Oncolytic Newcastle disease virus carrying the IL24 gene exerts antitumor effects by inhibiting tumor growth and vascular sprouting.

The second-leading cause of death, cancer, poses a significant threat to human life. Innovations in cancer therapies are crucial due to limitations in traditional approaches. Newcastle disease virus (NDV), a nonpathogenic oncolytic virus, exhibits multifunctional anticancer properties by selectively infecting, replicating, and eliminating tumor cells. To enhance NDV's antitumor activity, four oncolytic NDV viruses were developed, incorporating IL24 and/or GM-CSF genes at different gene loci using reverse genetics. In vitro experiments revealed that oncolytic NDV virus augmented the antitumor efficacy of the parental virus rClone30, inhibiting tumor cell proliferation, inducing tumor cell fusion, and promoting apoptosis. Moreover, NDV carrying the IL24 gene inhibited microvessel formation in CAM experiments. Evaluation in a mouse model of liver cancer confirmed the therapeutic efficacy of oncolytic NDV viral therapy. Tumors in mice treated with oncolytic NDV virus significantly decreased in size, accompanied by tumor cell detachment and apoptosis evident in pathological sections. Furthermore, oncolytic NDV virus enhanced T cell and dendritic cell production and substantially improved the survival rate of mice with hepatocellular carcinoma, with rClone30-IL24(P/M) demonstrating significant therapeutic effects. This study establishes a basis for utilizing oncolytic NDV virus as an antitumor agent in clinical practice.

Sensitivity-Enhancing Strategies of Graphene Field-Effect Transistor Biosensors for Biomarker Detection.

The ultrasensitive recognition of biomarkers plays a crucial role in the precise diagnosis of diseases. Graphene-based field-effect transistors (GFET) are considered the most promising devices among the next generation of biosensors. GFET biosensors possess distinct advantages, including label-free, ease of integration and operation, and the ability to directly detect biomarkers in liquid environments. This review summarized recent advances in GFET biosensors for biomarker detection, with a focus on interface functionalization. Various sensitivity-enhancing strategies have been overviewed for GFET biosensors, from the perspective of optimizing graphene synthesis and transfer methods, refinement of surface functionalization strategies for the channel layer and gate electrode, design of biorecognition elements and reduction of nonspecific adsorption. Further, this review extensively explores GFET biosensors functionalized with antibodies, aptamers, and enzymes. It delves into sensitivity-enhancing strategies employed in the detection of biomarkers for various diseases (such as cancer, cardiovascular diseases, neurodegenerative disorders, infectious viruses, etc.) along with their application in integrated microfluidic systems. Finally, the issues and challenges in strategies for the modulation of biosensing interfaces are faced by GFET biosensors in detecting biomarkers.

Prognosis of pediatric BCP-ALL with IKZF1 deletions and impact of intensive chemotherapy: Results of SCCLG-2016 study.

BACKGROUND: IKZF1 deletion (IKZF1del) is associated with poor prognosis in B-cell precursor acute lymphoblastic leukemia (BCP-ALL). But the prognosis of IKZF1del combined with other prognostic stratification factors remains unclear. Whether intensified treatment improves BCP-ALL prognosis has not been determined. METHODS: A retrospective analysis was performed on 1291 pediatric patients diagnosed with BCP-ALL and treated with the South China Children's Leukemia 2016 protocol. Patients were stratified based on IKZF1 status for comparison of characteristics and outcome. Additionally, IKZF1del patients were further divided based on chemotherapy intensity for outcome assessments. RESULTS: The BCP-ALL pediatric patients with IKZF1del in south China showed poorer early response. Notably, the DFS and OS for IKZF1del patients were markedly lower than IKZF1wt group (3-year DFS: 88.7% [95% CI: 83.4%-94.0%] vs. 93.5% [95% CI: 92.0%-94.9%], P = .021; 3-year OS: 90.7% [95% CI: 85.8% to 95.6%] vs. 96.1% [95% CI: 95% to 97.2%, P = .003]), with a concurrent increase in 3-year TRM (6.4% [95% CI: 2.3%-10.5%] vs. 2.9% [95% CI: 1.9%-3.8%], P = .025). However, the 3-year CIR was comparable between the two groups (5.7% [95% CI: 1.8%-9.5%] vs. 3.7% [95% CI: 2.6%-4.7%], P = .138). Subgroup analyses reveal no factor significantly influenced the prognosis of the IKZF1del cohort. Noteworthy, intensive chemotherapy improved DFS from 85.7% ± 4.1% to 94.1% ± 0.7% in IKZF1del group (P = .084). Particularly in BCR::ABL positive subgroup, the 3-year DFS was remarkably improved from 53.6% ± 20.1% with non-intensive chemotherapy to 100% with intensive chemotherapy (P = .026). CONCLUSIONS: Pediatric BCP-ALL patients with IKZF1del in South China manifest poor outcomes without independent prognostic significance. While no factor substantially alters the prognosis in the IKZF1del group. Intensified chemotherapy may reduce relapse rates and improve DFS in patients with IKZF1del subset, particularly in IKZFdel patients with BCR::ABL positive.

