A new method of alkalinity remediation for Cd-contaminated groundwater by PAAS-modified MgCO3/Mg(OH)2 colloid.

Mg(OH)2 dissolves slowly and can provide a long-term source of alkalinity, thus a promising alternative reagent for the in situ remediation of heavy metal polluted groundwater. Unfortunately, it exhibits a relatively poor stabilization effect on heavy metal Cd due to the higher solubility of the resulting stabilized product, Cd(OH)2. To overcome this limitation, we investigated the use of MgCO3/Mg(OH)2 colloid modified by sodium polyacrylate (PAAS) to remove Cd from groundwater. Through ultrasonic dispersion, the molecular chains of PAAS are broken, causing a transformation from flocculation to surface modification, resulting in the production of a stable colloid. The colloidal particles of MgCO3/Mg(OH)2 have a smaller size and a negatively charged surface, which significantly enhances their migration ability in aquifers. The combination of MgCO3 and Mg(OH)2 provides a complementary effect, where MgCO3 effectively precipitates Cd in the aquifer while Mg(OH)2 maintains the required pH level for stabilization. The optimal compounding ratio of MgCO3 to Mg(OH)2 for achieving the best stabilization effect on Cd is found to be 1:1. Column experiments demonstrate that the injection of MgCO3/Mg(OH)2 colloid substantially enhances Cd stability, reducing the exchangeable fraction of Cd in aquifer media from 88.61% to a range of 22.50-34.38%. Based on these results, the MgCO3/Mg(OH)2 colloid shows great potential as a reactive medium for remediating Cd-contaminated groundwater.

Dissipation and potential risk of tristyrylphenol ethoxylate homologs in peanuts by spraying and root irrigation: A comparative assessment.

Peanuts, known for their nutritional value, health benefits, and delicious taste, are susceptible to agricultural chemical contamination, posing a challenge to the peanut industry in China. While tristyrylphenol ethoxylates (TSPEOs) have garnered attention for their widespread use in pesticide formulations, their dissipation and potential risks in peanuts remain a gap in knowledge. This study, unique in its focus on TSPEOs, investigates their dissipation and potential risks under two common application modes: spraying and root irrigation. The concentration of total TSPEOs in peanut plants was significantly higher when sprayed (435-37,693 µg/kg) than in root irrigation (24-1602 µg/kg). The dissipation of TSPEOs was faster in peanuts and soil when sprayed, with half-lives of 3.67-5.59 d (mean: 4.37 d) and 5.41-7.07 d (mean: 5.95 d), respectively. The residue of TSPEOs in peanut shells and soil were higher with root irrigation (8.9-65.2 and 25.4-305.1 µg/kg, respectively) than with spraying (5.4-30.6 and 8.8-146.5 µg/kg, respectively). These results indicated that the dissipation behavior of TSPEOs in peanuts was influenced by application modes. While the healthy and ecological risk assessments of TSPEOs in soil and peanut shells showed no risks, root irrigation might pose a higher potential risk than spraying. This research provides valuable data for the judicious application of pesticides during peanut cultivation to enhance pesticide utilization and reduce potential risks.

Tumor-oriented and chemo-photothermal nanoplatform capable of sensitizing chemotherapy and ferroptosis against osteosarcoma metastasis.

The clinical use of chemotherapy for refractory osteosarcoma (OS) is limited due to its multiorgan toxicity. To overcome this challenge, new dosage forms and combination treatments, such as phototherapy, are being explored to improve targeted delivery and cytocompatibility of chemotherapeutic agents. In addition, inducing ferroptosis in iron-rich tumors could be a promising strategy to enhance OS therapy. In this study, a novel formulation was developed using natural biological H-ferritin (HFn) encapsulating the photosensitizer IR-780 and the chemotherapy drug gemcitabine (Gem) for OS-specific targeted therapy (HFn@Gem/IR-780 NPs). HFn@Gem/IR-780 NPs were designed to specifically bind and internalize into OS cells by interacting with transferrin receptor 1 (TfR1) which is overexpressed on the surface of OS cell membranes. The Gem and IR-780 were then released responsively under mildly acidic conditions in tumors. HFn@Gem/IR-780 NPs achieved cascaded antitumor therapeutic efficacy through the combination of chemotherapy and phototherapy under near-infrared irradiation in vitro and in vivo. Importantly, HFn@Gem/IR-780 NPs demonstrated excellent safety profile with significantly decreased drug exposure to normal organs, indicating its potential for reducing systemic toxicity. Thus, utilizing HFn as a vehicle to encapsulate highly effective antitumor drugs provides a promising approach for the treatment of OS metastasis and relapse.

