Blocking proteinase-activated receptor 2 signaling relieves pain, suppresses nerve sprouting, improves tissue repair, and enhances analgesic effect of B vitamins in rats with Achilles tendon injury.

ABSTRACT: Tendon injury produces intractable pain and disability in movement, but the medications for analgesia and restoring functional integrity of tendon are still limited. In this study, we report that proteinase-activated receptor 2 (PAR2) activation in dorsal root ganglion (DRG) neurons contributes to chronic pain and tendon histopathological changes produced by Achilles tendon partial transection injury (TTI). Tendon partial transection injury increases the expression of PAR2 protein in both somata of DRG neurons and their peripheral terminals within the injured Achilles tendon. Activation of PAR2 promotes the primary sensory neuron plasticity by activating downstream cAMP-PKA pathway, phosphorylation of PKC, CaMKII, and CREB. Blocking PAR2 signaling by PAR2 small-interference RNA or antagonistic peptide PIP delays the onset of TTI-induced pain, reverses the ongoing pain, as well as inhibits sensory nerve sprouting, and promotes structural remodeling of the injured tendon. Vitamin B complex (VBC), containing thiamine (B1), pyridoxine (B6), and cyanocobalamin (B12), is effective to ameliorate TTI-induced pain, inhibit ectopic nerve sprouting, and accelerate tendon repair, through suppressing PAR2 activation. These findings reveal a critical role of PAR2 signaling in the development of chronic pain and histopathological alterations of injured tendon following Achilles tendon injury. This study suggests that the pharmaceuticals targeting PAR2, such as VBC, may be an effective approach for the treatment of tendon injury-induced pain and promoting tendon repair.

Determining the Young's Modulus of the Bacterial Cell Envelope.

Bacteria experience substantial physical forces in their natural environment, including forces caused by osmotic pressure, growth in constrained spaces, and fluid shear. The cell envelope is the primary load-carrying structure of bacteria, but the mechanical properties of the cell envelope are poorly understood; reports of Young's modulus of the cell envelope of Escherichia coli range from 2 to 18 MPa. We developed a microfluidic system to apply mechanical loads to hundreds of bacteria at once and demonstrated the utility of the approach for evaluating whole-cell stiffness. Here, we extend this technique to determine Young's modulus of the cell envelope of E. coli and of the pathogens Vibrio cholerae and Staphylococcus aureus. An optimization-based inverse finite element analysis was used to determine the cell envelope Young's modulus from observed deformations. The Young's modulus values of the cell envelope were 2.06 ± 0.04 MPa for E. coli, 0.84 ± 0.02 MPa for E. coli treated with a chemical (A22) known to reduce cell stiffness, 0.12 ± 0.03 MPa for V. cholerae, and 1.52 ± 0.06 MPa for S. aureus (mean ± SD). The microfluidic approach allows examination of hundreds of cells at once and is readily applied to Gram-negative and Gram-positive organisms as well as rod-shaped and cocci cells, allowing further examination of the structural causes behind differences in cell envelope Young's modulus among bacterial species and strains.

Reversing the Interfacial Electric Field in Metal Phosphide Heterojunction by Fe-Doping for Large-Current Oxygen Evolution Reaction.

Developing non-precious-metal electrocatalysts that can operate with a low overpotential at a high current density for industrial application is challenging. Heterogeneous bimetallic phosphides have attracted much interest. Despite high hydrogen evolution reaction (HER) performance, the ordinary oxygen evolution reaction (OER) performance hinders their practical use. Herein, it is shown that Fe-doping reverses and enlarges the interfacial electrical field at the heterojunction, turning the H intermediate favorable binding sites for HER into O intermediate favorable sites for OER. Specifically, the self-supported heterojunction catalysts on nickel foam (CoP@Ni2P/NF and Fe-CoP@Fe-Ni2P/NF) are readily synthesized. They only require the overpotentials of 266 and 274 mV to drive a large current density of 1000 mA cm-2 (j1000) for HER and OER, respectively. Furthermore, a water splitting cell equipped with these electrodes only requires a voltage of 1.724 V to drive j1000 with excellent durability, demonstrating the potential of industrial application. This work offers new insights on interfacial engineering for heterojunction catalysts.

