Optimized inhaled LNP formulation for enhanced treatment of idiopathic pulmonary fibrosis via mRNA-mediated antibody therapy.

Lipid nanoparticle-assisted mRNA inhalation therapy necessitates addressing challenges such as resistance to shear force damage, mucus penetration, cellular internalization, rapid lysosomal escape, and target protein expression. Here, we introduce the innovative "LOOP" platform with a four-step workflow to develop inhaled lipid nanoparticles specifically for pulmonary mRNA delivery. iLNP-HP08LOOP featuring a high helper lipid ratio, acidic dialysis buffer, and excipient-assisted nebulization buffer, demonstrates exceptional stability and enhanced mRNA expression in the lungs. By incorporating mRNA encoding IL-11 single chain fragment variable (scFv), scFv@iLNP-HP08LOOP effectively delivers and secretes IL-11 scFv to the lungs of male mice, significantly inhibiting fibrosis. This formulation surpasses both inhaled and intravenously injected IL-11 scFv in inhibiting fibroblast activation and extracellular matrix deposition. The HP08LOOP system is also compatible with commercially available ALC0315 LNPs. Thus, the "LOOP" method presents a powerful platform for developing inhaled mRNA nanotherapeutics with potential for treating various respiratory diseases, including idiopathic pulmonary fibrosis.

Gestational exposure to the great Chinese famine: early life undernutrition impact on prostatic hyperplasia in adulthood.

Introduction: Benign prostatic hyperplasia (BPH) is a frequent illness in aged men that impacts their quality of life; early childhood exposure to famines may have long-term effects on the chance of developing BPH. The aim of this study is to investigate the relationship between early-life famine exposure and benign prostatic hyperplasia (BPH) risk in Chinese men born during 1959-1961. Methods: We used medical records from a large, comprehensive hospital to screen people born in China during the years of famine (1959-1961). Birthplaces were identified as indicators of famine exposure status. In the time window between 2017 and 2022, people born during the famine years who had prostatic ultrasonic examinations were selected, and their medical records were retrieved from the database. Univariate and multivariate logistic regression analyses investigated the relationship between famine exposure and BPH risk. Results: A total of 3,009 subjects were included in this study. Patients with heavy famine exposure had older age, shorter height, lighter weight, lower cholesterol, lower uric acid (UA), lower aspartate aminotransferase (ALT), and a higher incidence of BPH than those with light famine exposure (all p < 0.05). Univariate logistic regression showed that BPH was positively related to famine exposure, age, height, weight, and body mass index (BMI) but negatively related to UA (all p < 0.05). Multivariate logistic regression showed that age and famine exposure were still independent risk factors (p < 0.05), while UA was an independent protective factor for BPH (p < 0.05). Heavy famine exposure increased the risk of BPH (adjusted OR = 1.214, 95% CI = 1.05-1.467, p = 0.045). Conclusions and recommendation: Famine and malnutrition exposure during early life may be independent risk factors for BPH in Chinese adults. This relationship provides additional evidence to support the fetal origins of adult diseases and offers clues for the pathological mechanisms of BPH.

Retrosynthesis prediction with an iterative string editing model.

Retrosynthesis is a crucial task in drug discovery and organic synthesis, where artificial intelligence (AI) is increasingly employed to expedite the process. However, existing approaches employ token-by-token decoding methods to translate target molecule strings into corresponding precursors, exhibiting unsatisfactory performance and limited diversity. As chemical reactions typically induce local molecular changes, reactants and products often overlap significantly. Inspired by this fact, we propose reframing single-step retrosynthesis prediction as a molecular string editing task, iteratively refining target molecule strings to generate precursor compounds. Our proposed approach involves a fragment-based generative editing model that uses explicit sequence editing operations. Additionally, we design an inference module with reposition sampling and sequence augmentation to enhance both prediction accuracy and diversity. Extensive experiments demonstrate that our model generates high-quality and diverse results, achieving superior performance with a promising top-1 accuracy of 60.8% on the standard benchmark dataset USPTO-50 K.

Investigating the Mechanism of Cadmium-Tolerant Bacterium Cellulosimicrobium and Ryegrass Combined Remediation of Cadmium-Contaminated Soil.