Risk factors for suspected pulmonary embolism in children: Complication of Mycoplasma pneumoniae pneumonia.

PURPOSE: Pulmonary embolism (PE) is not a rare complication of Mycoplasma pneumoniae pneumonia (MPP) in children. We sought to determine the incidence of PE in children with MPP who underwent clinically indicated CT pulmonary angiography (CTPA) and to evaluate the risk factors for PE. METHODS: All 106 children with MPP who were clinically suspected of having PE and who underwent CTPA were retrospectively enrolled from June 2018 to December 2021. The clinical features, laboratory data, and radiological parameters were recorded (e.g., lung consolidation involved and the Qanadli score). A Cox proportional hazards model and area under the receiver operating characteristic (ROC) curve were used to evaluate the risk factors and prognostic discriminatory capacity for PE. RESULTS: PE was detected in 26 of 106 (24.5 %) children (mean age, 6.2 years ± 3.3 years; 53 boys). Sixteen of the 26 (61.5 %) children with PE were boys. The mean age of the children with PE was 8.1 ± 2.9 years, and the mean Qanadli score was 15.3 ± 10.2. Children with PE had higher D-dimer levels (9.3 ± 7.1 mg/Lvs. 3.6 ± 3.8 mg/L) and a greater frequency of lung lobe consolidation (25 (96.2 %) vs. 64 (80.0 %)) (all P < 0.05). For children with MPP, age (hazard ratio (HR) = 1.96 (95 % CI1.04, 3.71; P = 0.037), D-dimer level (HR = 1.52, 95 % CI: 1.03, 2.24; P = 0.029), and bilateral lung consolidation (HR = 2.41, 95 % CI: 1.03, 5.58; P = 0.043) were found to be independent predictors of PE. CONCLUSION: Clinical and CT radiological predictors could be used to predict PE in children with MPP. The use of risk factor assessment as a tool has the potential to guide more appropriate use of CTPA in children.

Accelerating ionizable lipid discovery for mRNA delivery using machine learning and combinatorial chemistry.

To unlock the full promise of messenger (mRNA) therapies, expanding the toolkit of lipid nanoparticles is paramount. However, a pivotal component of lipid nanoparticle development that remains a bottleneck is identifying new ionizable lipids. Here we describe an accelerated approach to discovering effective ionizable lipids for mRNA delivery that combines machine learning with advanced combinatorial chemistry tools. Starting from a simple four-component reaction platform, we create a chemically diverse library of 584 ionizable lipids. We screen the mRNA transfection potencies of lipid nanoparticles containing those lipids and use the data as a foundational dataset for training various machine learning models. We choose the best-performing model to probe an expansive virtual library of 40,000 lipids, synthesizing and experimentally evaluating the top 16 lipids flagged. We identify lipid 119-23, which outperforms established benchmark lipids in transfecting muscle and immune cells in several tissues. This approach facilitates the creation and evaluation of versatile ionizable lipid libraries, advancing the formulation of lipid nanoparticles for precise mRNA delivery.

Clonal expansion of shared T cell receptors reveals the existence of immune commonality among different lesions of synchronous multiple primary lung cancer.

The increase in the detection rate of synchronous multiple primary lung cancer (MPLC) has posed remarkable clinical challenges due to the limited understanding of its pathogenesis and molecular features. Here, comprehensive comparisons of genomic and immunologic features between MPLC and solitary lung cancer nodule (SN), as well as different lesions of the same patient, were performed. Compared with SN, MPLC displayed a lower rate of EGFR mutation but higher rates of BRAF, MAP2K1, and MTOR mutation, which function exactly in the upstream and downstream of the same signaling pathway. Considerable heterogeneity in T cell receptor (TCR) repertoire exists among not only different patients but also among different lesions of the same patient. Invasive lesions of MPLC exhibited significantly higher TCR diversity and lower TCR expansion than those of SN. Intriguingly, different lesions of the same patient always shared a certain proportion of TCR clonotypes. Significant clonal expansion could be observed in shared TCR clonotypes, particularly in those existing in all lesions of the same patient. In conclusion, this study provided evidences of the distinctive mutational landscape, activation of oncogenic signaling pathways, and TCR repertoire in MPLC as compared with SN. The significant clonal expansion of shared TCR clonotypes demonstrated the existence of immune commonality among different lesions of the same patient and shed new light on the individually tailored precision therapy for MPLC.