Cost-effectiveness analysis of amivantamab plus chemotherapy versus chemotherapy alone in NSCLC with EGFR Exon 20 insertions.

Objective: Amivantamab plus chemotherapy has been proved to be an efficient treatment strategy for non-small-cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 20 insertions. The aim of this study was to conduct the cost-effectiveness analysis of amivantamab-chemotherapy compared with chemotherapy alone in NSCLC harboring EGFR exon 20 insertion mutations. Methods: We constructed a Markov model based on the data derived from the PAPILLON trial. We evaluated the cost, quality-adjusted life years (QALYs), and incremental cost-effectiveness ratio (ICER). One-way and probabilistic sensitivity analyses were used to evaluate the influence of different parameters on this model. Results: Compared with chemotherapy alone, amivantamab combined with chemotherapy treatment gained an incremental effectiveness of 0.473 QALYs and an incremental cost of $361,950.952, which resulted in an ICER of $765,224/QALY. The ICER was much higher than the willingness-to-pay threshold of 15,0000/QALY. One-way sensitivity analysis revealed that amivantamab cost was the leading influential factor in the model. Conclusions: Compared with chemotherapy alone, amivantamab plus chemotherapy is not a cost-effective first-line treatment choice for NSCLC patients with EGFR exon 20 insertions. The costly price of amivantamab is one of the major reasons for the high cost of this combined treatment strategy. Therefore, it is imperative to take into account the high cost of amivantamab in the subsequent clinical application and strive to attain a relative equilibrium between its significant clinical benefit and economic encumbrance.

Spontaneous brain activity in the hippocampal regions could characterize cognitive impairment in patients with Parkinson's disease.

OBJECTIVE: This study aimed to investigate whether spontaneous brain activity can be used as a prospective indicator to identify cognitive impairment in patients with Parkinson's disease (PD). METHODS: Resting-state functional magnetic resonance imaging (RS-fMRI) was performed on PD patients. The cognitive level of patients was assessed by the Montreal Cognitive Assessment (MoCA) scale. The fractional amplitude of low-frequency fluctuation (fALFF) was applied to measure the strength of spontaneous brain activity. Correlation analysis and between-group comparisons of fMRI data were conducted using Rest 1.8. By overlaying cognitively characterized brain regions and defining regions of interest (ROIs) based on their spatial distribution for subsequent cognitive stratification studies. RESULTS: A total of 58 PD patients were enrolled in this study. They were divided into three groups: normal cognition (NC) group (27 patients, average MoCA was 27.96), mild cognitive impairment (MCI) group (21 patients, average MoCA was 23.52), and severe cognitive impairment (SCI) group (10 patients, average MoCA was 17.3). It is noteworthy to mention that those within the SCI group exhibited the most advanced chronological age, with an average of 74.4 years, whereas the MCI group displayed a higher prevalence of male participants at 85.7%. It was found hippocampal regions were a stable representative brain region of cognition according to the correlation analysis between the fALFF of the whole brain and cognition, and the comparison of fALFF between different cognitive groups. The parahippocampal gyrus was the only region with statistically significant differences in fALFF among the three cognitive groups, and it was also the only brain region to identify MCI from NC, with an AUC of 0.673. The paracentral lobule, postcentral gyrus was the region that identified SCI from NC, with an AUC of 0.941. The midbrain, hippocampus, and parahippocampa gyrus was the region that identified SCI from MCI, with an AUC of 0.926. CONCLUSION: The parahippocampal gyrus was the potential brain region for recognizing cognitive impairment in PD, specifically for identifying MCI. Thus, the fALFF of parahippocampal gyrus is expected to contribute to future study as a multimodal fingerprint for early warning.

