Short-peptide-based enteral nutrition affects rats MDP translocation and protects against gut-lung injury via the PepT1-NOD2-beclin-1 pathway in vivo.

BACKGROUND: Peptide transporter 1 (PepT1) transports bacterial oligopeptide products and induces inflammation of the bowel. Nutritional peptides compete for the binding of intestinal bacterial products to PepT1. We investigated the mechanism of short-peptide-based enteral nutrition (SPEN) on the damage to the gut caused by the bacterial oligopeptide product muramyl dipeptide (MDP), which is transported by PepT1. The gut-lung axis is a shared mucosal immune system, and immune responses and disorders can affect the gut-respiratory relationship. METHODS AND RESULTS: Sprague-Dawley rats were gavaged with solutions containing MDP, MDP + SPEN, MDP + intact-protein-based enteral nutrition (IPEN), glucose as a control, or glucose with GSK669 (a NOD2 antagonist). Inflammation, mitochondrial damage, autophagy, and apoptosis were explored to determine the role of the PepT1-nucleotide-binding oligomerization domain-containing protein 2 (NOD2)-beclin-1 signaling pathway in the small intestinal mucosa. MDP and proinflammatory factors of lung tissue were explored to determine that MDP can migrate to lung tissue and cause inflammation. Induction of proinflammatory cell accumulation and intestinal damage in MDP gavage rats was associated with increased NOD2 and Beclin-1 mRNA expression. IL-6 and TNF-α expression and apoptosis were increased, and mitochondrial damage was severe, as indicated by increased mtDNA in the MDP group compared with controls. MDP levels and expression of proinflammatory factors in lung tissue increased in the MDP group compared with the control group. SPEN, but not IPEN, eliminated these impacts. CONCLUSIONS: Gavage of MDP to rats resulted in damage to the gut-lung axis. SPEN reverses the adverse effects of MDP. The PepT1-NOD2-beclin-1 pathway plays a role in small intestinal inflammation, mitochondrial damage, autophagy, and apoptosis.

The Preparation of a Polyamidoxime-Phosphorylated Cellulose Nanofibrils Composite Aerogel for the Selective Extraction of Uranium from Seawater.

Uranium is the most important fuel for nuclear power operations, and the safe supply of its resources is the key to the development of nuclear power in China. Because of the complex seawater environment and extremely low uranium concentration, extracting uranium from natural seawater poses a significant challenge. In this study, a polyamidoxime-phosphorylated cellulose nanofibril composite aerogel was prepared as an adsorbent for uranium extraction from seawater. An adsorption kinetics test, equilibrium adsorption isotherm model fitting, an adsorption-desorption cycle test, and a selectivity test were carried out to evaluate the adsorption performance of the composite aerogel for uranium extraction. The adsorption capacities for the initial concentrations of 4 and 8 ppm in uranium-spiked pure water were 96.9 and 204.3 mg-U/g-Ads, respectively. The equilibrium uranium adsorption capacities of uranium-spiked simulated seawater were 38.9 and 51.7 mg-U/g-Ads, respectively. The distribution coefficient KD of uranium was calculated to be 2.5 × 107 mL/g. The results show that the polyamidoxime-phosphorylated cellulose nanofiber composite aerogels prepared in this study have the advantages of low cost and high uranium selectivity for uranium extraction from seawater.

Gut microbiota mediates anxiety-like behaviors induced by chronic infection of Toxoplasma gondii in mice.