Comparison of condylar position after free fibular flap mandibular reconstruction using computer-assisted and traditional techniques.

OBJECTIVES: To compare the changes in condylar position after mandibular reconstruction with free fibular flap(FFF) and the differences between computer-assisted techniques and traditional methods on CT images. METHODS: Thirty-four patients who underwent mandibular reconstruction with free fibular flap were selected according to the inclusion and exclusion criteria. In the 3D group, virtual surgical planning (VSP) with osteotomy cutting plate and placement guiding plate were used, while the traditional group underwent freehand reconstruction. The CT data of 68 temporomandibular joints (TMJs) were recorded before and immediately after surgery. The condylar position was evaluated by measuring the anterior space (AS), posterior space (PS) and superior space (SS), and the ln (PS/AS) was calculated according to the method proposed by Pullinger and Hollender. RESULTS: In the patients included in the 3D group, the condyle on the ipsilateral side moved slightly backward; however, in the patients in the traditional group, the ipsilateral side moved considerably anteroinferior. No obvious changes on the contralateral side were noted. In the 3D group, 33% of ipsilateral condyles were in the posterior position postoperatively when compared with the preoperative position (13%). In the traditional group, the number of ipsilateral condyles in the anterior position increased from 4 to 10, accounting for 53% postoperatively. Contrary to the traditional group, the 3D group presented less condylar displacement on the ipsilateral side postoperatively. CONCLUSIONS: This study showed a decreased percentage of change in condylar position postoperatively when VSP was used. Virtual surgical planning improved the accuracy of FFF mandibular reconstruction and made the condylar position more stable.

Identification and virus-induced gene silencing (VIGS) analysis of methyltransferase affecting tomato (Solanum lycopersicum) fruit ripening.

MAIN CONCLUSION: Six methyltransferase genes affecting tomato fruit ripening were identified through genome-wide screening, VIGS assay, and expression pattern analysis. The data provide the basis for understanding new mechanisms of methyltransferases. Fruit ripening is a critical stage for the formation of edible quality and seed maturation, which is finely modulated by kinds of factors, including genetic regulators, hormones, external signals, etc. Methyltransferases (MTases), important genetic regulators, play vital roles in plant development through epigenetic regulation, post-translational modification, or other mechanisms. However, the regulatory functions of numerous MTases except DNA methylation in fruit ripening remain limited so far. Here, six MTases, which act on different types of substrates, were identified to affect tomato fruit ripening. First, 35 MTase genes with relatively high expression at breaker (Br) stage of tomato fruit were screened from the tomato MTase gene database encompassing 421 genes totally. Thereafter, six MTase genes were identified as potential regulators of fruit ripening via virus-induced gene silencing (VIGS), including four genes with a positive regulatory role and two genes with a negative regulatory role, respectively. The expression of these six MTase genes exhibited diverse patterns during the fruit ripening process, and responded to various external ripening-related factors, including ethylene, 1-methylcyclopropene (1-MCP), temperature, and light exposure. These results help to further elaborate the biological mechanisms of MTase genes in tomato fruit ripening and enrich the understanding of the regulatory mechanisms of fruit ripening involving MTases, despite of DNA MTases.

A tough, reversible and highly sensitive humidity actuator based on cellulose nanofiber films by intercalation modulated plasticization.