Therapeutic application of decellularized porcine small intestinal submucosa scaffold in conjunctiva reconstruction.

The objective of this study was to investigate the biological feasibility and surgical applicability of decellularized porcine small intestinal submucosa (DSIS) in conjunctiva reconstruction. A total of 52 Balb/c mice were included in the study. We obtained the DSIS by decellularization, evaluated the physical and biological properties of DSIS in vitro, and further evaluated the effect of surgical transplantation of DSIS scaffold in vivo. The histopathology and ultrastructural analysis results showed that the scaffold retained the integrity of the fibrous morphology while removing cells. Biomechanical analysis showed that the elongation at break of the DSIS (239.00 ± 12.51%) were better than that of natural mouse conjunctiva (170.70 ± 9.41%, P < 0.05). Moreover, in vivo experiments confirmed the excellent biocompatibility of the decellularized scaffolds. In the DSIS group, partial epithelialization occurred at day-3 after operation, and the conjunctival injury healed at day-7, which was significantly faster than that in human amniotic membrane (AM) and sham surgery (SHAM) group (P < 0.05). The number and distribution of goblet cells of transplanted DSIS were significantly better than those of the AM and SHAM groups. Consequently, the DSIS scaffold shows excellent biological characteristics and surgical applicability in the mouse conjunctival defect model, and DSIS is expected to be an alternative scaffold for conjunctival reconstruction.

Chip-Inspired Design of High-Performance Lithium-Sulfur Batteries by Integrating Monodisperse Sulfur Nanoreactors on Graphene.

For practical application of lithium-sulfur batteries (LSBs), designing devices with an overall optimal structure instead of modifying electrode materials is significant. Herein, we report a chip-inspired design of a vertically integrated structure as an LSB cathode by implanting Mo2C nanoparticles and nanosulfur into the reduced graphene oxide (rGO) matrix. This configuration enabled the synthesis of isolated sulfur nanoreactors (S-NRs) integrated in a tandem array on the rGO, generating chip-like integrated LSBs. The spatial confinement/protection and concentration gradient of the S-NRs effectively avoided the dissolution, diffusion, and loss of polysulfides, thereby enhancing the sulfur utilization and redox reaction kinetics. Additionally, the adaptive storage energy can be improved by utilizing the tandem, isolation, and synergistic multiplicative effect among the nanoreactor units. As a result, the integrated LSB cathode obtained excellent electrochemical performances with an initial capacity of 1392 mAh g-1 at 0.1C, a low capacity decay rate of 0.017% per cycle during 1500 cycles of operation at 0.5C, and a superior rate performance. This work provides a rational design idea and method of further advancing the precise preparation of high-performance energy storage devices.

Stir-fried Semen Armeniacae Amarum Suppresses Aristolochic Acid I-Induced Nephrotoxicity and DNA Adducts.

