A two-sample Mendelian randomization study of mutual relations of six types of diets in atopic dermatitis.

BACKGROUND: In the continuous endeavor to find safe and efficient treatments for Atopic Dermatitis (AD), there remains a considerable focus on dietary adjustments. Nevertheless, the limited availability of research and conflicting findings in the academic literature pose a hurdle in establishing conclusive recommendations. METHOD: Mendelian randomization (MR) was applied to the most comprehensive genome-wide association studies (GWAS) data on tea intake (447 485), green tea intake (n = 64 949), flavored milk intake (n = 64 941), never eat eggs, dairy, wheat, sugar: Wheat products(n = 461 046), never eat eggs, dairy, wheat, sugar: Sugar or foods/drinks containing sugar (n = 461 046), never eat eggs, dairy, wheat, sugar: I eat all of the above (n = 461 046) and atopic dermatitis (n = 218 467). We used the inverse-variance weighted method (IVW) as the primary method. RESULTS: The IVW analyses have demonstrated an increased tea intake was genetically associated with a reduced risk of AD (odds ratio [OR]: 0.646, 95% confidence interval [CI]: 0.430-0.968, p = 0.034). Furthermore, green tea intake was significantly negatively associated with AD (IVW OR: 0.986, 95% CI: 0.975-0.998; p = 0.024) in the IVW model. AD risk could be reduced by never eating wheat products (IVW OR: 8.243E-04, 95% CI: 7.223E-06-9.408E-02, p = 0.003). There was no association between never eating eggs, dairy, wheat, sugar: Sugar, or foods/drinks containing sugar, I eat all of the above and AD. CONCLUSIONS: Our MR study suggests a causal relationship between tea intake, green tea intake, and the avoidance of eating wheat products with atopic dermatitis. Our findings recommend that preventing and managing atopic dermatitis may be achieved by never eating wheat products while increasing tea and green tea intake.

Diagnostic Accuracy of Ultra-Low Dose CT Compared to Standard Dose CT for Identification of Fresh Rib Fractures by Deep Learning Algorithm.

The present study aimed to evaluate the diagnostic accuracy of ultra-low dose computed tomography (ULD-CT) compared to standard dose computed tomography (SD-CT) in discerning recent rib fractures using a deep learning algorithm detection of rib fractures (DLADRF). A total of 158 patients undergoing forensic diagnosis for rib fractures were included in this study: 50 underwent SD-CT, and 108 were assessed using ULD-CT. Junior and senior radiologists independently evaluated the images to identify and characterize the rib fractures. The sensitivity of rib fracture diagnosis by radiologists and radiologist + DLADRF was better using SD-CT than ULD-CT. However, the diagnosis sensitivity of DLADRF using ULD-CT alone was slightly more than SD-CT. Nonetheless, no substantial differences were observed in specificity, positive predictive value, and negative predictive value between SD-CT and ULD-CT by the same radiologist, radiologist + DLADRF, and DLADRF (P > 0.05). The area under the curve (AUC) of receiver operating characteristic indicated that senior radiologist + DLADRF was significantly better than senior and junior radiologists, junior radiologists + DLADRF, and DLADRF alone using SD-CT or ULD-CT (all P < 0.05). Also, junior radiologists + DLADRF was better with ULD-CT than senior and junior radiologists (P < 0.05). The AUC of the rib fracture diagnosed by senior radiologists did not differ from DLADRF using ULD-CT. Also, no significant differences were observed between junior + AI and senior and between junior and DLADRF using SD-CT. DLADRF enhanced the diagnostic performance of radiologists in detecting recent rib fractures. The diagnostic outcomes between SD-CT and ULD-CT across radiologists' experience and DLADRF did not differ significantly.

Tri-signal CdS@SiO2 nanoprobes for accurate and sensitive detection of human immunoglobulin G with enhanced flexibility and internal validation.

Accurate and sensitive determination of human immunoglobulin G (HIgG) level is critical for diagnosis and treatment of various diseases, including rheumatoid arthritis, humoral immunodeficiencies, and infectious disease. In this study, versatile tri-signal probes were developed by preparing CdS@SiO2 nanorods that integrate photoluminescence (PL), multi-phonon resonant Raman scattering (MRRS) and infrared absorption (IRA) properties. Through the coating of multiple CdS nanoparticles as cores within SiO2 shells, the PL and MRRS properties of CdS were improved, resulting in a significantly lowered limit of detection (LOD), with the lowest LOD of 12.37 ag mL-1. Integration with the distinctive IRA property of SiO2 shells widened the detection range towards higher concentrations, establishing a final linear range of 50 ag mL-1 to 10 µg mL-1. The remarkable consistency among the three signals highlighted the robust internal verification capability for accurate detection. This approach enhances flexibility in selecting detection methodologies to suit diverse scenarios, facilitating HIgG detection. The tri-signal nanoprobes also exhibited excellent detection selectivity, specificity and repeatability. This study presents a fresh idea for developing high-performance detection strategies.