Cellulose nanofiber was an ideal candidate for humidity actuators based on its wide availability, biocompatibility and excellent hydrophilicity. However, conventional cellulose nanofiber-based actuators faced challenges like poor water resistance, flexibility, and sensitivity. Herein, water-resistant, flexible, and highly sensitive cross-linked cellulose nanofibers (CCNF) single-layer humidity actuators with remarkable reversible humidity responsiveness were prepared by combining the green click chemistry modification and intercalation modulated plasticization (IMP). The incorporation of phenyl ring and the crosslinked network structure in CCNF films contributed to its improved water resistance and mechanical properties (with a stress increased from 85.9 ± 3.1 MPa to 141.2 ± 21.5 MPa). SEM analysis confirmed enhanced interlaminar sliding properties facilitated by IMP. This resulted in increased flexibility and toughness of CCNF films, with a strain of 11.5 % and toughness of 9.9 MJ/m3. These improvements efficiently enhanced humidity sensitivity for cellulose nanofiber, with a 4.8-fold increase in bending curvature and a response time of only 3.4 ± 0.1 s. Finally, the good humidity sensitivity of modified CNF can be easily imparted to carbon nanotubes (CNTs) via simple self-assembly method, thus leading to a high-performance humidity-responsive actuator. The click chemistry modification and IMP offer a new avenue to fabricate tough, reversible and highly sensitive humidity actuator based on cellulose nanofiber.

Transcriptional patterns of human retinal pigment epithelial cells under protracted high glucose.

BACKGROUND: The retinal pigment epithelium (RPE) is essential for retinal homeostasis. Comprehensively exploring the transcriptional patterns of diabetic human RPE promotes the understanding of diabetic retinopathy (DR). METHODS AND RESULTS: A total of 4125 differentially expressed genes (DEGs) were screened out from the human primary RPE cells subjected to prolonged high glucose (HG). The subsequent bioinformatics analysis is divided into 3 steps. In Step 1, 21 genes were revealed by intersecting the enriched genes from the KEGG, WIKI, and Reactome databases. In Step 2, WGCNA was applied and intersected with the DEGs. Further intersection based on the enrichments with the GO biological processes, GO cellular components, and GO molecular functions databases screened out 12 candidate genes. In Step 3, 13 genes were found to be simultaneously up-regulated in the DEGs and a GEO dataset involving human diabetic retinal tissues. VEGFA and ERN1 were the 2 starred genes finally screened out by overlapping the 3 Steps. CONCLUSION: In this study, multiple genes were identified as crucial in the pathological process of RPE under protracted HG, providing potential candidates for future researches on DR. The current study highlights the importance of RPE in DR pathogenesis.

A novel near-infrared fluorescent probe for real-time monitoring of leucine aminopeptidase activity and metastatic tumor progression.

This article discusses the importance of early tumor detection, particularly in liver cancer, and the role of leucine aminopeptidase (LAP) as a potential marker for liver cancer diagnosis and prognosis assessment. The article highlights the limitations of current tumor markers and the need for new markers and multi-marker approaches to improve accuracy. The authors introduce a novel near-infrared fluorescent probe, NTAP, designed for LAP detection. They describe the synthesis of the probe and evaluate its spectral properties, including the LOD was 0.0038 U/mL, and QY was 0.32 %. The kinetic properties of NTAP, such as the relationship between LAP concentration (0-0.08 U/mL), reaction time (3 min), and fluorescence excitation spectra (475 nm) and emission spectra (715 nm) are investigated. The article also discusses the stability and selectivity of the probe and its ability to detect LAP in complex samples. Cellular imaging experiments demonstrate the NATP specificity and selectivity in detecting LAP activity and its inhibition. Animal models of liver and lung metastasis are used to evaluate the probe's imaging capabilities, showing its ability to accurately locate and detect metastatic lesions. The article concludes by emphasizing the potential applications of the NTAP probe in early tumor diagnosis, treatment monitoring, and the study of tumor metastasis mechanisms.

Bifidobacterium longum Subsp. infantis Promotes IgA Level of Growing Mice in a Strain-Specific and Intestinal Niche-Dependent Manner.

Throughout infancy, IgA is crucial for maintaining gut mucosal immunity. This study aims to determine whether supplementing newborn mice with eight different strains of Bifidobacterium longum subsp. infantis might regulate their IgA levels. The strains were gavaged to BALB/C female (n = 8) and male (n = 8) dams at 1-3 weeks old. Eight strains of B. longum subsp. infantis had strain-specific effects in the regulation of intestinal mucosal barriers. B6MNI, I4MI, and I10TI can increase the colonic IgA level in females and males. I8TI can increase the colonic IgA level in males. B6MNI was also able to significantly increase the colonic sIgA level in females. B6MNI, I4MI, I8TI, and I10TI regulated colonic and Peyer's patch IgA synthesis genes but had no significant effect on IgA synthesis pathway genes in the jejunum and ileum. Moreover, the variety of sIgA-coated bacteria in male mice was changed by I4MI, I5TI, I8TI, and B6MNI. These strains also can decrease the relative abundance of Escherichia coli. These results indicate that B. longum subsp. infantis can promote IgA levels but show strain specificity. Different dietary habits with different strains of Bifidobacterium may have varying effects on IgA levels when supplemented in early infancy.