Cadmium (Cd) pollution has been rapidly increasing due to the global rise in industries. Cd not only harms the ecological environment but also endangers human health through the food chain and drinking water. Therefore, the remediation of Cd-polluted soil is an imminent issue. In this work, ryegrass and a strain of Cd-tolerant bacterium were used to investigate the impact of inoculated bacteria on the physiology and biochemistry of ryegrass and the Cd enrichment of ryegrass in soil contaminated with different concentrations of Cd (4 and 20 mg/kg). The results showed that chlorophyll content increased by 24.7% and 41.0%, while peroxidase activity decreased by 56.7% and 3.9%. In addition, ascorbic acid content increased by 16.7% and 6.3%, whereas glutathione content decreased by 54.2% and 6.9%. The total Cd concentration in ryegrass increased by 21.5% and 10.3%, and the soil's residual Cd decreased by 86.0% and 44.1%. Thus, the inoculation of Cd-tolerant bacteria can improve the antioxidant stress ability of ryegrass in Cd-contaminated soil and change the soil's Cd form. As a result, the Cd enrichment in under-ground and above-ground parts of ryegrass, as well as the biomass of ryegrass, is increased, and the ability of ryegrass to remediate Cd-contaminated soil is significantly improved.

Delivery of mRNA Encoding Interleukin-12 and a Stimulator of Interferon Genes Agonist Potentiates Antitumor Efficacy through Reversing T Cell Exhaustion.

T cell exhaustion has emerged as a major hurdle that impedes the clinical translation of stimulator of interferon genes (STING) agonists. It is crucial to explore innovative strategies to rejuvenate exhausted T cells and potentiate the antitumor efficacy. Here, we propose an approach utilizing MSA-2 as a STING agonist, along with nanoparticle-mediated delivery of mRNA encoding interleukin-12 (IL-12) to restore the function of T cells. We developed a lipid nanoparticle (DMT7-IL12 LNP) that encapsulated IL12 mRNA. Our findings convincingly demonstrated that the combination of MSA-2 and DMT7-IL12 LNP can effectively reverse the exhausted T cell phenotype, as evidenced by the enhanced secretion of cytokines, such as tumor necrosis factor alpha, interferon gamma, and Granzyme B, coupled with reduced levels of inhibitory molecules such as T cell immunoglobulin and mucin domain-3 and programmed cell death protein-1 on CD8+ T cells. Furthermore, this approach led to improved survival and tumor regression without causing any systemic toxicity in melanoma and lung metastasis models. These findings suggest that mRNA encoding IL-12 in conjunction with STING agonists has the potential to confer superior clinical outcomes, representing a promising advancement in cancer immunotherapy.

Predicting intraoperative blood loss during cesarean sections based on multi-modal information: a two-center study.

PURPOSE: To develop and validate a nomogram model that combines radiomics features, clinical factors, and coagulation function indexes (CFI) to predict intraoperative blood loss (IBL) during cesarean sections, and to explore its application in optimizing perioperative management and reducing maternal morbidity. METHODS: In this retrospective consecutive series study, a total of 346 patients who underwent magnetic resonance imaging (156 for training and 68 for internal test, center 1; 122 for external test, center 2) were included. IBL+ was defined as more than 1000 mL estimated blood loss during cesarean sections. The prediction models of IBL were developed based on machine-learning algorithms using CFI, radiomics features, and clinical factors. ROC analysis was performed to evaluate the performance for IBL diagnosis. RESULTS: The support vector machine model incorporating all three modalities achieved an AUC of 0.873 (95% CI 0.769-0.941) and a sensitivity of 1.000 (95% CI 0.846-1.000) in the internal test set, with an AUC of 0.806 (95% CI 0.725-0.872) and a sensitivity of 0.873 (95% CI 0.799-0.922) in the external test set. It was also scored significantly higher than the CFI model (P = 0.035) on the internal test set, and both the CFI (P = 0.002) and radiomics-CFI models (P = 0.007) on the external test set. Additionally, the nomogram constructed based on three modalities achieved an internal testing set AUC of 0.960 (95% CI 0.806-0.999) and an external testing set AUC of 0.869 (95% CI 0.684-0.967) in the pregnant population without a pernicious placenta previa. It is noteworthy that the AUC of the proposed model did not show a statistically significant improvement compared to the Clinical-CFI model in both internal (P = 0.115) and external test sets (P = 0.533). CONCLUSION: The proposed model demonstrated good performance in predicting intraoperative blood loss (IBL), exhibiting high sensitivity and robust generalizability, with potential applicability to other surgeries such as vaginal delivery and postpartum hysterectomy. However, the performance of the proposed model was not statistically significantly better than that of the Clinical-CFI model.