BACKGROUND: Chronic infection with the neurotropic parasite Toxoplasma gondii (T. gondii) can cause anxiety and gut microbiota dysbiosis in hosts. However, the potential role of gut microbiota in anxiety induced by the parasite remains unclear. METHODS: C57BL/6J mice were infected with 10 cysts of T. gondii. Antibiotic depletion of gut microbiota and fecal microbiota transplantation experiments were utilized to investigate the causal relationship between gut microbiota and anxiety. Anxiety-like behaviors were examined by the elevated plus maze test and the open field test; blood, feces, colon and amygdala were collected to evaluate the profiles of serum endotoxin (Lipopolysaccharide, LPS) and serotonin (5-hydroxytryptamine, 5-HT), gut microbiota composition, metabolomics, global transcriptome and neuroinflammation in the amygdala. Furthermore, the effects of Diethyl butylmalonate (DBM, an inhibitor of mitochondrial succinate transporter, which causes the accumulation of endogenous succinate) on the disorders of the gut-brain axis were evaluated. RESULTS: Here, we found that T. gondii chronic infection induced anxiety-like behaviors and disturbed the composition of the gut microbiota in mice. In the amygdala, T. gondii infection triggered the microglial activation and neuroinflammation. In the colon, T. gondii infection caused the intestinal dyshomeostasis including elevated colonic inflammation, enhanced bacterial endotoxin translocation to blood and compromised intestinal barrier. In the serum, T. gondii infection increased the LPS levels and decreased the 5-HT levels. Interestingly, antibiotics ablation of gut microbiota alleviated the anxiety-like behaviors induced by T. gondii infection. More importantly, transplantation of the fecal microbiota from T. gondii-infected mice resulted in anxiety and the transcriptomic alteration in the amygdala of the antibiotic-pretreated mice. Notably, the decreased abundance of succinate-producing bacteria and the decreased production of succinate were observed in the feces of the T. gondii-infected mice. Moreover, DBM administration ameliorated the anxiety and gut barrier impairment induced by T. gondii infection. CONCLUSIONS: The present study uncovers a novel role of gut microbiota in mediating the anxiety-like behaviors induced by chronic T. gondii infection. Moreover, we show that DBM supplementation has a beneficial effect on anxiety. Overall, these findings provide new insights into the treatment of T. gondii-related mental disorders.

Cytogenetic identification and molecular mapping for the wheat-Thinopyrum ponticum introgression line with resistance to Fusarium head blight.

KEY MESSAGE: Xinong 511, a new wheat-Thinopyrum ponticum variety with excellent fusarium head blight resistance, the QTLs were mapped to the wheat chromosomes 5B and 7A with named QFhb.nwafu-5B and QFhb.nwafu-7A, respectively. Novel Fusarium head blight (FHB) resistance germplasms and genes are valuable for wheat improvement and breeding efforts. Thinopyrum ponticum, a wild relative of common wheat, is a valuable germplasm of disease resistance for wheat improvement and breeding. Xinong 511 (XN511) is a high-quality wheat variety widely cultivated in the Yellow and Huai Rivers Valley of China with stable FHB-resistance. Through analysis of pedigree materials of the wheat cultivar XN511, we found that the genetic material and FHB resistance from Th. ponticum were transmitted to the introgression line, indicating that the FHB resistance in XN511 likely originates from Th. ponticum. To further explore the genetic basis of FHB resistance in XN511, QTL mapping was conducted using the RILs population of XN511 and the susceptible line Aikang 58 (AK58). Survey with makers closely-linked to Fhb1, Fhb2, Fhb4, Fhb5, and Fhb7, indicated that both XN511 and the susceptible lines do not contain these QTL. Using bulked segregant analysis RNA-seq (BSR-Seq) and newly developed allele-specific PCR (AS-PCR) markers, QTLs in XN511 were successfully located on wheat chromosomes 5B and 7A. These findings are significant for further understanding and utilizing FHB resistance genes in wheat improvement.

An injectable adhesive hydrogel for photothermal ablation and antitumor immune activation against bacteria-associated oral squamous cell carcinoma.