OBJECTIVE: To investigate the protective effects of stir-fried Semen Armeniacae Amarum (SAA) against aristolochic acid I (AAI)-induced nephrotoxicity and DNA adducts and elucidate the underlying mechanism involved for ensuring the safe use of Asari Radix et Rhizoma. METHODS: In vitro, HEK293T cells overexpressing Flag-tagged multidrug resistance-associated protein 3 (MRP3) were constructed by Lentiviral transduction, and inhibitory effect of top 10 common pairs of medicinal herbs with Asari Radix et Rhizoma in clinic on MRP3 activity was verified using a self-constructed fluorescence screening system. The mRNA, protein expressions, and enzyme activity levels of NAD(P)H quinone dehydrogenase 1 (NQO1) and cytochrome P450 1A2 (CYP1A2) were measured in differentiated HepaRG cells. Hepatocyte toxicity after inhibition of AAI metabolite transport was detected using cell counting kit-8 assay. In vivo, C57BL/6 mice were randomly divided into 5 groups according to a random number table, including: control (1% sodium bicarbonate), AAI (10 mg/kg), stir-fried SAA (1.75 g/kg) and AAI + stir-fried SAA (1.75 and 8.75 g/kg) groups, 6 mice in each group. After 7 days of continuous gavage administration, liver and kidney damages were assessed, and the protein expressions and enzyme activity of liver metabolic enzymes NQO1 and CYP1A2 were determined simultaneously. RESULTS: In vivo, combination of 1.75 g/kg SAA and 10 mg/kg AAI suppressed AAI-induced nephrotoxicity and reduced dA-ALI formation by 26.7%, and these detoxification effects in a dose-dependent manner (P<0.01). Mechanistically, SAA inhibited MRP3 transport in vitro, downregulated NQO1 expression in vivo, increased CYP1A2 expression and enzymatic activity in vitro and in vivo, respectively (P<0.05 or P<0.01). Notably, SAA also reduced AAI-induced hepatotoxicity throughout the detoxification process, as indicated by a 41.3% reduction in the number of liver adducts (P<0.01). CONCLUSIONS: Stir-fried SAA is a novel drug candidate for the suppression of AAI-induced liver and kidney damages. The protective mechanism may be closely related to the regulation of transporters and metabolic enzymes.

Dietary glycine supplementation enhances syntheses of creatine and glutathione by tissues of hybrid striped bass (Morone saxatilis ♀ × Morone chrysops ♂) fed soybean meal-based diets.

BACKGROUND: We recently reported that supplementing glycine to soybean meal-based diets is necessary for the optimum growth of 5- to 40-g (Phase-I) and 110- to 240-g (Phase-II) hybrid striped bass (HSB), as well as their intestinal health. Although glycine serves as an essential substrate for syntheses of creatine and glutathione (GSH) in mammals (e.g., pigs), little is known about these metabolic pathways or their nutritional regulation in fish. This study tested the hypothesis that glycine supplementation enhances the activities of creatine- and GSH-forming enzymes as well as creatine and GSH availabilities in tissues of hybrid striped bass (HSB; Morone saxatilis♀ × Morone chrysops♂). METHODS: Phase-I and Phase-II HSB were fed a soybean meal-based diet supplemented with 0%, 1%, or 2% glycine for 8 weeks. At the end of the 56-d feeding, tissues (liver, intestine, skeletal muscle, kidneys, and pancreas) were collected for biochemical analyses. RESULTS: In contrast to terrestrial mammals and birds, creatine synthesis occurred primarily in skeletal muscle from all HSB. The liver was most active in GSH synthesis among the HSB tissues studied. In Phase-I HSB, supplementation with 1% or 2% glycine increased (P < 0.05) concentrations of intramuscular creatine (15%-19%) and hepatic GSH (8%-11%), while reducing (P < 0.05) hepatic GSH sulfide (GSSG)/GSH ratios by 14%-15%, compared with the 0-glycine group; there were no differences (P > 0.05) in these variables between the 1% and 2% glycine groups. In Phase-II HSB, supplementation with 1% and 2% glycine increased (P < 0.05) concentrations of creatine and GSH in the muscle (15%-27%) and liver (11%-20%) in a dose-dependent manner, with reduced ratios of hepatic GSSG/GSH in the 1% or 2% glycine group. In all HSB, supplementation with 1% and 2% glycine dose-dependently increased (P < 0.05) activities of intramuscular arginine:glycine amidinotransferase (22%-41%) and hepatic γ-glutamylcysteine synthetase (17%-37%), with elevated activities of intramuscular guanidinoacetate methyltransferase and hepatic GSH synthetase and GSH reductase in the 1% or 2% glycine group. Glycine supplementation also increased (P < 0.05) concentrations of creatine and activities of its synthetic enzymes in tail kidneys and pancreas, and concentrations of GSH and activities of its synthetic enzymes in the proximal intestine. CONCLUSIONS: Skeletal muscle and liver are the major organs for creatine and GSH syntheses in HSB, respectively. Dietary glycine intake regulates creatine and GSH syntheses by both Phase-I and Phase-II HSB in a tissue-specific manner. Based on the metabolic data, glycine is a conditionally essential amino acid for the growing fish.