Exposure of pregnant women to neonicotinoids in Wenzhou City, East China: A biomonitoring study.

BACKGROUND: China produces and consumes a large amount of neonicotinoids. A non-negligible exposure to neonicotinoids might occur for Chinese pregnant women, but relevant data remain limited. OBJECTIVE: To investigate the exposure to neonicotinoids by urinary biomonitoring in pregnant women from Wenzhou City, East China. METHODS: We selected 432 pregnant women in Wenzhou City in 2022. A total of eight parent neonicotinoids and four metabolites were determined in single spot urine by liquid chromatography coupled to mass spectrometry. Basic characteristics, physical activity, pre-pregnant body mass index, and intake of drinking water and food were investigated by the questionnaire. Health risk was assessed by hazard quotient (HQ) and hazard index (HI) based on human safety thresholds derived from different health endpoints. RESULTS: Neonicotinoids and their metabolites in urine had a detection frequency between 0 % and 80.1 %. At least one neonicotinoid or metabolite was detected in 93.5 % of urine samples. Except for clothianidin (51.2 %) and N-desmethyl-acetamiprid (80.1 %), the detection frequencies of other neonicotinoids and metabolites ranged from 0 % to 43.8 %. The summed concentrations of all neonicotinoids and their metabolites ranged from < LOD to 222.83 µg/g creatinine with the median concentration of 2.58 µg/g creatinine. Maternal age, educational level, occupation, household income, screen time, and pre-pregnant body mass index were associated with detection frequencies or concentrations of neonicotinoids and their metabolites. Pregnant women with higher consumption frequencies of wheat, fresh vegetable, shellfish, fresh milk, and powdered milk had higher detection frequencies of neonicotinoids and their metabolites. Both HQ and HI were less than one. CONCLUSIONS: Overall, pregnant women in Wenzhou City showed a notable frequency of exposure to at least one neonicotinoid, although the exposure frequency for each specific neonicotinoid was generally low. Several food items derived from plants and animals were potential exposure sources. A low health risk was found based on current safety thresholds.

Adiponectin mRNA Conjugated with Lipid Nanoparticles Specifically Targets the Pathogenesis of Type 2 Diabetes.

Type 2 diabetes (T2D) is a widespread health condition both in the United States and around the world, with insulin resistance playing a critical role in its development. Effective treatment strategies are essential for managing T2D and mitigating associated risks. Adiponectin (APN), secreted by adipocytes, exhibits an inverse correlation with obesity-related adiposity, and its levels are negatively associated with insulin resistance and body mass index. This study aimed to enhance endogenous APN levels in a diet-induced obese (DIO) mouse model using lipid nanoparticles (LNP) as safe delivery agents for APN mRNA conjugates. The results indicate that APN-mRNA-LNP administration successfully induced APN synthesis in various tissues, including muscle, liver, kidney, pancreas, and adipose cells. This induction was associated with several positive outcomes, such as preventing diet-induced body weight gain, improving hyperglycemia by promoting Glut-4 expression, alleviating diabetic nephropathy symptoms by blocking the EGFR pathway, and reducing pro-inflammatory cytokine production. In addition, the treatment demonstrated enhanced insulin sensitivity by activating DGKd and inhibiting PKCε. This resulted in reactivation of insulin receptors in insulin target tissues and stimulation of insulin secretion from pancreatic beta cells. The findings of the present study highlight the potential of APN-mRNA-LNP-based nucleic acid therapy as a treatment for type 2 diabetes, offering a comprehensive approach to addressing its complexities.

Cardiometabolic and Metabolic Profiles of Lean/Normal, Overweight and Obese Patients with Nonalcoholic Fatty Liver Disease.