Pathogenic bacteria are closely associated with the occurrence, development and metastasis of oral squamous cell carcinoma (OSCC). Antibacterial therapy has been considered an enhancement strategy to suppress bacteria-associated tumors and promote anti-tumor immune responses. Herein, we developed an injectable adhesive hydrogel, PNIPAM/DL@TIR, for the in situ photothermal ablation and robust stimulation of antitumor immunity against OSCC colonized by Porphyromonas gingivalis (Pg), one of the major oral pathogenic bacteria. PNIPAM/DL@TIR, composed of poly(N-isopropylacrylamide), demethylated lignin, and TAT peptide-conjugated IR820, was prepared using a simple dissolve-dry-swell solvent exchange method. Upon 808 nm laser irradiation, PNIPAM/DL@TIR exerted photothermal effects to ablate Pg-colonized OSCC and generate dual tumor and bacterial antigens. Owing to its large number of catechol groups, PNIPAM/DL@TIR efficiently captured these antigens to form an in situ antigen repository, thereby eliciting robust and durable antitumor immune responses. Proteomic analysis revealed that the captured antigens comprised both tumor neoantigens and bacterial antigens. The catechol groups endowed PNIPAM/DL@TIR with antioxidant activity, which was also conducive to stimulating antitumor immunity. Altogether, this study develops an injectable adhesive hydrogel and provides a combination strategy for treating bacteria-associated OSCC. STATEMENT OF SIGNIFICANCE: In this study, we developed an injectable adhesive hydrogel, PNIPAM/DL@TIR, for in situ photothermal ablation and robust stimulation of antitumor immunity against OSCC colonized by Porphyromonas gingivalis, one of the major oral pathogenic bacteria. PNIPAM/DL@TIR, which consists of poly(N-isopropylacrylamide), demethylated lignin, and TAT peptide-conjugated IR820 exhibited outstanding photothermal performance. Owing to the presence of catechol groups, PNIPAM/DL@TIR has good bioadhesive properties and can capture protein antigens to form in situ antigen repository, thus initiating robust and long-term antitumor immune responses. In addition, PNIPAM/DL@TIR exhibited strong antioxidant activity that is favorable for promoting antitumor immunity. In the mouse model of OSCC with bacterial infection, PNIPAM/DL@TIR not only ablated the primary tumors upon NIR laser irradiation, but also induced tumor and bacterial vaccination in situ to suppress distant tumors and lung metastasis.

Chlorogenic acid alleviates renal fibrosis by reducing lipid accumulation in diabetic kidney disease through suppressing the Notch1 and Stat3 signaling pathway.

AIMS: Abnormal renal lipid metabolism causes renal lipid deposition, which leads to the development of renal fibrosis in diabetic kidney disease (DKD). The aim of this study was to investigate the effect and mechanism of chlorogenic acid (CA) on reducing renal lipid accumulation and improving DKD renal fibrosis. METHODS: This study evaluated the effects of CA on renal fibrosis, lipid deposition and lipid metabolism by constructing in vitro and in vivo models of DKD, and detected the improvement of Notch1 and Stat3 signaling pathways. Molecular docking was used to predict the binding between CA and the extracellular domain NRR1 of Notch1 protein. RESULTS: In vitro studies have shown that CA decreased the expression of Fibronectin, α-smooth muscle actin (α-SMA), p-smad3/smad3, alleviated lipid deposition, promoted the expression of carnitine palmitoyl transferase 1 A (CPT1A), and inhibited the expression of cholesterol regulatory element binding protein 1c (SREBP1c). The expression of Notch1, Cleaved Notch1, Hes1, and p-stat3/stat3 were inhibited. These results suggested that CA might reduce intercellular lipid deposition in human kidney cells (HK2) by inhibiting Notch1 and stat3 signaling pathways, thereby improving fibrosis. Further, in vivo studies demonstrated that CA improved renal fibrosis and renal lipid deposition in DKD mice by inhibiting Notch1 and stat3 signaling pathways. Finally, molecular docking experiments showed that the binding energy of CA and NRR1 was -6.6 kcal/mol, which preliminarily predicted the possible action of CA on Notch1 extracellular domain NRR1. CONCLUSION: CA reduces renal lipid accumulation and improves DKD renal fibrosis by inhibiting Notch1 and stat3 signaling pathways.

Comparison of Objective Visual Quality Following SMILE and SmartPulse Technology-Assisted TransPRK at a 1,050-Hz Ablation Frequency for Moderate-to-High Myopia.