Co-adsorption and selective-adsorption of heavy metals and dyes from aqueous solution by bio-based humus/chitosan hydrogels.

An eco-friendly adsorbent was prepared by reverse suspension crosslinking method to remove multiple pollutants from aqueous solution. Both raw materials, derived from humus (HS) and chitosan (CS), are biodegradable and low-cost natural biopolymers. After combining HS with CS, the adsorption capacity was significantly improved due to compensation effects between the two components. HS/CS exhibited the features of amphoteric adsorption through pH adjustment, enabling it to adsorb not only anionic pollutants (Methyl Orange (MO) and Cr(VI)), but also cationic ones (Methylene Blue (MB) and Pb(II)). The adsorption capacities were approximately 242 mg/g, 69 mg/g, 188 mg/g and 57 mg/g for MO, Cr(VI), MB and Pb(II), respectively. HS/CS showed a slight preference for MO in MO/Cr(VI) co-adsorption system, whereas strong selectivity for MB over Pb(II) in MB/Pb(II) system under acidic condition (pH<3.0). This selective behavior would allow for potential applications in separating MB/Pb(II) effluents and selectively recycling Pb(II) in acidic environment. The isothermal and kinetic adsorption behaviors followed Langmuir model and pseudo-second-order model, respectively. The density functional theory (DFT) confirmed that the interaction between metal ions and adsorbents was primarily attributed to chelation and electrostatic adsorption, owing to nitric and oxygenic functional groups. Whereas, the adsorption mechanisms for dyes were involved in electrostatic attraction, H-bond and π-π bond, due to available hydrogen, oxygen, nitrogen atoms and aromatic groups on the surface of adsorbent and adsorbates. The adsorbent could be efficiently regenerated and retained over 90% of its adsorption capacity after five cycles, which has a potential for practical applications in water treatment.

Engineering viral vectors for acoustically targeted gene delivery.

Targeted gene delivery to the brain is a critical tool for neuroscience research and has significant potential to treat human disease. However, the site-specific delivery of common gene vectors such as adeno-associated viruses (AAVs) is typically performed via invasive injections, which limit its applicable scope of research and clinical applications. Alternatively, focused ultrasound blood-brain-barrier opening (FUS-BBBO), performed noninvasively, enables the site-specific entry of AAVs into the brain from systemic circulation. However, when used in conjunction with natural AAV serotypes, this approach has limited transduction efficiency and results in substantial undesirable transduction of peripheral organs. Here, we use high throughput in vivo selection to engineer new AAV vectors specifically designed for local neuronal transduction at the site of FUS-BBBO. The resulting vectors substantially enhance ultrasound-targeted gene delivery and neuronal tropism while reducing peripheral transduction, providing a more than ten-fold improvement in targeting specificity in two tested mouse strains. In addition to enhancing the only known approach to noninvasively target gene delivery to specific brain regions, these results establish the ability of AAV vectors to be evolved for specific physical delivery mechanisms.

Effects of emulsifiers on lipid metabolism and performance of yellow-feathered broilers.