Next-generation sequencing reveals relapse and leukemia-free survival risks in newly diagnosed acute myeloid leukemia treated with CAG regimen combined with decitabine.

Background: Acute myeloid leukemia (AML) is a heterogeneous hematopoietic malignancy whose prognosis is associated with several biomarkers. Decitabine, a deoxyribonucleic acid (DNA) methyltransferase (DNMT) inhibitor, combined with cytarabine, aclarubicin hydrochloride, and granulocyte colony-stimulating factor (DCAG), has been used in patients newly diagnosed with AML. This regimen has been especially used in older and fragile patients who are immunocompromised or have co-morbidities, as well as those with specific gene mutations. However, the integration of molecular risk stratification and treatment guidance for the DCAG regimen has not been well defined. Therefore, this study aimed to investigate the genetic mutations associated with AML and establish appropriate treatment strategies for patients newly diagnosed with AML. Methods: This study analyzed the clinical data and genetic mutations based on next-generation sequencing (NGS) in 124 newly diagnosed patients with AML who received the DCAG regimen at the People's Liberation Army (PLA) General Hospital from January 2008 to August 2020. Factors associated with the cumulative incidence of relapse (CIR) and leukemia-free survival (LFS) in patients newly diagnosed with AML were analyzed. Results: The most adverse prognosis of DCAG-treated patients was observed in those with FLT3-ITD, KIT, PTPN11, GATA2, or IDH1 mutations during univariable analysis, whereas PTPN11 mutation was solely significant in multivariable analysis, with an increased likelihood of CIR (P = 0.001) and reduced LFS duration (P = 0.077). Hyperleukocytosis was maintained as an independent risk factor for increased CIR risk (P = 0.044) and decreased LFS duration (P = 0.042) in multivariable analysis. In this study, we validated the risk classification of patients with AML receiving an epigenetic modifier-based induction regimen across a broad age range. Conclusion: NGS demonstrated a dismal overall outcome in patients with the rare PTPN11 mutations, indicating the need for new therapies that target this high-risk subtype of AML. These results offer a potential molecular stratification and treatment guidance for patients with AML.

Dynamic Reconfiguration and Local Polarization of NiFe-Layered Double Hydroxide-Bi2MoO6- x Heterojunction for Enhancing Piezo-Photocatalytic Nitrogen Oxidation to Nitric Acid.

Constructing heterojunctions with vacancies has garnered substantial attention in the field of piezo-photocatalysis. However, the presence of interfacial vacancies can serve as charge-trapping sites, leading to the localization of electrons and hindering interfacial charge transfer. Herein, dual oxygen vacancies in the NiFe-layered double hydroxide and Bi2MoO6- x induced interfacial bonds have been designed for the piezo-photocatalytic N2 oxidation to NO3 -. Fortunately, it achieves sensational nitric acid production rates (7.23 mg g-1 h-1) in the absence of cocatalysts and sacrificial agents, which is 6.03 times of pure Bi2MoO6 that under ultrasound and light illumination. Theoretical and experimental results indicate that interfacial bonds act as "charge bridge" and "strain center" to break the carrier local effect and negative effects with piezocatalysis and photocatalysis for promoting exciton dissociation and charge transfer. Moreover, the strong electronic interaction of the interfacial bond induces internal reconstruction under ultrasound for promoting the local polarization and adsorption of N2, which accelerates the fracture of the N≡N bonds and reduces the activation energy of the reaction. The research not only establishes a novel approach for optimizing the combined effects of piezo-catalysis and photocatalysis, but also achieves equilibrium between the synergistic impacts of vacancies and heterojunctions.

Revealing the Origin of Cooperative Adsorption of Chains on Nanoparticle Surfaces through Coarse-Grained Simulations.