Purpose: Disagreements about the risk of non-obese, non-alcoholic fatty liver disease for cardiometabolic outcomes occurred widely. This study aims to characterize the cardiometabolic and metabolic profile of lean/normal, overweight and obese patients with nonalcoholic fatty liver disease on a big sample. Patients and methods: Appeared healthy adults who participated in health examinations during the year of 2019-2022 were screened for fatty liver diagnosis. BMI classified fatty livers as lean, overweight and obese. Eleven cardiometabolic metrics (SBP: systolic blood pressure; DBP: diastolic blood pressure; TC: total cholesterol; TG: triglycerides; HDL: high-density lipoprotein cholesterol; LDL: low-density lipoprotein cholesterol) and metabolic metrics (GLU: blood glucose; GHB: glycated haemoglobin; UA: uric acid; AST: aspartate aminotransferase; ALT: alanine aminotransferase) were included, described and compared among BMI categories. Results: There were 56,496 fatty livers diagnosed by ultrasound in this study. In total, the lean fatty liver had lowest mean SBP, DBP, GLU, TG, UA, AST, and ALT but highest TC and HDL among BMI categories (all p < 0.001). The number of abnormal metrics in total was 2.5, 2.9 and 3.4 in lean, overweight, and obesity, respectively (p < 0.001, p_trend < 0.001). Visualized data showed that lean fatty liver was similar but milder in all metabolic metrics than overweight and obesity at the young ages. However, lean fatty liver had higher coefficients of age and risk of metabolic abnormality regression (p <0.001 for SBP, DBP, GLU, GHB, TC). Conclusion: The lean type of fatty livers at a younger age has a relatively favourable cardiometabolic and metabolic profile compared to overweight and obese fatty livers. Due to the possible catch-up effect of metabolic dysfunctions in young lean fatty liver, lean fatty liver may have the same health outcomes as overweight/obesity fatty liver in long term. The evaluation and intervention may be critical for young lean fatty liver management to slowdown the rapid progress of metabolic dysfunction.

Association of maternal mineral status with the risk of preterm birth: a retrospective cohort study.

Background: There has been a gradual increase in the proportion of preterm birth in China during the past several decades. Maternal malnutrition is a significant determinant for preterm birth. Nevertheless, comprehensive studies investigating serum mineral levels during pregnancy associated with preterm birth remain scarce. This study aims to assess the associations between maternal serum mineral levels and the risk of preterm birth. Methods: This retrospective cohort study of 18,048 pregnant women used data from a tertiary hospital in China from January 2016 to December 2022. Demographic data and serum mineral concentrations in the second and third trimesters of mothers were collected from the hospital information system. Analysis was performed using restricted cubic splines and logistic regression models. Results: The proportion of preterm birth in this study was 6.01%. Phosphorus [P for overall = 0.005; P for nonlinear = 0.490; OR (95%CI) = 1.11 (1.04, 1.18)] and chlorine [P for overall = 0.002; P for nonlinear = 0.058; OR (95%CI) = 1.11 (1.03, 1.19)] showed a significant positive correlation with preterm birth in a linear fashion. Furthermore, serum levels of potassium (P for nonlinear <0.001), sodium (P for nonlinear = 0.004), and magnesium (P for nonlinear <0.001) exhibited non-linear relationships with the risk of preterm birth. Conclusion: Serum levels of some minerals during pregnancy were associated with the risk of preterm birth among pregnant women. In addition to commonly recognized micronutrients such as folic acid, iron, and vitamin D, healthcare providers should also pay attention to the levels of these minerals during pregnancy.

NudCL2 is required for cytokinesis by stabilizing RCC2 with Hsp90 at the midbody.

Cytokinesis is required for faithful division of cytoplasmic components and duplicated nuclei into two daughter cells. Midbody, a protein-dense organelle that forms at the intercellular bridge, is indispensable for successful cytokinesis. However, the regulatory mechanism of cytokinesis at the midbody still remains elusive. Here, we unveil a critical role for NudC-like protein 2 (NudCL2), a co-chaperone of heat shock protein 90 (Hsp90), in cytokinesis regulation by stabilizing regulator of chromosome condensation 2 (RCC2) at the midbody in mammalian cells. NudCL2 localizes at the midbody, and its downregulation results in cytokinesis failure, multinucleation and midbody disorganization. Using iTRAQ-based quantitative proteomic analysis, we find that RCC2 levels are decreased in NudCL2 knockout (KO) cells. Moreover, Hsp90 forms a complex with NudCL2 to stabilize RCC2, which is essential for cytokinesis. RCC2 depletion mirrors phenotypes observed in NudCL2-downregulated cells. Importantly, ectopic expression of RCC2 rescues the cytokinesis defects induced by NudCL2 deletion, but not vice versa. Together, our data reveal the significance of the NudCL2/Hsp90/RCC2 pathway in cytokinesis at the midbody.

