALT, AST, TC, TG, inflammatory markers (IL-1ß, IL-6, and TNF-α), and oxidative stress markers (SOD, MDA) and used H&E and ORO staining to evaluate the hepatoprotective effect of both AST-IV and PPC on ALD. Subsequently, we performed untargeted metabolomics to predict the influence of AST-IV on lipid metabolism in rats with ALD. We then used a network pharmacology approach to identify the core targets through which AST-IV corrected lipid metabolism disorders and validated these targets through molecular docking, qRT-PCR and western blot analyses. Finally, we calculated the relationships between ALD-related biochemical markers, differential liver metabolites, and core targets using Spearman's correlation analysis. RESULTS: AST-IV improved pathological damage and reduced lipid accumulation in the hepatocytes of rats with ALD. Furthermore, AST-IV inhibited oxidative stress and inflammatory responses in rats with ALD. The metabolomic results showed that AST-IV corrected hepatic lipid metabolism disorders by targeting linoleic acid, necrosis, sphingolipid, and glycerophospholipid metabolism. The Network pharmacology analysis revealed that the core targets of AST-IV exerting the above effects were p-RIPK3, p-MLKL, CYP1A2, CYP2C19, PPARα, PCSK9. Spearman's correlation analysis showed a strong correlation between ALD-related serum biochemical indices, core targets, and liver differential metabolites. CONCLUSION: AST-IV corrects the metabolic disorders of linoleic acid, sphingolipid, and glycerophospholipid, and alleviates necrosis in rats with ALD through the core targets p-RIPK3, p-MLKL, CYP1A2, CYP2C19, PPARα, and PCSK9. This study is the first to reveal the mechanism of ALD protection through AST-IV from the perspective of metabolomics and network pharmacology. Therefore, a novel target has been identified to exert protection against ALD. This study provides a reference for ALD treatment.

Transcriptome Analysis Reveals the Effect of Oyster Mushroom Spherical Virus Infection in Pleurotus ostreatus.

Oyster mushroom spherical virus (OMSV) is a mycovirus that inhibits mycelial growth, induces malformation symptoms, and decreases the yield of fruiting bodies in Pleurotus ostreatus. However, the pathogenic mechanism of OMSV infection in P. ostreatus is poorly understood. In this study, RNA sequencing (RNA-seq) was conducted, identifying 354 differentially expressed genes (DEGs) in the mycelium of P. ostreatus during OMSV infection. Verifying the RNA-seq data through quantitative real-time polymerase chain reaction on 15 DEGs confirmed the consistency of gene expression trends. Both Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses highlighted the pivotal role of primary metabolic pathways in OMSV infection. Additionally, significant changes were noted in the gene expression levels of carbohydrate-active enzymes (CAZymes), which are crucial for providing the carbohydrates needed for fungal growth, development, and reproduction by degrading renewable lignocellulose. The activities of carboxymethyl cellulase, laccase, and amylase decreased, whereas chitinase activity increased, suggesting a potential mechanism by which OMSV influenced mycelial growth through modulating CAZyme activities. Therefore, this study provided insights into the pathogenic mechanisms triggered by OMSV in P. ostreatus.

Synergistic effect between sulfur vacancies and S-scheme heterojunctions in WO3/VS-Zn3In2S6 for enhanced photocatalytic CO2 reduction in H2O vapor.

Converting CO2 into CO, CH4, and other hydrocarbons using solar energy presents a viable approach for addressing energy shortages. In this study, photocatalysts with S-deficient WO3/Zn3In2S6 (WO3/VS-ZIS) S-scheme heterojunctions have been successfully synthesized. Under UV-vis light irradiation, 20 %WO3/VS-ZIS demonstrated significantly improved CO2 reduction activity and CH4 selectivity. Detailed characterization and density functional theory (DFT) calculations reveal that the enhanced performance is due to the synergistic optimization of the S-scheme heterojunction and sulfur vacancies (VS) for CO2 reduction. The presence of VS aids in the adsorption and activation of CO2 and enhances the separation of charge carriers. The 2D/2D S-scheme heterostructure assembled with WO3 nanosheets not only accelerates the migration and separation of photoexcited charge carriers but also improves the adsorption of H2O and the formation of VS, thereby increasing the adsorption and activation of CO2 and facilitating the protonation of CO* to produce CH4. This study clarifies the synergistic effect of VS and S-scheme heterostructures in improving photocatalytic performance, offering valuable insights into the photoactivation process of CO2 at VS in S-scheme heterojunctions.