PURPOSE: To compare the objective visual quality of moderate-to-high myopia corrected by small incision lenticule extraction (SMILE) and transepithelial photorefractive keratectomy (TransPRK) at a 1,050-Hz ablation frequency, assisted by Smart-Pulse technology (SCHWIND eye-tech-solutions). METHODS: This study involved 123 patients (123 eyes) with moderate-to-high myopia between July 2020 and January 2021. They were categorized into the SMILE group (67 patients, 67 eyes) and the TransPRK group (56 patients, 56 eyes). Follow-ups were conducted at 6 months postoperatively to record the logarithm of the minimum angle of resolution visual acuity, and the Strehl ratio and higher order aberrations were measured using the Sirius anterior segment analysis device (SCHWIND eye-tech-solutions) under a 6-mm pupil diameter at various postoperative intervals. RESULTS: At 1 week and 1 month postoperatively, the uncorrected distance visual acuity (UDVA) in the SMILE group was superior to that in the TransPRK group (P < .05 for both). At 1 week and 1 month postoperatively, the Strehl ratio value in the SMILE group was higher than that in the TransPRK group (P < .05 for both). At 1, 3, and 6 months postoperatively, coma was greater in the SMILE group than in the TransPRK group (P < .05 for all). Spherical aberrations were lower in the SMILE group than in the TransPRK group at 3 and 6 months postoperatively (P < .05). At 6 months postoperatively, UDVA was -0.09 ± 0.08 and -0.11 ± 0.05 logMAR in the SMILE and TransPRK groups, respectively, which exceeded their preoperative corrected distance visual acuity of -0.05 ± 0.04 and -0.09 ± 0.08 logMAR (all P < .001). Compared with preoperative values, the Strehl ratio, total higher order, coma, and spherical aberration differences were significantly increased postoperatively in both groups (all P < .001). CONCLUSIONS: Both surgical methods improved UDVA and each had its advantages. The visual quality of SMILE was superior at 1 week and 1 month postoperatively (Strehl ratio values were higher than those of the TransPRK group), and its spherical aberration was lower than that of the TransPRK group at 3 and 6 months; TransPRK with SmartPulse technology with a 1,050-Hz ablation frequency showed that coma was significantly lower than that of the SMILE group at 1, 3, and 6 months postoperatively. [J Refract Surg. 2024;40(7):e490-e498.].

The Development of an Isotope Dilution Mass Spectrometry Method for Interleukin-6 Quantification.

Inflammatory responses and tumor developments are closely related, with interleukin-6 (IL-6) playing important roles in both processes. IL-6 has been extensively identified as a potential tumor biomarker. This study developed an isotope dilution mass spectrometry (IDMS) method for quantifying IL-6 based on signature peptides. These peptides were screened by excluding those with missed cleavage or post-translational modification. The method's accuracy was verified using amino acid-based IDMS, in which purified IL-6 protein samples were quantified after hydrolyzing them into amino acids, and no significant difference was observed (p-value < 0.05). The method demonstrated good linearity and sensitivity upon testing. The specificity and matrix effect of the method were verified, and a precision study showed that the coefficient of variation was less than 5% for both the intra-day and inter-day tests. Compared to immunoassays, this method offers distinct advantages, such as the facilitation of multi-target analysis. Furthermore, the peptides used in this study are much more convenient for storage and operation than the antibodies or purified proteins typically used in immunoassays.

The opposing effect of acute and chronic Toxoplasma gondii infection on tumor development.

BACKGROUND: The interplay between Toxoplasma gondii infection and tumor development is intriguing and not yet fully understood. Some studies showed that T. gondii reversed tumor immune suppression, while some reported the opposite, stating that T. gondii infection promoted tumor growth. METHODS: We created three mouse models to investigate the interplay between T. gondii and tumor. Model I aimed to study the effect of tumor growth on T. gondii infection by measuring cyst number and size. Models II and III were used to investigate the effect of different stages of T. gondii infection on tumor development via flow cytometry and bioluminescent imaging. Mouse strains (Kunming, BALB/c, and C57BL/6J) with varying susceptibilities to tumors were used in the study. RESULTS: The size and number of brain cysts in the tumor-infected group were significantly higher, indicating that tumor presence promotes T. gondii growth in the brain. Acute T. gondii infection, before or after tumor cell introduction, decreased tumor growth manifested by reduced bioluminescent signal and tumor size and weight. In the tumor microenvironment, CD4+ and CD8+ T cell number, including their subpopulations (cytotoxic CD8+ T cells and Th1 cells) had a time-dependent increase in the group with acute T. gondii infection compared with the group without infection. However, in the peripheral blood, the increase of T cells, including cytotoxic CD8+ T cells and Th1 cells, persisted 25 days after Lewis lung carcinoma (LLC) cell injection in the group with acute T. gondii. Chronic T. gondii infection enhanced tumor growth as reflected by increase in tumor size and weight. The LLC group with chronic T. gondii infection exhibited decreased percentages of cytotoxic CD8+ T cells and Th1 cells 25 days post-LLC injection as compared with the LLC group without T. gondii infection. At week 4 post-LLC injection, chronic T. gondii infection increased tumor formation rate [odds ratio (OR) 1.71] in both KM and BALB/c mice. CONCLUSIONS: Our research elucidates the dynamics between T. gondii infection and tumorigenesis. Tumor-induced immune suppression promoted T. gondii replication in the brain. Acute and chronic T. gondii infection had opposing effects on tumor development.