This work aims to deepen our understanding of the molecular origin of the recently observed phenomenon of polymer cooperative adsorption onto faceted nanoparticle (NP) surfaces. By exploring a large parameter space for polymer/NP interactions through coarse-grained (CG) molecular dynamics (MD) simulations, it is found that consistent with experiments the presence or absence of cooperativity is related to solvent quality and relative interaction strengths between the polymer and the adsorbent. Specifically, positive cooperativity is associated with stronger polymer-polymer interaction than polymer-surface interactions and vice versa for negative cooperativity. This contrast in interaction energies manifests in positive cooperativity (i.e., increased affinity) and negative cooperativity (i.e., decreased affinity) as concentration increases. It is also found that increasing chain length strengthens cooperativity effects and that the nanoscale confinement of polymer chains to the adsorbing facet (due to weaker affinity to corners and edges) enhances positive cooperativity but weakens negative cooperativity. Moreover, adsorption onto a spherical NP shows stronger positive cooperativity but weaker negative cooperativity compared with adsorption onto a cubic NP of equal surface area. It was further found that as polymer bulk concentration increases, the free energy of adsorption decreases in positive cooperativity, increases in negative cooperativity, and is independent of concentration in noncooperative systems consistent with the phenomenological explanation of cooperativity. We further found that positive cooperativity is associated with growing fluctuations in the adsorption density at critical bulk polymer concentrations. This behavior can be attributed to the competition between enthalpic gains and entropic losses upon adsorption. Overall, our results shed light on the microscopic origin of cooperative adsorption and the role of solvent quality, which can be leveraged in, for example, controlling NP growth into target shapes and designing NP catalysts with improved performance.

Local polarization redistribution in ZnmIn2S3+m for the enhancing synergetic piezo-photocatalytic overall water splitting.

Piezo-photocatalytic water (deuterium oxide) decomposition is a promising strategy for realizing renewable energy, but the manipulation of the polar center remains a big challenge. This study uses a simple low-temperature hydrothermal process to successfully manufacture ZnmIn2Sm+3 (m = 1-3) (ZnIn2S4, Zn2In2S5 and Zn3In2S6). Incorporating both experimental and theoretical analyses, the structural contraction and local polarization of the Zn-S bond in Zn2In2S5 enhance the piezoelectric response and surface charge accumulation, which facilitate charge transfer and reduce the activation energy of water. Remarkably, Zn2In2S5 exhibits excellent piezoelectric photocatalytic total water splitting performance (H2/O2: 4284.72/1967.00 µmol g-1h-1), which is 1.77 times that of photocatalytic performance. Moreover, a significant enhancement in D2O splitting performance can be obtained for the optimized Zn2In2S5. Our work offers valuable insights into the disclosure of local polarization in catalysts for enhancing piezo-photocatalytic overall water splitting.

Characterization and safety assessment of bamboo shoot shell cellulose nanofiber: Prepared by acidolysis combined with dynamic high-pressure microfluidization.

The preparation of cellulose nanofiber (CNF) using traditional methods is currently facing challenges due to concerns regarding environmental pollution and safety. Herein, a novel CNF was obtained from bamboo shoot shell (BSS) by low-concentration acid and dynamic high-pressure microfluidization (DHPM) treatment. The resulting CNF was then characterized, followed by in vitro and in vivo safety assessments. Compared to insoluble dietary fiber (IDF), the diameters of HIDF (IDF after low-concentration acid hydrolysis) and CNF were significantly decreased to 167.13 nm and 70.97 nm, respectively. Meanwhile, HIDF and CNF showed a higher crystallinity index (71.32 % and 74.35 %). Structural analysis results indicated the successful removal of lignin and hemicellulose of HIDF and CNF, with CNF demonstrating improved thermostability. In vitro, a high dose of CNF (1500 µg/mL) did not show any signs of cytotoxicity on Caco-2 cells. In vivo, no death was observed in the experimental mice, and there was no significant difference between CNF (1000 mg/kg·bw) and control group in hematological index and histopathological analysis. Overall, this study presents an environmentally friendly method for preparing CNF from BSS while providing evidence regarding its safety through in vitro and in vivo assessments, laying the foundation for its potential application in food.