Nobiletin protects against alcohol-induced mitochondrial dysfunction and liver injury by regulating the hepatic NRF1-TFAM signaling pathway.

OBJECTIVES: Alcohol and its metabolites, such as acetaldehyde, induced hepatic mitochondrial dysfunction play a pathological role in the development of alcohol-related liver disease (ALD). METHODS: In this study, we investigated the potential of nobiletin (NOB), a polymethoxylated flavone, to counter alcohol-induced mitochondrial dysfunction and liver injury. RESULTS: Our findings demonstrate that NOB administration markedly attenuated alcohol-induced hepatic steatosis, endoplasmic reticulum stress, inflammation, and tissue damage in mice. NOB reversed hepatic mitochondrial dysfunction and oxidative stress in both alcohol-fed mice and acetaldehyde-treated hepatocytes. Mechanistically, NOB restored the reduction of hepatic mitochondrial transcription factor A (TFAM) at both mRNA and protein levels. Notably, the protective effects of NOB against acetaldehyde-induced mitochondrial dysfunction and cell death were abolished in hepatocytes lacking Tfam. Furthermore, NOB administration reinstated the levels of hepatocellular NRF1, a key transcriptional regulator of TFAM, which were decreased by alcohol and acetaldehyde exposure. Consistent with these findings, hepatocyte-specific overexpression of Nrf1 protected against alcohol-induced hepatic Tfam reduction, mitochondrial dysfunction, oxidative stress, and liver injury. CONCLUSIONS: Our study elucidates the involvement of the NRF1-TFAM signaling pathway in the protective mechanism of NOB against chronic-plus-binge alcohol consumption-induced mitochondrial dysfunction and liver injury, suggesting NOB supplementation as a potential therapeutic strategy for ALD.

Understanding the Adsorption and Diffusion Behaviors of PBUT in Biocompatible MOFs.

With the increasing incidence of chronic kidney disease, the effective control of protein-bound uremic toxins (PBUTs), which are difficult to remove through dialysis, has become a priority. In this study, the adsorption and diffusion behaviors of several metal-organic frameworks (MOFs) for PBUTs (indoxyl sulfate and p-cresyl sulfate) were studied by molecular dynamics (MD) simulations and umbrella sampling. For the NU series of MOFs, good correlations between the Gibbs free energy (ΔG) and the experimental clearance rates of PBUTs are found. For the adsorption behaviors, in terms of ΔG, DAJWET exhibits the best adsorption effect for indoxyl sulfate (IS), whereas NU-1000 shows the best effect for p-cresyl sulfate (pCS). Similar trends observed in the radial distribution function and mean square displacement results suggest that the π-π stacking interactions play a crucial role in the adsorption and diffusion of PBUTs by MOFs. Furthermore, it can be concluded that MOFs with highly conjugated groups (porphyrin rings and pyrene groups) tend to generate more PBUT attraction, and provide design principles for potential MOF candidates in the removal of PBUTs.

Strain- and sex-specific differences in intestinal microhemodynamics and gut microbiota composition.

Background: Intestinal microcirculation is a critical interface for nutrient exchange and energy transfer, and is essential for maintaining physiological integrity. Our study aimed to elucidate the relationships among intestinal microhemodynamics, genetic background, sex, and microbial composition. Methods: To dissect the microhemodynamic landscape of the BALB/c, C57BL/6J, and KM mouse strains, laser Doppler flowmetry paired with wavelet transform analysis was utilized to determine the amplitude of characteristic oscillatory patterns. Microbial consortia were profiled using 16S rRNA gene sequencing. To augment our investigation, a broad-spectrum antibiotic regimen was administered to these strains to evaluate the impact of gut microbiota depletion on intestinal microhemodynamics. Immunohistochemical analyses were used to quantify platelet endothelial cell adhesion molecule-1 (PECAM-1), estrogen receptor α (ESR1), and estrogen receptor ß (ESR2) expression. Results: Our findings revealed strain-dependent and sex-related disparities in microhemodynamic profiles and characteristic oscillatory behaviors. Significant differences in the gut microbiota contingent upon sex and genetic lineage were observed, with correlational analyses indicating an influence of the microbiota on microhemodynamic parameters. Following antibiotic treatment, distinct changes in blood perfusion levels and velocities were observed, including a reduction in female C57BL/6J mice and a general decrease in perfusion velocity. Enhanced erythrocyte aggregation and modulated endothelial function post-antibiotic treatment indicated that a systemic response to microbiota depletion impacted cardiac amplitude. Immunohistochemical data revealed strain-specific and sex-specific PECAM-1 and ESR1 expression patterns that aligned with observed intestinal microhemodynamic changes. Conclusions: This study highlights the influence of both genetic and sex-specific factors on intestinal microhemodynamics and the gut microbiota in mice. These findings also emphasize a substantial correlation between intestinal microhemodynamics and the compositional dynamics of the gut bacterial community.