FUT11 expression in gastric cancer: its prognostic significance and role in immune regulation.

BACKGROUND: Gastric cancer (GC) is a malignant digestive tract tumor with a high recurrence rate and poor prognosis. Fucosylation is important in tumor glycosylation, in which the key enzyme is fucosyltransferase (FUT). FUT11 is a member of the fucosyltransferase family and has been closely associated with the development of multiple cancers. However, the specific relationship between FUT11 and GC prognosis and its molecular mechanism has not been fully studied. This study explored FUT11 expression, clinical correlation, and its role in GC occurrence and development to deepen understanding of its function. METHODS: FUT11 expression in 33 cancers was preliminarily analyzed using the Tumor Immunoassay Resource (TIMER2.0) database. FUT11 expression in GC was evaluated using The Cancer Genome Atlas stomach adenocarcinoma (TCGA-STAD) and Gene Expression Profiling Interactive Analysis (GEPIA2) data and verified using the Gene Expression Omnibus (GEO) GSE65801 dataset. Furthermore, we studied the survival prognosis of FUT11 in GC and analyzed its effect on the survival rate of patients with GC using the KM-plotter. We also performed COX regression analysis on TCGA GC clinical data and analyzed FUT11 expression in the pathway using the STRING and LinkedOmics databases. Moreover, the relationship between FUT11 and GC immune infiltration level was examined, and the Kaplan-Meier survival analysis diagram was constructed. The FUT11 genetic variation information was retrieved using cBioPortal, and its drug sensitivity was analyzed using CellMiner. Finally, differential FUT11 expression in GC tissues was verified using immunohistochemistry. RESULTS: The data mining and analysis demonstrated that FUT11 expression was abnormally elevated in GC tissues and correlated with poor patient prognosis. The FUT11 expression level was an independent prognostic factor for GC. The difference in FUT11 expression level resulted in different degrees of immune cell infiltration in the patients with GC, which might regulate the tumor microenvironment. FUT11 affected GC development by participating in cancer pathways such as PI3K-AKT, neuroactive ligand-receptor, and MAPK. Immunohistochemical staining revealed that FUT11 was highly expressed in GC. CONCLUSIONS: This study revealed that FUT11 expression is significantly increased in GC tissues. This increase is associated with poor prognosis and might affect immune regulation. FUT11 might have immunological and targeted therapeutic value, providing a new approach to GC treatment.

Electron Manipulation and Surface Reconstruction of Bimetallic Iron-Nickel Phosphide Nanotubes for Enhanced Alkaline Water Electrolysis.

Developing high-efficiency and stable bifunctional electrocatalysts for water splitting remains a great challenge. Herein, NiMoO4 nanowires as sacrificial templates to synthesize Mo-doped NiFe Prussian blue analogs are employed, which can be easily phosphorized to Mo-doped Fe2xNi2(1-x)P nanotubes (Mo-FeNiP NTs). This synthesis method enables the controlled etching of NiMoO4 nanowires that results in a unique hollow nanotube architecture. As a bifunctional catalyst, the Mo-FeNiP NTs present lower overpotential and Tafel slope of 151.3 (232.6) mV at 100 mA cm-2 and 76.2 (64.7) mV dec-1 for HER (OER), respectively. Additionally, it only requires an ultralow cell voltage of 1.47 V to achieve 10 mA cm-2 for overall water splitting and can steadily operate for 200 h at 100 mA cm-2. First-principles calculations demonstrate that Mo doping can effectively adjust the electron redistribution of the Ni hollow sites to optimize the hydrogen adsorption-free energy for HER. Besides, in situ Raman characterization reveals the dissolving of doped Mo can promote a rapid surface reconstruction on Mo-FeNiP NTs to dynamically stable (Fe)Ni-oxyhydroxide layers, serving as the actual active species for OER. The work proposes a rational approach addressed by electron manipulation and surface reconstruction of bimetallic phosphides to regulate both the HER and OER activity.