Enhanced Sb(V) removal of sulfate-rich wastewater by anaerobic granular sludge assisted with Fe/C amendment.

Antimony (Sb) and sulfate are two common pollutants in Sb mine drainage and Sb-containing textile wastewater. In this paper, it was found that iron­carbon (Fe/C) enhanced Sb(V) removal from sulfate-rich wastewater by anaerobic granular sludge (AnGS). Sulfate inhibited Sb(V) removal (S + Sb, k = 0.101), while Fe/C alleviated the inhibition and increased Sb(V) removal rate by 2.3 times (Fe/C + S + Sb, k = 0.236). Fe/C could promote the removal of Sb(III), and Sb(III) content decreased significantly after 8 h. Meanwhile, Fe/C enhanced the removal of sulfate. The 3D-EEM spectrum of supernatant in Fe/C + S + Sb group (at 24 h) showed that Fe/C stimulated the production of soluble microbial products (SMP) in wastewater. SMP alleviated the inhibition of sulfate, promoting AnGS to reduce Sb(V). Sb(V) could be reduced to Sb(III) both by AnGS and sulfides produced from sulfate reduction. Further analysis of extracellular polymeric substances (EPS) and AnGS showed that Fe/C increased the adsorbed Sb(V) in EPS and the c-type cytochrome content in AnGS, which may be beneficial for Sb(V) removal. Sb(V) reduction in Fe/C + S + Sb group may be related to the genus Acinetobacter, while in Sb group, several bacteria may be involved in Sb(V) reduction, such as Acinetobacter, Pseudomonas and Corynebacterium. This study provided insights into Fe/C-enhanced Sb(V) removal from sulfate-rich wastewater.

All-Covalent Organic Framework Nanofilms Assembled Lithium-Ion Capacitor to Solve the Imbalanced Charge Storage Kinetics.

Free-standing covalent organic framework (COFs) nanofilms exhibit a remarkable ability to rapidly intercalate/de-intercalate Li+ in lithium-ion batteries, while simultaneously exposing affluent active sites in supercapacitors. The development of these nanofilms offers a promising solution to address the persistent challenge of imbalanced charge storage kinetics between battery-type anode and capacitor-type cathode in lithium-ion capacitors (LICs). Herein, for the first time, custom-made COFBTMB-TP and COFTAPB-BPY nanofilms are synthesized as the anode and cathode, respectively, for an all-COF nanofilm-structured LIC. The COFBTMB-TP nanofilm with strong electronegative-CF3 groups enables tuning the partial electron cloud density for Li+ migration to ensure the rapid anode kinetic process. The thickness-regulated cathodic COFTAPB-BPY nanofilm can fit the anodic COF nanofilm in the capacity. Due to the aligned 1D channel, 2D aromatic skeleton and accessible active sites of COF nanofilms, the whole COFTAPB-BPY//COFBTMB-TP LIC demonstrates a high energy density of 318 mWh cm-3 at a high-power density of 6 W cm-3, excellent rate capability, good cycle stability with the capacity retention rate of 77% after 5000-cycle. The COFTAPB-BPY//COFBTMB-TP LIC represents a new benchmark for currently reported film-type LICs and even film-type supercapacitors. After being comprehensively explored via ex situ XPS, 7Li solid-state NMR analyses, and DFT calculation, it is found that the COFBTMB-TP nanofilm facilitates the reversible conversion of semi-ionic to ionic C-F bonds during lithium storage. COFBTMB-TP exhibits a strong interaction with Li+ due to the C-F, C=O, and C-N bonds, facilitating Li+ desolation and absorption from the electrolyte. This work addresses the challenge of imbalanced charge storage kinetics and capacity between the anode and cathode and also pave the way for future miniaturized and wearable LIC devices.

Deep Learning Radiomic Analysis of MRI Combined with Clinical Characteristics Diagnoses Placenta Accreta Spectrum and its Subtypes.