Cinobufagin inhibits M2­like tumor­associated macrophage polarization to attenuate the invasion and migration of lung cancer cells.

Macrophages have crucial roles in immune responses and tumor progression, exhibiting diverse phenotypes based on environmental cues. In the present study, the impact of cinobufagin (CB) on macrophage polarization and the consequences on tumor­associated behaviors were investigated. Morphological transformations of THP­1 cells into M0, M1 and M2 macrophages were observed, including distinct changes in the size, shape and adherence properties of these cells. CB treatment inhibited the viability of A549 and LLC cells in a concentration­dependent manner, with an IC50 of 28.8 and 30.12 ng/ml, respectively. CB at concentrations of <30 ng/ml had no impact on the viability of M0 macrophages and lung epithelial (BEAS­2B) cells. CB influenced the expression of macrophage surface markers, reducing CD206 positivity in M2 macrophages without affecting CD86 expression in M1 macrophages. CB also altered certain expression profiles at the mRNA level, notably downregulating macrophage receptor with collagenous structure (MARCO) expression in M2 macrophages and upregulating tumor necrosis factor­α and interleukin­1ß in both M0 and M1 macrophages. Furthermore, ELISA analyses revealed that CB increased the levels of pro­inflammatory cytokines in M1 macrophages and reduced the levels of anti­inflammatory factors in M2 macrophages. CB treatment also attenuated the migration and invasion capacities of A549 and LLC cells stimulated by M2 macrophage­conditioned medium. Additionally, CB modulated peroxisome proliferator­activated receptor γ (PPARγ) and MARCO expression in M2 macrophages and epithelial­mesenchymal transition in A549 cells, which was partially reversed by rosiglitazone, a PPARγ agonist. Finally, CB and cisplatin treatments hindered tumor growth in vivo, with distinct impacts on animal body weight and macrophage marker expression in tumor tissues. In conclusion, the results of the present study demonstrated that CB exerted complex regulatory effects on macrophage polarization and tumor progression, suggesting its potential as a modulator of the tumor microenvironment and a therapeutic for cancer treatment.

Effects of Traditional Chinese Medicine Acupoint Massage and Acupoint Application on Defecation Status and Quality of Life in Patients with Constipation and Psychogenic Drug-Induced Heat.

Background: Constipation is a prevalent adverse drug reaction during the treatment of mental illnesses. Traditional Chinese medicine boasts substantial expertise in addressing constipation. Objective: To investigate the impact of traditional Chinese medicine acupoint massage combined with acupoint application on the quality of life of patients experiencing solid heat constipation induced by psychogenic drugs. Design: This study employed a randomized controlled design. Setting: This study was conducted at the Seventh People's Hospital of Hangzhou. Participants: Between May 2019 and August 2020, 150 hospitalized patients from the Department of Psychiatry at the Seventh People's Hospital of Hangzhou, Zhejiang Province, were selected through convenience sampling. The clinical diagnosis type was intestinal solid fever. The patients were divided into three groups using a random number table method: observation group, intervention group 1, and intervention group 2, each consisting of 50 cases. Interventions: The observation group underwent acupoint massage combined with application treatment. Intervention group 1 received an acupoint massage. Intervention group 2 underwent Shenque acupoint application treatment. Primary Outcome Measures: (1) Defecation characteristics; (2) Defecation difficulty scores; and (3) Quality of life of patients. Results: The observation group exhibited superior improvement in Bristol constipation stool character and defecation difficulty compared to intervention group 1 and intervention group 2 (P < .05 and P < .01). In the quality-of-life assessment scale, the observation group outperformed intervention group 1 and intervention group 2 in physical, psychological, worry, and satisfaction aspects (P < .05 and P < .01). Conclusions: Traditional Chinese medicine acupoint massage combined with acupoint application demonstrates significant effects on constipation characteristics, defecation difficulties, and the overall quality of life of patients. These findings merit consideration for clinical application.