High-Pressure Induced Continuous Structural Evolution of Kagome Antiferromagnet MgMn3(OH)6Cl2: A Structural Analogue to Quantum Spin Liquid Herbertsmithite.

MgMn3(OH)6Cl2 serves readily as the classical Heisenberg kagome antiferromagnet lattice spin frustration material, due to its similarity to herbertsmithite in composition and crystal structure. In this work, nanosheets of MgMn3(OH)6Cl2 are synthesized through a solid-phase reaction. Low-temperature magnetic measurements revealed two antiferromagnetic transitions, occurring at ∼8 and 55 K, respectively. Utilizing high-pressure synchrotron radiation X-ray diffraction techniques, the topological structural evolution of MgMn3(OH)6Cl2 under pressures up to 24.8 GPa was investigated. The sample undergoes a second-order structural phase transition from the rhombohedral phase to the monoclinic phase at pressures exceeding 7.8 GPa. Accompanying the disappearance of the Fano-like line shape in the high-pressure Raman spectra were the emergence of new Raman active modes and discontinuities in the variations of Raman shifts in the high-frequency region. The phase transition to a structure with lower symmetry was attributed to the pressure-induced enhancement of cooperative Jahn-Teller distortion, which is caused by the mutual substitution of Mn2+ ions from the kagome layer and Mg2+ ions from the triangular interlayer. High-pressure ultraviolet-visible absorption measurements support the structural evolution. This research provides a robust experimental approach and physical insights for further exploration of classical geometrical frustration materials with kagome lattice.

MORN motif-containing protein OsMORN1 and OsMORN2 are crucial for rice pollen viability and cold tolerance.

The pollen viability directly affects the pollination process and the ultimate grain yield of rice. Here, we identified that the MORN motif-containing proteins, OsMORN1 and OsMORN2, had a crucial role in maintaining pollen fertility. Compared with the wild type (WT), the pollen viability of the osmorn1 and osmorn2 mutants was reduced, and pollen germination was abnormal, resulting in significantly lower spikelet fertility, seed-setting rate, and grain yield per plant. Further investigation revealed that OsMORN1 was localized to the Golgi apparatus and lipid droplets. Lipids associated with pollen viability underwent alterations in osmorn mutants, such as the diacylglyceride (18:3_18:3) was 5.1-fold higher and digalactosyldiacylglycerol (18:2_18:2) was 5.2-fold lower in osmorn1, while the triacylglycerol (TG) (16:0_18:2_18:3) was 8.3-fold higher and TG (16:0_18:1_18:3) was 8.5-fold lower in osmorn2 than those in WT. Furthermore, the OsMORN1/2 was found to be associated with rice cold tolerance, as osmorn1 and osmorn2 mutants were more sensitive to chilling stress than WT. The mutants displayed increased hydrogen peroxide accumulation, reduced antioxidant enzyme activities, elevated malondialdehyde content, and a significantly decreased seedling survival rate. Lipidomics analysis revealed distinct alterations in lipids under low temperature, highlighting significant changes in TG (18:2_18:3_18:3) and TG (18:4_18:2_18:2) in osmorn1, TG (16:0_18:2_18:2) and PI (17:2_18:3) in osmorn2 compared to the WT. Therefore, it suggested that OsMORN1 and OsMORN2 regulate both pollen viability and cold tolerance through maintaining lipid homeostasis.

Adipose stem cells-derived small extracellular vesicles transport Thrombospondin 1 cargo to promote insulin resistance in gestational diabetes mellitus.