Artificial intelligence-based tools with automated segmentation and measurement on CT images to assist accurate and fast diagnosis in acute pancreatitis.

PURPOSE: To develop an artificial intelligence (AI) tool with automated pancreas segmentation and measurement of pancreatic morphological information on CT images to assist improved and faster diagnosis in acute pancreatitis. METHODS: This study retrospectively contained 1124 patients suspected for AP and received non-contrast and enhanced abdominal CT examination between September 2013 to September 2022. Patients were divided into training (N = 688), validation (N = 145), testing dataset (N = 291, N = 104 for normal pancreas, N = 98 for AP, N = 89 for AP complicated with PDAC (AP&PDAC)). A model based on convolutional neural network (MSAnet) was developed. The pancreas segmentation and measurement were performed via eight open-source models and MSAnet based tools, and the efficacy was evaluated using Dice similarity coefficient (DSC) and Intersection over union (IoU). The DSC and IoU for patients with different ages were also compared. The outline of tumor and edema in the AP and were segmented by clustering. The diagnostic efficacy for radiologists with or without the assistance of MSAnet tool in AP and AP&PDAC was evaluated using receiver operation curve and confusion matrix. RESULTS: Among all models, MSAnet based tool showed best performance on the training and validation dataset, and had high efficacy on testing dataset. The performance was age-affected. With assistance of the AI tool, the diagnosis time was significantly shortened by 26.8% and 32.7% for junior and senior radiologists, respectively. The area under curve in diagnosis of AP was improved from 0.91 to 0.96 for junior radiologist and 0.98 to 0.99 for senior radiologist. In AP&PDAC diagnosis, AUC was increased from 0.85 to 0.92 for junior and 0.97 to 0.99 for senior. CONCLUSION: MSAnet based tools showed good pancreas segmentation and measurement performance, which help radiologists improve diagnosis efficacy and workflow in both AP and AP with PDAC conditions. ADVANCES IN KNOWLEDGE: This study developed an AI tool with automated pancreas segmentation and measurement and provided evidence for AI tool assistance in improving the workflow and accuracy of AP diagnosis.

Probiotic-derived amphiphilic exopolysaccharide self-assembling adjuvant delivery platform for enhancing immune responses.

Enhancing immune response activation through the synergy of effective antigen delivery and immune enhancement using natural, biodegradable materials with immune-adjuvant capabilities is challenging. Here, we present NAPSL.p that can activate the Toll-like receptor 4 (TLR4) pathway, an amphiphilic exopolysaccharide, as a potential self-assembly adjuvant delivery platform. Its molecular structure and unique properties exhibited remarkable self-assembly, forming a homogeneous nanovaccine with ovalbumin (OVA) as the model antigen. When used as an adjuvant, NAPSL.p significantly increased OVA uptake by dendritic cells. In vivo imaging revealed prolonged pharmacokinetics of NAPSL. p-delivered OVA compared to OVA alone. Notably, NAPSL.p induced elevated levels of specific serum IgG and isotype titers, enhancing rejection of B16-OVA melanoma xenografts in vaccinated mice. Additionally, NAPSL.p formulation improved therapeutic effects, inhibiting tumor growth, and increasing animal survival rates. The nanovaccine elicited CD4+ and CD8+ T cell-based immune responses, demonstrating the potential for melanoma prevention. Furthermore, NAPSL.p-based vaccination showed stronger protective effects against influenza compared to Al (OH)3 adjuvant. Our findings suggest NAPSL.p as a promising, natural self-adjuvanting delivery platform to enhance vaccine design across applications.

Modulating Valence Electrons and Na Occupancy in Layered Cathodes for High-Performance Na-Ion Batteries.