Noble-Metal-Free High-Entropy Alloy Nanoparticles for Efficient Solar-Driven Photocatalytic CO2 Reduction.

Metal nanoparticle (NP) cocatalysts are widely investigated for their ability to enhance the performance of photocatalytic materials; however, their practical application is often limited by the inherent instability under light irradiation. This challenge has catalyzed interest in exploring high-entropy alloys (HEAs), which, with their increased entropy and lower Gibbs free energy, provide superior stability. In this study, 3.5 nm-sized noble-metal-free NPs composed of a FeCoNiCuMn HEA are successfully synthesized. With theoretic calculation and experiments, the electronic structure of HEA in augmenting the catalytic CO2 reduction has been uncovered, including the individual roles of each element and the collective synergistic effects. Then, their photocatalytic CO2 reduction capabilities are investigated when immobilized on TiO2. HEA NPs significantly enhance the CO2 photoreduction, achieving a 23-fold increase over pristine TiO2, with CO and CH4 production rates of 235.2 and 19.9 µmol g-1 h-1, respectively. Meanwhile, HEA NPs show excellent stability under simulated solar irradiation, as well high-energy X-ray irradiation. This research emphasizes the promising role of HEA NPs, composed of earth-abundant elements, in revolutionizing the field of photocatalysis.

Role of extracellular vesicles associated with microRNAs and their interplay with cuproptosis in osteoporosis.

Osteoporosis (OP)-associated fractures can result in severe morbidity and disability, reduced quality of life, and death. Previous studies have suggested that small noncoding RNAs, for example, small regulatory microRNAs (miRNAs), play a key role in OP by inhibiting target gene expression. Cuproptosis, a recently proposed copper-induced cell death pathway, is linked with OP. Here, we describe the contribution of exosomal miRNAs and cuproptosis to OP. First, we highlight the characteristics of exosomes and roles of exosome-related miRNAs. Next, we discuss the relationship between cuproptosis and OP. Subsequently, we analyze the crosstalk of exosomal miRNAs with cuproptosis in the development of OP. This review aims to investigate a new clinical treatment method for OP.

Deep learning evaluation of echocardiograms to identify occult atrial fibrillation.

Atrial fibrillation (AF) often escapes detection, given its frequent paroxysmal and asymptomatic presentation. Deep learning of transthoracic echocardiograms (TTEs), which have structural information, could help identify occult AF. We created a two-stage deep learning algorithm using a video-based convolutional neural network model that (1) distinguished whether TTEs were in sinus rhythm or AF and then (2) predicted which of the TTEs in sinus rhythm were in patients who had experienced AF within 90 days. Our model, trained on 111,319 TTE videos, distinguished TTEs in AF from those in sinus rhythm with high accuracy in a held-out test cohort (AUC 0.96 (0.95-0.96), AUPRC 0.91 (0.90-0.92)). Among TTEs in sinus rhythm, the model predicted the presence of concurrent paroxysmal AF (AUC 0.74 (0.71-0.77), AUPRC 0.19 (0.16-0.23)). Model discrimination remained similar in an external cohort of 10,203 TTEs (AUC of 0.69 (0.67-0.70), AUPRC 0.34 (0.31-0.36)). Performance held across patients who were women (AUC 0.76 (0.72-0.81)), older than 65 years (0.73 (0.69-0.76)), or had a CHA2DS2VASc ≥2 (0.73 (0.79-0.77)). The model performed better than using clinical risk factors (AUC 0.64 (0.62-0.67)), TTE measurements (0.64 (0.62-0.67)), left atrial size (0.63 (0.62-0.64)), or CHA2DS2VASc (0.61 (0.60-0.62)). An ensemble model in a cohort subset combining the TTE model with an electrocardiogram (ECGs) deep learning model performed better than using the ECG model alone (AUC 0.81 vs. 0.79, p = 0.01). Deep learning using TTEs can predict patients with active or occult AF and could be used for opportunistic AF screening that could lead to earlier treatment.