BACKGROUND: Different placenta accreta spectrum (PAS) subtypes pose varying surgical risks to the parturient. Machine learning model has the potential to diagnose PAS disorder. PURPOSE: To develop a cascaded deep semantic-radiomic-clinical (DRC) model for diagnosing PAS and its subtypes based on T2-weighted MRI. STUDY TYPE: Retrospective. POPULATION: 361 pregnant women (mean age: 33.10 ± 4.37 years), suspected of PAS, divided into segment training cohort (N = 40), internal training cohort (N = 139), internal testing cohort (N = 60), and external testing cohort (N = 122). FIELD STRENGTH/SEQUENCE: Coronal T2-weighted sequence at 1.5 T and 3.0 T. ASSESSMENT: Clinical characteristics such as history of uterine surgery and the presence of placenta previa, complete placenta previa and dangerous placenta previa were extracted from clinical records. The DRC model (incorporating radiomics, deep semantic features, and clinical characteristics), a cumulative radiological score method performed by radiologists, and other models (including a radiomics and clinical, the clinical, radiomics and deep learning models) were developed for PAS disorder diagnosing (existence of PAS and its subtypes). STATISTICAL TESTS: AUC, ACC, Student's t-test, the Mann-Whitney U test, chi-squared test, dice coefficient, intraclass correlation coefficients, least absolute shrinkage and selection operator regression, receiver operating characteristic curve, calibration curve with the Hosmer-Lemeshow test, decision curve analysis, DeLong test, and McNemar test. P < 0.05 indicated a significant difference. RESULTS: In PAS diagnosis, the DRC-1 outperformed than other models (AUC = 0.850 and 0.841 in internal and external testing cohorts, respectively). In PAS subtype classification (abnormal adherent placenta and abnormal invasive placenta), DRC-2 model performed similarly with radiologists (P = 0.773 and 0.579 in the internal testing cohort and P = 0.429 and 0.874 in the external testing cohort, respectively). DATA CONCLUSION: The DRC model offers efficiency and high diagnostic sensitivity in diagnosis, aiding in surgical planning. LEVEL OF EVIDENCE: 3 TECHNICAL EFFICACY: Stage 2.

Nitrogen starvation modulates the sensitivity of rhizobacterial community to drought stress in Stevia rebaudiana.

Alterations in water regimes or nitrogen (N) availability lead to shifts in the assemblage of rhizosphere microbial community; however, how the rhizosphere microbiome response to concurrent changes in water and N availability remains largely unclear. Herein, we investigated the taxonomic and functional characteristics of rhizobacteria associated with stevia (Stevia rebaudiana Bertoni) under varying combinations of water and N levels. Community diversity and predicted functions of rhizobacteria were predominantly altered by drought stress, with N-starvation modulating these effects. Moreover, N fertilization simplified the ecological interactions within rhizobacterial communities and heightened the relative role of stochastic processes on community assembly. In terms of rhizobacterial composition, we observed both common and distinctive changes in drought-responsive bacterial taxa under different N conditions. Generally, the relative abundance of Proteobacteria and Bacteroidetes phyla were depleted by drought stress but the Actinobacteria phylum showed increases. The rhizobacterial responses to drought stress were influenced by N availability, where the positive response of δ-proteobacteria and the negative response of α- and γ-proteobacteria, along with Bacteroidetes, were further heightened under N starvation. By contrast, under N fertilization conditions, an amplified negative or positive response to drought were demonstrated in Firmicutes and Actinobacteria phyla, respectively. Further, the drought-responsive rhizobacteria were mostly phylogenetically similar, but this pattern was modulated under N-rich conditions. Overall, our findings indicate an N-dependent specific restructuring of rhizosphere bacteria under drought stress. These changes in the rhizosphere microbiome could contribute to enhancing plant stress tolerance.

The phase separation of extracellular matrix protein matrilin-3 from cancer-associated fibroblasts contributes to gastric cancer invasion.