Na-ion batteries (NIBs) hold promise as a leading option for large-scale energy storage. However, their development faces challenges due to the lack of high-performance cathode materials. P2-type layered oxides are seen as potential cathode materials for NIBs due to higher structure stability, yet their commercialization is hindered by limited capacity and subpar phase transitions during Na extraction and insertion at high voltages. In this study, we introduce a new P2-type cathode material, Na0.76Ni0.23Li0.1Ti0.02Mn0.65O1.998F0.02 (NLTMOF), synthesized with ternary Li/Ti/F substitution. This modification of ternary Li/Ti/F substitution significantly tailors the electronic structures, increasing the number of valence electrons near the Fermi energy level. This facilitates the electronic conductivity and their involvement in charge compensation, thereby enhancing reversible capacity. Additionally, ternary doping synergistically adjusts the Na occupancy at the Na layer for favorable Na extraction without P2-O2 phase transitions even under a high voltage of 4.4 V, boosting cycling stability. As a result, NLTMOF demonstrates a reversible capacity of 110.0 and 132.2 mAh g-1 at 2-4.2 and 2-4.4 V, respectively, and maintains greatly enhanced cycling stability over long cycles. This study sheds light on the design of transition metal oxides for advanced cathode materials through the modulation of electronic structure and Na occupancy in cathode materials, thus promoting the development of NIBs.

Extension of interval between adjacent pulse delivery cycles to deal with myocardial ischemia by intravascular lithotripsy: case report.

BACKGROUND: Intravascular lithotripsy (IVL) represents a novel approach in the management of coronary calcification. This technique employs acoustic pressure waves, generated by a shockwave balloon, to effectively fracture both superficial and deep calcification in situ. The efficacy and safety of IVL have been convincingly demonstrated through the Disrupt CAD I-IV studies. While IVL is associated with the occurrence of atrial and ventricular arrhythmias, there is no evidence to indicate it causes myocardial ischemia. CASE DESCRIPTION: A 71-year-old man was admitted presenting with chest pain. His previous coronary angiography revealed stenosis and calcification in the left anterior descending branch. An attempt to predilate the lesion using two Lacrosse non-slip element balloons was unsuccessful. Ventricular premature beats and transient ST-segment depression were captured during the utilization of IVL. The operator gradually extended the pulse emission interval across two consecutive cycles to mitigate myocardial ischemia. Notably, when the interval reached 30s, the patient had no chest pain or ST-segment changes. Subsequent images of intravascular ultrasound confirmed calcification ruptures. Therapeutic intervention included the placement of a stent and the application of a drug-coated balloon in the left anterior descending branch. A telephonic follow-up six months later indicated the patient had no discomfort. CONCLUSIONS: This case underscores the effectiveness of gradually extending the pulse emission interval as a strategic complement to the clinical application of IVL. In certain clinical scenarios, it may become imperative to suspend the pulse delivery to improve myocardial blood supply.

Enhanced biodegradation of phenol under Cr(VI) stress by microbial collaboration and potential application of machine learning for phenol biodegradation.

Cr(VI) and phenol commonly coexist in wastewater, posing a great threat to the environment and human health. However, it is still a challenge for microorganisms to degrade phenol under high Cr(VI) stress. In this study, the phenol-degrading strain Bacillus cereus ZWB3 was co-cultured with the Cr(VI)-reducing strain Bacillus licheniformis MZ-1 to enhance phenol biodegradation under Cr(Ⅵ) stress. Compared with phenol-degrading strain ZWB3, which has weak tolerance to Cr(Ⅵ), and Cr(Ⅵ)-reducing strain MZ-1, which has no phenol-degrading ability, the co-culture of two strains could significantly increase the degraded rate and capacity of phenol. In addition, the co-cultured strains exhibited phenol degradation ability over a wide pH range (7-10). The reduced content of intracellular proteins and polysaccharides produced by the co-cultured strains contributed to the enhancement of phenol degradation and Cr(Ⅵ) tolerance. The determination coefficients R2, RMSE, and MAPE showed that the BP-ANN model could predict the degradation of phenol under various conditions, which saved time and economic cost. The metabolic pathway of microbial degradation of phenol was deduced by metabolic analysis. This study provides a valuable strategy for wastewater treatment containing Cr(Ⅵ) and phenol.

A Cable-Stayed Honeycomb Superstructure to Improve the Stability of Li-Rich Materials via Inhibiting Interlaminar Lattice Strain.