BACKGROUND: Gestational diabetes mellitus (GDM) is a highly prevalent disease and poses a significant risk to the health of pregnant women. Abdominal adipose tissue (AT) contributes to insulin resistance (IR) associated with GDM. However, the underlying mechanisms remain unclear. METHODS: In this study, we developed a mouse model of GDM by subjecting mice to a high-fat diet. We collected adipose-derived stem cells (ADSCs) from the abdominal and inguinal regions and examined their role in inducing IR in normal tissues through the secretion of small extracellular vesicles (sEVs). The sEVs derived from ADSCs isolated from GDM mice (ADSC/GDM) were found to inhibit cell viability and insulin sensitivity in AML12, a normal mouse liver cell line. RESULTS: Through proteomic analysis, we identified high levels of the thrombospondin 1 (Thbs1) protein in the sEVs derived from ADSC/GDM. Subsequent overexpression of Thbs1 protein in AML12 cells demonstrated similar IR as observed with ADSC/GDM-derived sEVs. Mechanistically, the Thbs1 protein within the sEVs interacted with CD36 and transforming growth factor (Tgf) ß receptors in AML12 cells, leading to the activation of Tgfß/Smad2 signaling. Furthermore, the administration of LSKL, an antagonistic peptide targeting Thbs1, suppressed Thbs1 expression in ADSC/GDM-derived sEVs, thereby restoring insulin sensitivity in AML12 cells and GDM mice in vivo. CONCLUSIONS: These findings shed light on the intercellular transmission mechanism through which ADSCs influence hepatic insulin sensitivity and underscore the therapeutic potential of targeting the Thbs1 protein within sEVs.

The influence of social feedback on reward learning in the Iowa gambling task.

Learning, an important activity for both human and animals, has long been a focal point of research. During the learning process, subjects assimilate not only their own information but also information from others, a phenomenon known as social learning. While numerous studies have explored the impact of social feedback as a reward/punishment during learning, few studies have investigated whether social feedback facilitates or inhibits the learning of environmental rewards/punishments. This study aims to test the effects of social feedback on economic feedback and its cognitive processes by using the Iowa Gambling Task (IGT). One hundred ninety-two participants were recruited and categorized into one non-social feedback group and four social feedback groups. Participants in the social feedback groups were informed that after the outcome of each choice, they would also receive feedback from an online peer. This peer was a fictitious entity, with variations in identity (novice or expert) and feedback type (random or effective). The Outcome-Representation Learning model (ORL model) was used to quantify the cognitive components of learning. Behavioral results showed that both the identity of the peer and the type of feedback provided significantly influenced the deck selection, with effective social feedback increasing the ratio of chosen good decks. Results in the ORL model showed that the four social feedback groups exhibited lower learning rates for gain and loss compared to the nonsocial feedback group, which suggested, in the social feedback groups, the impact of the recent outcome on the update of value decreased. Parameters such as forgetfulness, win frequency, and deck perseverance in the expert-effective feedback group were significantly higher than those in the non-social feedback and expert-random feedback groups. These findings suggest that individuals proactively evaluate feedback providers and selectively adopt effective feedback to enhance learning.

Corrigendum to "Optical measurements of dissolved organic matter as proxies for CODMn and BOD5 in plateau lakes" [Environ. Sci. Ecotech. 19 (2024) 100326].

[This corrects the article DOI: 10.1016/j.ese.2023.100326.].

A Phase 1a Study to Evaluate Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of RO7303509, an Anti-TGFß3 Antibody, in Healthy Volunteers.