Cancer-associated fibroblast (CAF) has emerged as a key contributor to the remodeling of tumor microenvironment through the expression and secretion of extracellular matrix (ECM) proteins, thereby promoting carcinogenesis. However, the precise contribution of ECM proteins from CAFs to gastric carcinogenesis remains poorly understood. In this study, we find that matrilin-3 (MATN3), an upregulated ECM protein associated with poorer prognosis in gastric cancer patients, originates from CAFs in gastric cancer tissues. Ectopic expression of MATN3 in CAFs significantly promotes the invasion of gastric cancer cells, which can be attenuated by neutralizing MATN3 with its antibody. Notably, a portion of MATN3 protein is found to form puncta in gastric cancer tissues ECM. MATN3 undergoes phase separation, which is mediated by its low complexity (LC) and coiled-coil (CC) domains. Moreover, overexpression of MATN3 deleted with either LC or CC in CAFs is unable to promote the invasion of gastric cancer cells, suggesting that LC or CC domain is required for the effect of CAF-secreted MATN3 in gastric cancer cell invasion. Additionally, orthotopic co-injection of gastric cancer cells and CAFs expressing MATN3, but not its ΔLC and ΔCC mutants, leads to enhanced gastric cancer cell invasion in mouse models. Collectively, our works suggest that MATN3 is secreted by CAFs and undergoes phase separation, which promotes gastric cancer invasion.

Inoculation of cadmium-tolerant bacteria to regulate microbial activity and key bacterial population in cadmium-contaminated soils during bioremediation.

The perennial ryegrass Lolium perenne can be used in conjunction with cadmium (Cd)-tolerant bacteria such as Cdq4-2 (Enterococcus spp.) for bioremediation of Cd-contaminated soil. In this study, a theoretical basis was provided to increase the efficiency of L. perenne remediation of Cd-contaminated soil using microorganisms to maintain the stability of the soil microbiome. The experimental design involved three treatment groups: CK (soil without Cd addition) as the control, 20 mg·kg-1 Cd-contaminated soil, and 20 mg·kg-1 Cd-contaminated soil + Cdq4-2, all planted with L. perenne. The soil was collected on day 60 to determine the soil microbial activity and bacterial community structure and to analyze the correlation between soil variables, the bacterial community, available Cd content in the soil, Cd accumulation, and L. perenne growth. The soil microbial activity and bacterial community diversity decreased under Cd stress, and the soil microbial community composition was changed; while inoculation with Cdq4-2 significantly increased soil basal respiration and the activities of urease, invertase, and fluorescein diacetate (FDA) hydrolase by 83.65%, 79.72%, 19.88%, and 96.15% respectively; and the stability of the community structure was also enhanced. The Actinobacteriota biomass, the amount of available Cd, and the above- and belowground Cd content of L. perenne were significantly negatively correlated with the total phosphorus, total potassium, and pH. The activity of urease, invertase, and FDA hydrolase were significantly positively correlated with the biomasses of Acidobacteriota and L. perenne and significantly negatively correlated with the Chloroflexi biomass. Further, the available soil Cd content and the above- and belowground Cd levels of L. perenne were significantly positively correlated with the Actinobacteriota biomass and significantly negatively correlated with the Gemmatimonadetes biomass. Overall, inoculating Cd-tolerant bacteria improved the microbial activity, diversity, and abundance, and changed the microbial community composition, facilitating the remediation of Cd-contaminated soil by L. perenne.

Targeted mRNA Nanoparticles Ameliorate Blood-Brain Barrier Disruption Postischemic Stroke by Modulating Microglia Polarization.

The ischemic stroke is a major global health concern, with high mortality and disability rates. Unfortunately, there is a dearth of effective clinical interventions for managing poststroke neuroinflammation and blood-brain barrier (BBB) disruption that are crucial for the brain injury evolving and neurological deficits. By leveraging the pathological progression of an ischemic stroke, we developed an M2 microglia-targeting lipid nanoparticle (termed MLNP) approach that can selectively deliver mRNA encoding phenotype-switching interleukin-10 (mIL-10) to the ischemic brain, creating a beneficial feedback loop that drives microglial polarization toward the protective M2 phenotypes and augments the homing of mIL-10-loaded MLNPs (mIL-10@MLNPs) to ischemic regions. In a transient middle cerebral artery occlusion (MCAO) mouse model of an ischemic stroke, our findings demonstrate that intravenously injected mIL-10@MLNPs induce IL-10 production and enhance the M2 polarization of microglia. The resulting positive loop reinforces the resolution of neuroinflammation, restores the impaired BBB, and prevents neuronal apoptosis after stroke. Using a permanent distal MCAO mouse model of an ischemic stroke, the neuroprotective effects of mIL-10@MLNPs have been further validated by the attenuation of the sensorimotor and cognitive neurological deficits. Furthermore, the developed mRNA-based targeted therapy has great potential to extend the therapeutic time window at least up to 72 h poststroke. This study depicts a simple and versatile LNP platform for selective delivery of mRNA therapeutics to cerebral lesions, showcasing a promising approach for addressing an ischemic stroke and associated brain conditions.