Developing a novel immune infiltration-associated mitophagy prediction model for amyotrophic lateral sclerosis using bioinformatics strategies.

Background: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease, which leads to muscle weakness and eventual paralysis. Numerous studies have indicated that mitophagy and immune inflammation have a significant impact on the onset and advancement of ALS. Nevertheless, the possible diagnostic and prognostic significance of mitophagy-related genes associated with immune infiltration in ALS is uncertain. The purpose of this study is to create a predictive model for ALS using genes linked with mitophagy-associated immune infiltration. Methods: ALS gene expression profiles were downloaded from the Gene Expression Omnibus (GEO) database. Univariate Cox analysis and machine learning methods were applied to analyze mitophagy-associated genes and develop a prognostic risk score model. Subsequently, functional and immune infiltration analyses were conducted to study the biological attributes and immune cell enrichment in individuals with ALS. Additionally, validation of identified feature genes in the prediction model was performed using ALS mouse models and ALS patients. Results: In this study, a comprehensive analysis revealed the identification of 22 mitophagy-related differential expression genes and 40 prognostic genes. Additionally, an 18-gene prognostic signature was identified with machine learning, which was utilized to construct a prognostic risk score model. Functional enrichment analysis demonstrated the enrichment of various pathways, including oxidative phosphorylation, unfolded proteins, KRAS, and mTOR signaling pathways, as well as other immune-related pathways. The analysis of immune infiltration revealed notable distinctions in certain congenital immune cells and adaptive immune cells between the low-risk and high-risk groups, particularly concerning the T lymphocyte subgroup. ALS mouse models and ALS clinical samples demonstrated consistent expression levels of four mitophagy-related immune infiltration genes (BCKDHA, JTB, KYNU, and GTF2H5) with the results of bioinformatics analysis. Conclusion: This study has successfully devised and verified a pioneering prognostic predictive risk score for ALS, utilizing eighteen mitophagy-related genes. Furthermore, the findings indicate that four of these genes exhibit promising roles in the context of ALS prognostic.

Osimertinib in the treatment of resected EGFR-mutated non-small cell lung cancer: a cost-effectiveness analysis in the United States.

Background: In the double-blind phase III ADAURA randomized clinical trial, adjuvant osimertinib showed a substantial overall survival benefit in patients with stage IB to IIIA, EGFR-mutated, completely resected non-small cell lung cancer (NSCLC). We conduct a cost-effectiveness analysis comparing the use of adjuvant osimertinib to placebo in patients with stage IB to IIIA, EGFR-mutated, resected NSCLC. Methods: Based on the results obtained from the ADAURA trial, a Markov model with three-state was employed to simulate patients who were administered either osimertinib or placebo until disease recurrence or completion of the study period (3 years). Quality-adjusted life-years (QALYs), lifetime costs, and incremental cost-effectiveness ratio (ICER) were calculated with a willingness-to-pay (WTP) threshold of $150,000 per QALY. Both univariate and probabilistic sensitivity analyses were carried out to explore the robustness of the model. Results: Osimertinib produced additional 1.59 QALYs with additional costs of $492,710 compared to placebo, giving rise to ICERs of $309,962.66/QALY. The results of the univariate sensitivity analysis indicated that the utility of disease-free survival (DFS), cost of osimertinib, and discount rate had the greatest impact on the outcomes. Probabilistic sensitivity analysis showed that osimertinib exhibited a 0% chance of being considered cost-effective for patients using a WTP threshold $150,000/QALY. Conclusion: In our model, osimertinib was unlikely to be cost-effective compared to placebo for stage IB to IIIA, EGFR-mutated, completely resected NSCLC patients from the perspective of a U.S. payer at a WTP threshold of $150,000 per QALY.

MFEM-CIN: A Lightweight Architecture Combining CNN and Transformer for the Classification of Pre-Cancerous Lesions of the Cervix.