Neoadjuvant Immunotherapy for Patients With Microsatellite Instability-High or POLE-Mutated Locally Advanced Colorectal Cancer With Bulky Tumors: New Optimization Strategy.

OBJECTIVE: To evaluate the efficacy and safety of neoadjuvant immunotherapy for patients with microsatellite instability-high (MSI-H) or DNA polymerase ε (POLE)-mutated locally advanced colorectal cancer (LACRC) with bulky tumors.  PATIENTS: We retrospectively reviewed 22 consecutive patients with MSI-H or POLE-mutated LACRC with bulky tumors (>8 cm in diameter) who received preoperative programmed death-1 blockade, with or without CapOx chemotherapy.  MAIN OUTCOME MEASURES: Pathological complete response (pCR), clinical complete response (cCR), toxicity, R0 resection rate, and complications were evaluated. Survival outcomes were analyzed using the Kaplan-Meier method. Multiplex immunofluorescence analysis were performed before and after treatment.  RESULTS: The incidence of immune-related adverse events (irAEs) was 36.4% (8/22). Five of 22 patients presented with surgical emergencies, most commonly perforation or obstruction. The 22 patients underwent a median 4 (1-8) cycles. Two patients were evaluated as cCR and underwent a watch and wait strategy. The R0 resection rate was 100.0% (20/20) and pCR rate was 70.0% (14/20). Twelve of 14 cT4b patients (85.7%) avoided multivisceral resection, and 10 of them achieved pCR or cCR. In the two patients with POLE mutations, one each achieved pCR and cCR. No Grade III/IV postoperative complications occurred. The median follow-up was 16.0 months. Two-year event-free and overall survival for the whole cohort was both 100%.  CONCLUSIONS: Preoperative immunotherapy is the optimal option for MSI-H or POLE-mutated LACRC with bulky tumors, especially cT4b. Preoperative immunotherapy in patients with T4b CRC can reduce multivisceral resection and achieve high CR rate.

Clean air policy reduces the atherogenic lipid profile levels: Results from China Health Evaluation And risk Reduction through nationwide Teamwork (ChinaHEART) Study.

Evidence of the associations between long-term exposure to PM2.5 and O3 and human blood lipid concentrations is abundant yet inconclusive. Whether clean air policies could improve lipid profiles remains unclear. In total, 2979312 participants from a Chinese nationwide prospective study were included. For cross-sectional analyses, linear mixed-effects models were utilized to assess the associations of pollutants with lipid profiles (TC, LDL-C, TG, HDL-C). For longitudinal analyses, a quasi-experimental design and difference-in-differences models were employed to investigate the impact of China's Clean Air Act. In the cross-sectional analyses, each IQR increase in PM2.5 was associated with 2.49 % (95 % CI: 2.36 %, 2.62 %), 2.51 % (95 % CI: 2.26 %, 2.75 %), 3.94 % (95 % CI: 3.65 %, 4.23 %), and 1.54 % (95 % CI: 1.38 %, 1.70 %) increases in TC, LDL-C, TG, and HDL-C, respectively. For each IQR increase in O3, TC, LDL-C, TG, and HDL-C changed by 1.06 % (95 % CI: 0.95 %, 1.17 %), 1.21 % (95 % CI: 1.01 %, 1.42 %), 1.78 % (95 % CI: 1.54 %, 2.02 %), and -0.63 % (95 % CI: -0.76 %, -0.49 %), respectively. Longitudinal analyses showed that the intervention group experienced greater TC, LDL-C, and HDL-C reductions (1.77 %, 4.26 %, and 7.70 %, respectively). Our findings suggest that clean air policies could improve lipid metabolism and should be implemented in countries with heavy air pollution burdens.