In layered Li-rich materials, over stoichiometric Li forms an ordered occupation of LiTM6 in transition metal (TM) layer, showing a honeycomb superstructure along [001] direction. At the atomic scale, the instability of the superstructure at high voltage is the root cause of problems such as capacity/voltage decay of Li-rich materials. Here a Li-rich material with a high Li/Ni disorder is reported, these interlayer Ni atoms locate above the honeycomb superstructure and share adjacent O coordination with honeycomb TM. These Ni─O bonds act as cable-stayed bridge to the honeycomb plane, and improve the high-voltage stability. The cable-stayed honeycomb superstructure is confirmed by in situ X-ray diffraction to have a unique cell evolution mechanism that it can alleviate interlaminar lattice strain by promoting in-plane expansion along a-axis and inhibiting c-axis stretching. Electrochemical tests also demonstrate significantly improved long cycle performance after 500 cycles (86% for Li-rich/Li half cell and 82% for Li-rich/Si-C full cell) and reduced irreversible oxygen release. This work proves the feasibility of achieving outstanding stability of lithium-rich materials through superstructure regulation and provides new insights for the development of the next-generation high-energy-density cathodes.

Direct investigations of interactions between nucleolins and aptamers on pancreatic cancer and normal cells by atomic force microscopy.

Nucleolin is overexpressed on the surface of pancreatic cancer cells and are regarded as the remarkable therapeutic target. Aptamers are capable of binding the external domain of nucleolin on the cell surface with high affinity and specificity. But nucleolin has not been localized on pancreatic cancer cells at very high spatial resolution, and the interactions between nucleolin and aptamers have not been investigated at very high force resolution level. In this work, nucleolin was localized on pancreatic cancer and normal cells by aptamers (9FU-AS1411-NH2, AS1411-NH2 and CRONH2) in Single Molecule Recognition Imaging mode of Atomic Force Microscopy. There are plenty of nucleolin on the surfaces of pancreatic cancer cells (area percentage about 5 %), while there are little nucleolin on the surfaces of normal cells. The interactions between three types of aptamers and nucleolins on the surfaces of pancreatic cancer cells were investigated by Single Molecule Force Spectroscopy. The unbinding forces of nucleolins-(9FU-AS1411-NH2) are larger than nucleolins-(AS1411-NH2). The dissociation activation energy on nucleolin-(9FU-AS1411-NH2) is higher than nucleolin-(AS1411-NH2), which indicates that the former complex is more stable and harder to dissociate than the later complex. There are no unbinding forces between nucleolin and CRONH2. All these demonstrate that nucleolin was localized on pancreatic cancer and normal cells at single molecule level quantitatively, and the interactions (unbinding forces and kinetics) between nucleolin and aptamers were studied at picoNewton level. The approaches and results of this work will pave new ways in the investigations of nucleolin and aptamers, and will also be useful in the studies on other proteins and their corresponding aptamers.

Leucine promotes energy metabolism and stimulates slow-twitch muscle fibers expression through AMPK/mTOR signaling in equine skeletal muscle satellite cells.

Previous research has shown that leucine (Leu) can stimulate and enhance the proliferation of equine skeletal muscle satellite cells (SCs). The gene expression profile associated with Leu-induced proliferation of equine SCs has also been documented. However, the specific role of Leu in regulating the expression of slow-twitch muscle fibers (slow-MyHC) and mitochondrial function in equine SCs, as well as the underlying mechanism, remains unclear. During this investigation, equine SCs underwent culturing in differentiation medium and were subjected to varying concentrations of Leu (0 mM, 0.5 mM, 1 mM, 2 mM, 5 mM, and 10 mM) over a span of 3 days. AMP-activated protein kinase (AMPK) inhibitor Compound C and mammalian target of rapamycin complex (mTOR) inhibitor Rapamycin were utilized to explore its underlying mechanism. Here we showed that the expression of slow-MyHC at 2 mM Leu level was significantly higher than the concentration levels of 0 mM,0.5 mM and 10 mM (P <0.01), and there was no significant difference compared to other groups (P > 0.05); the basal respiration, maximum respiration, standby respiration and the expression of slow-MyHC, PGC-1α, Cytc, ND1, TFAM, and COX1 were significantly increased with Leu supplementation (P < 0.01). We also found that Leu up-regulated the expression of key proteins on AMPK and mTOR signaling pathways, including LKB1, p-LKB1, AMPK, p-AMPK, S6, p-S6, 4EBP1, p-4EBP1, mTOR and p-mTOR (P < 0.05 or P < 0.01). Notably, when we treated the equine SCs with the AMPK inhibitor Compound C and the mTOR inhibitor Rapamycin, we observed a reduction in the beneficial effects of Leu on the expression of genes related to slow-MyHC and signaling pathway-related gene expressions. This study provides novel evidence that Leu promotes slow-MyHC expression and enhances mitochondrial function in equine SCs through the AMPK/mTOR signaling pathways, shedding light on the underlying mechanisms involved in these processes for the first time.