ML365 ameliorates postoperative cognitive impairment in aged mice by inhibiting NLRP3 inflammasome activation in the hippocampus.

The aim of this study was to examine the effects of ML365, a two-pore potassium channel (K2P) inhibitor, on postoperative cognitive impairment (POCD). A mouse model of POCD was constructed by subjecting aged C57BL/6 mice to exploratory laparotomy. Changes in cognitive function were assessed using the Morris water maze test. Western blotting and qPCR were used to detect hippocampal NLRP3, Caspase-1 and IL-1ß expression levels on days 3 and 7 post-surgery. Apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) expression level was also assessed by western blotting. Pathological changes and nerve damage in the hippocampal CA1 and CA3 regions were detected by H&E staining, while the concentration of malondialdehyde (MDA) in the plasma was measured. We found that pretreatment with ML365 (administered intraperitoneally at a dose of 10 mg/kg) 30 min prior to exploratory laparotomy effectively ameliorated POCD in mice. ML365 pretreatment also reduced NLRP3, Caspase-1, ASC and IL-1ß expression levels in the hippocampus, improved POCD-induced pathological changes in the hippocampal CA1 and CA3 areas of aged mice, and decreased levels of plasma MDA and oxidative stress. Together, our findings indicate that ML365 can alleviate POCD in mice by inhibiting NLRP3 inflammasome activation in the hippocampus.

The correlation study between the length and angle of ascending aortic and the incidence risk of acute type A aortic dissection.

Objective: This study utilized computed tomography angiography (CTA) to assess the risk of acute type A aortic dissection (ATAAD) by analyzing the imaging morphology indicators of the ascending aorta, along with the relevant risk factors associated with aortic dissection. Methods: The study utilized a retrospective observational research design. The population consisted of 172 patients who received treatment in the Department of Cardiothoracic Surgery at Qilu Hospital, Shandong University, from January 2018 to December 2022. The patients were divided into two groups: the ATAAD group (n = 97) and the thoracic aortic aneurysm group (TAA, n = 75). Demographic data and ascending aorta CTA measurements were collected from all patients. Single factor and multivariate logistic regression were employed to analyze the statistical differences in clinical data and ascending aorta CTA imaging morphology indicators between the two groups. Results: The variables were included in logistic multivariate analysis for further screening, indicating that the length of the ascending aorta (LAA) before ATAAD (OR = 3.365; 95% CI :1.742-6.500, P<0.001), ascending arch angle (asc-arch angle, OR = 0.902; 95% CI: 0.816-0.996, P = 0.042) and the maximum aortic diameter (MAD) before ATAAD, (OR = 0.614; 95% CI: 0.507-0.743, P<0.001) showed statistically significant differences. Conclusions: This study suggests that increased LAA and MAD, as well as a smaller asc-arch angle may be high-risk factors for the onset of ATAAD.

Investigation on the Correlation between Biaxial Stretching Process and Macroscopic Properties of BOPA6 Film.

Biaxially oriented polyamide 6 (BOPA6) films were prepared by extrusion casting and biaxial stretching with polyamide 6. The effects of different biaxially oriented on the macroscopic properties of BOPA6 were investigated by characterizing the rheological, crystallization, optical, barrier and mechanical properties. The results show that the increase of stretching temperature leads to the diffusion and regular stacking rate of BOPA6 chain segments towards crystal nuclei increases, the relative crystallinity increases, reaching 27.87% at 180 °C, and the mechanical strength and optical performance decrease. Heat-induced crystallization promotes the transformation of ß-crystals to α-crystals in BOPA6, resulting in a more perfect crystalline structure and enhancing oxygen barrier properties. BOPA6 chains are oriented, and strain-induced crystallization (SIC) occurs during the biaxial stretching. Further increasing the stretch ratio, the relative crystallinity increased to 30.34%. The machine direction (MD) and transverse direction (TD) tensile strength of BOPA6 (B-33) are nearly two times higher than the unstretched film, reaching 134.33 MPa and 155.28 MPa, respectively. In addition, the permeation decreases to 57.61 cc·mil/(m2 day), and the oxygen barrier performance has improved by nearly 30% compared to the sample B-22. BOPA6 has a high storage modulus at a high stretching rate (300%/s). Rapid chain relaxation would promote the molecular chain disorientation, destroy the entangled network of the molecular chain, and lead to a decrease in tensile strength, reducing to about 110 MPa.