Bioelectrocatalytic reduction by integrating pyrite assisted manganese cobalt-doped carbon nanofiber anode and bacteria for sustainable antimony catalytic removal.

A novel manganese cobalt metal-organic framework based carbon nanofiber electrode (MnCo/CNF) was prepared and used as microbial fuel cell (MFC) anode. Pyrite was introduced into the anode chamber (MnCoPy_MFC). Synergistic function between pyrite and MnCo/CNF facilitated the pollutants removal and energy generation in MnCoPy_MFC. MnCoPy_MFC showed the highest chemical oxygen demand removal efficiency (82 ± 1%) and the highest coulombic efficiency (35 ± 1%). MnCoPy_MFC achieved both efficient electricity generation (maximum voltage: 658 mV; maximum power density: 3.2 W/m3) and total antimony (Sb) removal efficiency (99%). The application of MnCo/CNF significantly enhanced the biocatalytic efficiency of MnCoPy_MFC, attributed to its large surface area and abundant porous structure that provided ample attachment sites for electroactive microorganisms. This study revealed the synergistic interaction between pyrite and MnCo/CNF anode, which provided a new strategy for the application of composite anode MFC in heavy metal removal and energy recovery.

Exosomes Derived from Human Adipose Mesenchymal Stem Cells Inhibits Fibrosis and Treats Oral Submucous Fibrosis via the miR-181a-5p/Smad2 Axis.

BACKGROUND: Oral submucous fibrosis (OSF) is a chronic disease with carcinogenic tendency that poses a non-negligible threat to human health. Exosomes derived from human adipose mesenchymal stem cells (ADSC-Exo) reduces visceral and cutaneous fibroses, but their role in OSF has received little attention. The aim of this study was to investigate the effects of ADSC-Exo on OSF and elucidate the mechanism. METHODS: In brief, ADSCs were extracted from adipose tissues and subjected to flow cytometry and induction culture. Fibroblasts were isolated from human buccal mucosa and subjected to immunofluorescence. Myofibroblasts were obtained from fibroblasts induced by arecoline and identified. Immunofluorescence assay confirmed that myofibroblasts could take up ADSC-Exo. The effects of ADSC-Exo on the proliferative and migratory capacities of myofibroblasts were examined using the Cell Counting Kit-8 and scratch assay. Real-time quantitative polymerase chain reaction (qPCR) was performed to evaluate mothers against decapentaplegic homolog 2 (Smad2), Smad3, Smad7, collagen type 1 (Col1), Col3, alpha smooth muscle actin (α-SMA), fibronectin, and vimentin. Western blotting was performed to detect phospho (p)-Smad2, Smad2, p-Smad2/3, Smad2/3, Smad7, Col1, Col3, α-SMA, fibronectin, and vimentin. Furthermore, the dual-luciferase reporter assay was performed to prove that miR-181a-5p in ADSC-Exo directly inhibited the expression of Smad2 mRNA to regulate the transforming growth factor beta (TGF-ß) pathway. We also performed qPCR and western blotting to verify the results. RESULTS: ADSC-Exo could promote the proliferation and migration of myofibroblasts, reduce the expressions of p-smad2, Smad2, p-smad2/3, Smad2/3, Col1, αSMA, fibronectin, and vimentin and elevated the levels of Smad7 and Col3. In addition, miR-181a-5p was highly expressed in ADSC-Exo and bound to the 3'-untranslated region of Smad2. ADSC-Exo enriched with miR-181a-5p reduced collagen production in myofibroblasts and modulated the TGF-ß pathway. CONCLUSIONS: ADSC-Exo promoted the proliferative and migratory capacities of myofibroblasts and inhibited collagen deposition and trans-differentiation of myofibroblasts in vitro. miR-181a-5p in exosomes targets Smad2 to regulate the TGF-ß pathway in myofibroblasts. ADSC-Exo perform antifibrotic actions through the miR-181a-5p/Smad2 axis and may be a promising clinical treatment for OSF.