Goal: Cervical cancer is one of the most common cancers in women worldwide, ranking among the top four. Unfortunately, it is also the fourth leading cause of cancer-related deaths among women, particularly in developing countries where incidence and mortality rates are higher compared to developed nations. Colposcopy can aid in the early detection of cervical lesions, but its effectiveness is limited in areas with limited medical resources and a lack of specialized physicians. Consequently, many cases are diagnosed at later stages, putting patients at significant risk. Methods: This paper proposes an automated colposcopic image analysis framework to address these challenges. The framework aims to reduce the labor costs associated with cervical precancer screening in undeserved regions and assist doctors in diagnosing patients. The core of the framework is the MFEM-CIN hybrid model, which combines Convolutional Neural Networks (CNN) and Transformer to aggregate the correlation between local and global features. This combined analysis of local and global information is scientifically useful in clinical diagnosis. In the model, MSFE and MSFF are utilized to extract and fuse multi-scale semantics. This preserves important shallow feature information and allows it to interact with the deep feature, enriching the semantics to some extent. Conclusions: The experimental results demonstrate an accuracy rate of 89.2% in identifying cervical intraepithelial neoplasia while maintaining a lightweight model. This performance exceeds the average accuracy achieved by professional physicians, indicating promising potential for practical application. Utilizing automated colposcopic image analysis and the MFEM-CIN model, this research offers a practical solution to reduce the burden on healthcare providers and improve the efficiency and accuracy of cervical cancer diagnosis in resource-constrained areas.

Scutellarin activates IDH1 to exert antitumor effects in hepatocellular carcinoma progression.

Isochlorate dehydrogenase 1 (IDH1) is an important metabolic enzyme for the production of α-ketoglutarate (α-KG), which has antitumor effects and is considered to have potential antitumor effects. The activation of IDH1 as a pathway for the development of anticancer drugs has not been attempted. We demonstrated that IDH1 can limit glycolysis in hepatocellular carcinoma (HCC) cells to activate the tumor immune microenvironment. In addition, through proteomic microarray analysis, we identified a natural small molecule, scutellarin (Scu), which activates IDH1 and inhibits the growth of HCC cells. By selectively modifying Cys297, Scu promotes IDH1 active dimer formation and increases α-KG production, leading to ubiquitination and degradation of HIF1a. The loss of HIF1a further leads to the inhibition of glycolysis in HCC cells. The activation of IDH1 by Scu can significantly increase the level of α-KG in tumor tissue, downregulate the HIF1a signaling pathway, and activate the tumor immune microenvironment in vivo. This study demonstrated the inhibitory effect of IDH1-α-KG-HIF1a on the growth of HCC cells and evaluated the inhibitory effect of Scu, the first IDH1 small molecule agonist, which provides a reference for cancer immunotherapy involving activated IDH1.

The effect of biochar types on carbon cycles in farmland soils: A meta analysis.

Application of biochar has been demonstrated to be a successful strategy for boosting soil carbon sequestration and altering the agricultural soil carbon cycle. However, in the studies involving biochar worldwide, the effects of different types of biochar on the soil carbon component response direction and increase are not consistent. Therefore, to assess the effects of applying four types of biochar during the soil carbon cycle on carbon components on a farmland, we performed a meta-analysis of 1150 comparisons from 86 peer-reviewed publications. Generally speaking, the types of biochar raw materials have a significant impact on soil carbon cycle. The application of chaff biochar significantly inhibited (10.0 %) soil respiration, while the application of manure biochar (47.0 %), straw biochar (11.2 %) and wood biochar (8.7 %) showed a strong promotion effect on CO2 emission. In addition, although the soil organic C, microbial biomass C and dissolved organic C all had positive responses to the application of the four biochar types, the degree and increase in their response varied greatly due to the differences in biomass raw materials. Moreover, by increasing the biochar rates applied to coarse-textured soils with low average annual rainfall and an average temperature under controlled circumstances, the relative increase in SOC was encouraged. Meanwhile, applying low temperature pyrolytic biochar (≤400 °C) at a lower rate (<25 t/ha) in the long-term experiment (>3 years) is more beneficial to soil C sequestration and emission reduction. Hence, climatic conditions, agricultural management practices, and initial soil properties jointly constrained and influenced the ability of biochar to alter the soil C cycle. Based on this, our research offers a fresh viewpoint for making a profound study biochar-enhanced soil C cycle.