Novel Gain-of-Function Mutation in the Kv11.1 Channel Found in the Patient with Brugada Syndrome and Mild QTc Shortening.

Brugada syndrome (BrS) is an inherited disease characterized by right precordial ST-segment elevation in the right precordial leads on electrocardiograms (ECG), and high risk of life-threatening ventricular arrhythmia and sudden cardiac death (SCD). Mutations in the responsible genes have not been fully characterized in the BrS patients, except for the SCN5A gene. We identified a new genetic variant, c.1189C>T (p.R397C), in the KCNH2 gene in the asymptomatic male proband diagnosed with BrS and mild QTc shortening. We hypothesize that this variant could alter IKr-current and may be causative for the rare non-SCN5A-related form of BrS. To assess its pathogenicity, we performed patch-clamp analysis on IKr reconstituted with this KCNH2 mutation in the Chinese hamster ovary cells and compared the phenotype with the wild type. It appeared that the R397C mutation does not affect the IKr density, but facilitates activation, hampers inactivation of the hERG channels, and increases magnitude of the window current suggesting that the p.R397C is a gain-of-function mutation. In silico modeling demonstrated that this missense mutation potentially leads to the shortening of action potential in the heart.

Comparatively analysing the postoperative optical performance of different intraocular lenses: a prospective observational study.

BACKGROUND: Postoperative performance, including best corrected distance visual acuity (BCDVA) and optical metrics (from the OQAS and iTrace devices), was compared among 4 different intraocular lenses (IOLs). METHODS: This prospective observational study included 104 eyes from 104 subjects who underwent cataract surgery combined with implantation of 4 different IOLs: monofocal (Mon) IOLs, segmental refractive (SegRef) IOLs, diffractive (Dif) IOLs and extended depth of focus (EDoF) IOLs. Postoperative BCDVA and optical metrics were collected at the 6th month. The OQAS optical metrics included the objective scattering index (OSI), Strehl ratio (SR), modulation transfer function (MTF) cut-off frequency, and predicted visual acuity (PVA); the iTrace optical metrics included blur/double vision, glare/halo, starburst, mixed focus, night myopia, and night hyperopia. RESULTS: There was no significant difference in BCDVA among the 4 groups (P = 0.059; power = 70.3%). Differences were observed in all OQAS optical metrics among the groups (all P < 0.001). Overall, Mon IOLs and EDoF IOLs exhibited better performance than Dif IOLs and SegRef IOLs. Starburst was the only iTrace optical metric that differed among the groups (P < 0.001): SegRef IOLs caused more starbursts than Mon IOLs (P = 0.001), Dif IOLs (P = 0.006) and EDoF IOLs (P < 0.001). Spearman rank correlation analysis was used to determine the relationships among the iTrace optical metrics, OQAS optical metrics and BCDVA: starburst was negatively correlated with BCDVA, PVA at contrasts of 100% and 20%, OSI, and MTF cut-off frequency (all P ≤ 0.001); mixed focus was positively correlated with BCDVA, PVA at contrasts of 100% and 20%, OSI, and MTF cut-off frequency (all P ≤ 0.001). CONCLUSIONS: Postoperative BCDVA and optical metrics varied among the different IOLs, which should be taken into account in the selection and management of IOLs for cataract patients. TRIAL REGISTRATION: This study was approved by the First Affiliated Hospital of Guangzhou Medical University Ethical Review Board (No. 50 2022).

Fusobacterium nucleatum induces oxaliplatin resistance by inhibiting ferroptosis through E-cadherin/ß-catenin/GPX4 axis in colorectal cancer.