INTRODUCTION: Transforming growth factor beta (TGFß) cytokines (TGFß1, TGFß2, and TGFß3) play critical roles in tissue fibrosis. However, treatment with systemic pan-TGFß inhibitors have demonstrated unacceptable toxicities. In this study, we evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics of RO7303509, a high-affinity, TGFß3-specific, humanized immunoglobulin G1 monoclonal antibody, in healthy adult volunteers (HVs). METHODS: This phase 1a, randomized, double-blind trial included six cohorts for evaluation, with each cohort receiving single doses of placebo or RO7303509, administered intravenously (IV; 50 mg, 150 mg, 240 mg) or subcutaneously (SC; 240 mg, 675 mg, 1200 mg). The frequency and severity of adverse events (AEs) and RO7303509 serum concentrations were monitored throughout the study. We also measured serum periostin and cartilage oligomeric matrix protein (COMP) by immunoassay and developed a population pharmacokinetics model to characterize RO7303509 serum concentrations. RESULTS: The study enrolled 49 HVs, with a median age of 39 (range 18-73) years. Ten (27.8%) RO7303509-treated subjects reported 24 AEs, and six (30.8%) placebo-treated subjects reported six AEs. The most frequent AEs related to the study drug were injection site reactions and infusion-related reactions. Maximum serum concentrations (Cmax) and area under the concentration-time curve from time 0 to infinity (AUC0-inf) values for RO7303509 appeared to increase dose-proportionally across all doses tested. Serum concentrations across cohorts were best characterized by a two-compartment model plus a depot compartment with first-order SC absorption kinetics. No subjects tested positive for anti-drug antibodies (ADAs) at baseline; one subject (2.8%; 50 mg IV) tested positive for ADAs at a single time point (day 15). No clear pharmacodynamic effects were observed for periostin or COMP upon TGFß3 inhibition. CONCLUSION: RO7303509 was well tolerated at single SC doses up to 1200 mg in HVs with favorable pharmacokinetic data that appeared to increase dose-proportionally. TGFß3-specific inhibition may be suitable for development as a chronic antifibrotic therapy. TRIAL REGISTRATION: ISRCTN13175485.

Alterations in gut microbiota contribute to cognitive deficits induced by chronic infection of Toxoplasma gondii.

Chronic infection with Toxoplasma gondii (T. gondii) emerges as a risk factor for neurodegenerative diseases in animals and humans. However, the underlying mechanisms are largely unknown. We aimed to investigate whether gut microbiota and its metabolites play a role in T. gondii-induced cognitive deficits. We found that T. gondii infection induced cognitive deficits in mice, which was characterized by synaptic ultrastructure impairment and neuroinflammation in the hippocampus. Moreover, the infection led to gut microbiota dysbiosis, barrier integrity impairment, and inflammation in the colon. Interestingly, broad-spectrum antibiotic ablation of gut microbiota attenuated the adverse effects of the parasitic infection on the cognitive function in mice; cognitive deficits and hippocampal pathological changes were transferred from the infected mice to control mice by fecal microbiota transplantation. In addition, the abundance of butyrate-producing bacteria and the production of serum butyrate were decreased in infected mice. Interestingly, dietary supplementation of butyrate ameliorated T. gondii-induced cognitive impairment in mice. Notably, compared to the healthy controls, decreased butyrate production was observed in the serum of human subjects with high levels of anti-T. gondii IgG. Overall, this study demonstrates that gut microbiota is a key regulator of T. gondii-induced cognitive impairment.

IFIT1 modulates the proliferation, migration and invasion of pancreatic cancer cells via Wnt/ß-catenin signaling.

OBJECTIVES: Previously, Interferon-induced Protein with Tetratricopeptide Repeats 1 (IFIT1) has been shown to promote cancer development. Here, we aimed to explore the role of IFIT1 in the development and progression of pancreatic cancer, including the underlying mechanisms. METHODS: We explored IFIT1 expression in pancreatic cancer samples using The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) datasets. Cell Counting Kit-8 (CCK8), colony formation, scratch wound-healing and Transwell assays were performed to assess the proliferation, migration and invasion abilities of pancreatic cancer cells. Gene Set Enrichment Analysis (GSEA) and Western blotting were performed to assess the regulatory effect of IFIT1 on the Wnt/ß-catenin pathway. RESULTS: We found that upregulation of IFIT1 expression is common in pancreatic cancer and is negatively associated with overall patient survival. Knockdown of IFIT1 expression led to decreased proliferation, migration and invasion of pancreatic cancer cells. We also found that IFIT1 could regulate Wnt/ß-catenin signaling, and that a Wnt/ß-catenin agonist could reverse this effect. In addition, we found that IFIT1 can promote epithelial-mesenchymal transition (EMT) of pancreatic cancer cells. CONCLUSIONS: Our data indicate that IFIT1 increases pancreatic cancer cell proliferation, migration and invasion by activating the Wnt/ß-catenin pathway. In addition, we found that EMT could be regulated by IFIT1. IFIT1 may serve as a potential therapeutic target for pancreatic cancer.