The promotion of the polycyclic aromatic hydrocarbons degradation mechanism by humic acid as electron mediator in a sediment microbial electrochemical system.

To enhance the removal efficiencies of polycyclic aromatic hydrocarbons (PAHs) in sediments and to elucidate the mechanisms by which microbial electrochemical action aids in the degradation of PAHs, humic acid was used as an electron mediator in the microbial electrochemical system in this study. The results revealed that the addition of humic acids led to increases in the removal efficiencies of naphthalene, phenanthrene, and pyrene by 45.91%, 97.83%, and 85.56%, respectively, in areas remote from the anode, when compared to the control group. The investigation into the microbial community structure and functional attributes showed that the presence of humic acid did not significantly modify the microbial community composition or its functional expression at the anode. However, an examination of humic acid transformations demonstrated that humic acid extended the electron transfer range in sediment via the redox reactions of quinone and semiquinone groups, thereby facilitating the PAHs degradation within the sediment.

The influence of water safety knowledge on adolescents' drowning risk behaviors: a framework of risk-protect integrated and KAP theory.

Introduction: Although previous research has examined the risk factors for drowning behavior among adolescents, it is unclear whether this association is influenced by water safety knowledge. This study aimed to examine whether water safety knowledge is associated with adolescents' drowning risk behaviors and whether drowning risk perceptions and attitudes could have a chain mediating role in the association between water safety knowledge and adolescents' drowning risk behaviors. Methods: This study included 7,485 adolescents from five Chinese provinces and cities. We used the Drowning Risk Behaviors Scales (DRBS) to evaluate the risk of drowning behaviors. The Water Safety Knowledge Scale (WSKS) was used to evaluate the competence level of water safety knowledge. The Drowning Risk Perceptions Scale (DRPS) was used to evaluate the risk level of perceptions, and the Drowning Risk Attitudes Scale (DRAS) was used to evaluate the risk level of attitudes. Results: The results of the mediating effect test showed that water safety knowledge (WSK) affected drowning risk behaviors (DRB) through three indirect paths. Drowning risk perceptions (DRP) and attitudes (DRA) have significantly mediated the association between WSK and DRB. In conclusion, DRP and DRA can act as mediators between WSK and DRB, not only individually, but also as chain mediators, where the direct effect is-0.301, the total indirect effect is-0.214, and the total mediated indirect effect is 41.5%. Discussion: Water safety knowledge negatively predicts adolescents' drowning risk behaviors; water safety knowledge has an inhibitory effect on drowning risk perceptions. Water safety knowledge can directly influence adolescents' drowning risk perceptions and indirectly affect drowning risk behaviors through the mediation of drowning risk perceptions and attitudes comprising three paths: (1) the drowning risk perceptions mediation path, (2) the drowning risk attitudes mediation path, and (3) the drowning risk perceptions and attitudes mediation paths.

Absence of PD-L1 signaling hinders macrophage defense against Mycobacterium tuberculosis via upregulating STAT3/IL-6 pathway.