Fusobacterium (F.) nucleatum is a carcinogenesis microbiota in colorectal cancer (CRC). Growing evidence shows that F. nucleatum contributes to chemoresistance. Ferroptosis is reported to restore the susceptibility of resistant cells to chemotherapy. However, the role of gut microbiota affecting ferroptosis in chemoresistance remains unclear. Here, we examined the CRC tissues of patients using 16S rRNA sequencing to investigate the possible connection between gut microbiota dysbiosis and the relapse of CRC. We found that a high abundance of F. nucleatum in CRC tissue is associated with relapse. We further demonstrated that F. nucleatum induced oxaliplatin resistance in vitro and in vivo. The transcriptome of an F. nucleatum-infected cell revealed ferroptosis was associated with F. nucleatum infection. We perform malondialdehyde, ferrous iron, and glutathione assays to verify the effect of F. nucleatum on ferroptosis under oxaliplatin treatment in vivo and in vitro. Mechanistically, F. nucleatum promoted oxaliplatin resistance by overexpressing GPX4 and then inhibiting ferroptosis. E-cadherin/ß-catenin/TCF4 pathway conducted the GPX4 overexpression effect of F. nucleatum. The chromatin immuno-precipitation quantitative PCR (CHIP-qPCR) and dual-luciferase reporter assay showed that F. nucleatum promoted TCF4 binding with GPX4. We also determined the E-cadherin/ß-catenin/TCF4/GPX4 axis related to tumor tissue F. nucleatum status and CRC relapse clinically. Here, we revealed the contribution of F. nucleatum to oxaliplatin resistance by inhibiting ferroptosis in CRC. Targeting F. nucleatum and ferroptosis will provide valuable insight into chemoresistance management and may improve outcomes for patients with CRC.

A mutation in the cardiac KV7.1 channel possibly disrupts interaction with Yotiao protein.

Here, we characterized the p.Arg583His (R583H) Kv7.1 mutation, identified in two unrelated families suffered from LQT syndrome. This mutation is located in the HС-HD linker of the cytoplasmic portion of the Kv7.1 channel. This linker, together with HD helix are responsible for binding the A-kinase anchoring protein 9 (AKAP9), Yotiao. We studied the electrophysiological characteristics of the mutated channel expressed in CHO-K1 along with KCNE1 subunit and Yotiao protein, using the whole-cell patch-clamp technique. We found that R583H mutation, even at the heterozygous state, impedes IKs activation. Molecular modeling showed that HС and HD helixes of the C-terminal part of Kv7.1 channel are swapped along the C-terminus length of the channel and that R583 position is exposed to the outer surface of HC-HD tandem coiled-coil. Interestingly, the adenylate cyclase activator, forskolin had a smaller effect on the mutant channel comparing with the WT protein, suggesting that R583H mutation may disrupt the interaction of the channel with the adaptor protein Yotiao and, therefore, may impair phosphorylation of the KCNQ1 channel.

Smart Nanoassembly Enabling Activatable NIR Fluorescence and ROS Generation with Enhanced Tumor Penetration for Imaging-Guided Photodynamic Therapy.

Fluorescence imaging-guided photodynamic therapy (FIG-PDT) holds promise for cancer treatment, yet challenges persist in poor imaging quality, phototoxicity, and insufficient anti-tumor effect. Herein, a novel nanoplatform, LipoHPM, designed to address these challenges, is reported. This approach employs an acid-sensitive amine linker to connect a biotin-modified hydrophilic polymer (BiotinPEG) with a new hydrophobic photosensitizer (MBA), forming OFF-state BiotinPEG-MBA (PM) micelles via an aggregation-caused quenching (ACQ) effect. These micelles are then co-loaded with the tumor penetration enhancer hydralazine (HDZ) into pH-sensitive liposomes (LipoHPM). Leveraging the ACQ effect, LipoHPM is silent in both fluorescence and reactive oxygen species (ROS) generation during blood circulation but restores both properties upon disassembly. Following intravenous injection in tumor-bearing mice, LipoHPM actively targets tumor cells overexpressing biotin-receptors, contributing to enhanced tumor accumulation. Upon cellular internalization, LipoHPM disassembles within lysosomes, releasing HDZ to enhance tumor penetration and inhibit tumor metastasis. Concurrently, the micelles activate fluorescence for tumor imaging and boost the production of both type-I and type-II ROS for tumor eradication. Therefore, the smart LipoHPM synergistically integrates near-infrared emission, activatable tumor imaging, robust ROS generation, efficient anti-tumor and anti-metastasis activity, successfully overcoming limitations of conventional photosensitizers and establishing itself as a promising nanoplatform for potent FIG-PDT applications.