Effect of angled abutments in the posterior maxillary region on tilted implants: a 3D finite element analysis.

The aim of this study was to evaluate the bone tissue effects under dynamic loading using finite element analysis (FEA) for four angled abutments with different deviated palatal lateral tilt angles. A three-dimensional model of the posterior maxillary region and an implant crown model were reconstructed and assembled with a three-dimensional model of the implant, angled abutment, and central screw to create a total of 10 three-dimensional finite element models tilted at 15 ∘ , 20 ∘ , 25 ∘ , and 30 ∘ in three groups, and the dynamic loads simulating oral mastication were loaded on the implant crown to analyze the equivalent stresses and strains in the peri-implant bone tissues. Under the dynamic loading, the cortical bone on the buccal side of the implant neck showed different degrees of stress concentration, and the cortical bone stress was much higher than the cancellous bone, and the strain concentration area of each model was located in the bone tissue around the implant neck and base. For the use of angular abutment, under the premise that the cortical bone stresses and strains of the 10 models meet the requirements for use, the peak stresses of 2.907 MPa, 3.018 MPa, and 2.164 MPa were achieved by using the 20 ∘ angular abutment to achieve the tilt angles of 20 ∘ , 25 ∘ , and 30 ∘ implantation, which is more advantageous compared with other models.

Type III interferon inhibits bladder cancer progression by reprogramming macrophage-mediated phagocytosis and orchestrating effective immune responses.

BACKGROUND: Interferons (IFNs) are essential for activating an effective immune response and play a central role in immunotherapy-mediated immune cell reactivation for tumor regression. Type III IFN (λ), related to type I IFN (α), plays a crucial role in infections, autoimmunity, and cancer. However, the direct effects of IFN-λ on the tumor immune microenvironment have not been thoroughly investigated. METHODS: We used mouse MB49 bladder tumor models, constructed a retroviral vector expressing mouse IFN-λ3, and transduced tumor cells to evaluate the antitumor action of IFN-λ3 in immune-proficient tumors and T cell-deficient tumors. Furthermore, human bladder cancer samples (cohort 1, n=15) were used for immunohistochemistry and multiplex immunoflurescence analysis to assess the expression pattern of IFN-λ3 in human bladder cancer and correlate it with immune cells' infiltration. Immunohistochemistry analysis was performed in neoadjuvant immunotherapy cohort (cohort 2, n=20) to assess the correlation between IFN-λ3 expression and the pathological complete response rate. RESULTS: In immune-proficient tumors, ectopic Ifnl3 expression in tumor cells significantly increased the infiltration of cytotoxic CD8+ T cells, Th1 cells, natural killer cells, proinflammatory macrophages, and dendritic cells, but reduced neutrophil infiltration. Transcriptomic analyses revealed significant upregulation of many genes associated with effective immune response, including lymphocyte recruitment, activation, and phagocytosis, consistent with increased antitumor immune infiltrates and tumor inhibition. Furthermore, IFN-λ3 activity sensitized immune-proficient tumors to anti-PD-1/PD-L1 blockade. In T cell-deficient tumors, increased Ly6G-Ly6C+I-A/I-E+ macrophages still enhanced tumor cell phagocytosis in Ifnl3 overexpressing tumors. IFN-λ3 is expressed by tumor and stromal cells in human bladder cancer, and high IFN-λ3 expression was positively associated with effector immune infiltrates and the efficacy of immune checkpoint blockade therapy. CONCLUSIONS: Our study indicated that IFN-λ3 enables macrophage-mediated phagocytosis and antitumor immune responses and suggests a rationale for using Type III IFN as a predictive biomarker and potential immunotherapeutic candidate for bladder cancer.