The blockade of programmed death-ligand 1 (PD-L1) pathway has been clinically used in cancer immunotherapy, while its effects on infectious diseases remain elusive. Roles of PD-L1 signaling in the macrophage-mediated innate immune defense against M.tb is unclear. In this study, the outcomes of tuberculosis (TB) in wild-type (WT) mice treated with anti-PD-1/PD-L1 therapy and macrophage-specific Pdl1-knockout (Pdl1ΔΜΦ) mice were compared. Treatment with anti-PD-L1 or anti-PD-1 benefited protection against M.tb infection in WT mice, while Pdl1ΔΜΦ mice exhibited the increased susceptibility to M.tb infection. Mechanistically, the absence of PD-L1 signaling impaired M.tb killing by macrophages. Furthermore, elevated STAT3 activation was found in PD-L1-deficient macrophages, leading to increased interleukin (IL)-6 production and reduced inducible nitric oxide synthase (iNOS) expression. Inhibiting STAT3 phosphorylation partially impeded the increase in IL-6 production and restored iNOS expression in these PD-L1-deficient cells. These findings provide valuable insights into the complexity and mechanisms underlying anti-PD-L1 therapy in the context of tuberculosis.

Structural investigation of Fun168A unraveling the recognition mechanism of endo-1,3-fucanase towards sulfated fucan.

BACKGROUND: Sulfated fucan has gained interest due to its various physiological activities. Endo-1,3-fucanases are valuable tools for investigating the structure and establishing structure-activity relationships of sulfated fucan. However, the substrate recognition mechanism of endo-1,3-fucanases towards sulfated fucan remains unclear, limiting the application of endo-1,3-fucanases in sulfated fucan research. SCOPE AND APPROACH: This study presented the first crystal structure of endo-1,3-fucanase (Fun168A) and its complex with the tetrasaccharide product, utilizing X-ray diffraction techniques. The novel subsite specificity of Fun168A was identified through glycomics and nuclear magnetic resonance (NMR). KEY FINDINGS AND CONCLUSIONS: The structure of Fun168A was determined at 1.92 Å. Residues D206 and E264 acted as the nucleophile and general acid/base, respectively. Notably, Fun168A strategically positioned a series of polar residues at the subsites ranging from -2 to +3, enabling interactions with the sulfate groups of sulfated fucan through salt bridges or hydrogen bonds. Based on the structure of Fun168A and its substrate recognition mechanisms, the novel subsite specificities at the -2 and +2 subsites of Fun168A were identified. Overall, this study provided insight into the structure and substrate recognition mechanism of endo-1,3-fucanase for the first time and offered a valuable tool for further research and development of sulfated fucan.

Naringin as a natural candidate for anti-autoimmune hepatitis: Inhibitory potency and hepatoprotective mechanism.

BACKGROUND: Autoimmune hepatitis (AIH), primarily mediated by T cells, is characterized by liver inflammation. Despite the advancements in understanding its pathogenesis, effective therapeutic options are limited. Naringin, a flavonoid abundant in citrus fruits, is recognized for its anti-inflammatory properties and ability to protect against various inflammatory diseases, including drug-induced liver injury. However, the exact effects of naringin on AIH and the mechanisms involved remain poorly understood. PURPOSE: We aim to determine the role of naringin in AIH, exploring its targets and actions in this disease. METHODS: Network pharmacology, molecular docking, and molecular dynamics simulations were utilized to predict the HUB targets connecting naringin, T cell-mediated autoimmune disorders, and AIH. Cellular thermal shift assays were used to determine the binding abilities of naringin with the HUB targets. An in vivo experiment confirmed the impact of naringin treatment on AIH development and underlying mechanisms. RESULTS: Naringin demonstrated therapeutic effects on ConA-induced AIH. There were 455 shared targets between naringin, T cell-mediated autoimmune diseases, and AIH. Ten HUB genes (AKT1, ALB, IL-6, IL-1ß, CTNNB1, TNF, TP53, MAPK3, VEGFA, and JUN) were identified through the PPI network. Gene ontology analysis revealed involvement in gene expression regulation, lipopolysaccharide-mediated signaling, and I-kappa kinase/NFκB signaling. Pathway analysis suggested TNF, Th1/Th2 cell differentiation, and Toll-like receptor pathways, with favorable naringin-HUB gene binding. Molecular docking confirmed albumin (ALB), IL-1ß, IL-6, and TNF as primary targets for naringin. Molecular dynamics simulations showed stable binding in ALB-naringin, TNF-naringin, and IL-1ß-naringin complexes. Naringin's hepatoprotective effect on AIH was supported by increased serum ALB and decreased hepatic inflammatory cytokines including IL-1ß, IL-6, and TNF-α. CONCLUSION: Our data underscore the potential of naringin as a preventive or therapeutical agent in T cell-mediated autoimmune diseases including AIH.