BACKGROUND: Reducing production costs while producing high-quality livestock and poultry products is an ongoing concern in the livestock industry. The addition of oil to livestock and poultry diets can enhance feed palatability and improve growth performance. Emulsifiers can be used as potential feed supplements to improve dietary energy utilization and maintain the efficient productivity of broilers. Therefore, further investigation is warranted to evaluate whether dietary emulsifier supplementation can improve the efficiency of fat utilization in the diet of yellow-feathered broilers. In the present study, the effects of adding emulsifier to the diet on lipid metabolism and the performance of yellow-feathered broilers were tested. A total of 240 yellow-feasted broilers (21-day-old) were randomly divided into 4 groups (6 replicates per group, 10 broilers per replicate, half male and half female within each replicate). The groups were as follows: the control group (fed with basal diet), the group fed with basal diet supplemented with 500 mg/kg emulsifier, the group fed with a reduced oil diet (reduced by 1%) supplemented with 500 mg/kg emulsifier, and the group fed with a reduced oil diet supplemented with 500 mg/kg emulsifier. The trial lasted for 42 days, during which the average daily feed intake, average daily gain, and feed-to-gain ratio were measured. Additionally, the expression levels of lipid metabolism-related genes in the liver, abdominal fat and each intestinal segment were assessed. RESULTS: The results showed that compared with the basal diet group, (1) The average daily gain of the basal diet + 500 mg/kg emulsifier group significantly increased (P < 0.05), and the half-even-chamber rate was significantly increased (P < 0.05); (2) The mRNA expression levels of Cd36, Dgat2, Apob, Fatp4, Fabp2, and Mttp in the small intestine were significantly increased (P < 0.05). (3) Furthermore, liver TG content significantly decreased (P < 0.05), and the mRNA expression level of Fasn in liver was significantly decreased (P < 0.05), while the expression of Apob, Lpl, Cpt-1, and Pparα significantly increased (P < 0.05). (4) The mRNA expression levels of Lpl and Fatp4 in adipose tissue were significantly increased (P < 0.05), while the expression of Atgl was significantly decreased (P < 0.05). (5) Compared with the reduced oil diet group, the half-evading rate and abdominal fat rate of broilers in the reduced oil diet + 500 mg/kg emulsifier group were significantly increased (P < 0.05), and the serum level of LDL-C increased significantly (P < 0.05)0.6) The mRNA expression levels of Cd36, Fatp4, Dgat2, Apob, and Mttp in the small intestine were significantly increased (P < 0.05). 7) The mRNA expression levels of Fasn and Acc were significantly decreased in the liver (P < 0.05), while the mRNA expression levels of Lpin1, Dgat2, Apob, Lpl, Cpt-1, and Pparα were significantly increased (P < 0.05). CONCLUSIONS: These results suggest that dietary emulsifier can enhance the fat utilization efficiency of broilers by increasing the small intestinal fatty acid uptake capacity, inhibiting hepatic fatty acid synthesis and promoting hepatic TG synthesis and transport capacity. This study provides valuable insights for the potential use of emulsifier supplementation to improve the performance of broiler chickens.

Six new diterpenoids with anti-inflammatory and cytotoxic activity from Isodon serra.

Diterpenoids occupy an important slot of the natural products diversity space with wide ranges of bioactivities and complex structures, providing potential applications for the development of therapeutics. In this study, we reported four new abietane-type diterpenoids viroxocin B-E (1-4), a new totarane-type diterpenoid viroxocin F (5), and a new sempervirane-type diterpenoid viroxocin G (6) along with four known compounds (7-10), isolated and identified from a widely used Traditional Chinese Medicine, Isodon serra (I. serra). Their structures were established by spectroscopic data analysis, experimental and calculated electronic circular dichroism (ECD) data, as well as X-ray diffraction analysis. Compounds 2, 5, 7, 8 and 10 exhibited promising anti-inflammatory activities in lipopolysaccharide (LPS)-induced RAW 267.4 cells, and their inhibition rates on NO production were more than 60% at 10 µM. Compound 7 showed cytotoxicity against human renal cell carcinoma 769P at 20 µM, the inhibition rate was 52.66%.

Quantifying uncertainty in graph neural network explanations.

In recent years, analyzing the explanation for the prediction of Graph Neural Networks (GNNs) has attracted increasing attention. Despite this progress, most existing methods do not adequately consider the inherent uncertainties stemming from the randomness of model parameters and graph data, which may lead to overconfidence and misguiding explanations. However, it is challenging for most of GNN explanation methods to quantify these uncertainties since they obtain the prediction explanation in a post-hoc and model-agnostic manner without considering the randomness of graph data and model parameters. To address the above problems, this paper proposes a novel uncertainty quantification framework for GNN explanations. For mitigating the randomness of graph data in the explanation, our framework accounts for two distinct data uncertainties, allowing for a direct assessment of the uncertainty in GNN explanations. For mitigating the randomness of learned model parameters, our method learns the parameter distribution directly from the data, obviating the need for assumptions about specific distributions. Moreover, the explanation uncertainty within model parameters is also quantified based on the learned parameter distributions. This holistic approach can integrate with any post-hoc GNN explanation methods. Empirical results from our study show that our proposed method sets a new standard for GNN explanation performance across diverse real-world graph benchmarks.

Immune-tumor interaction dictates spatially directed evolution of esophageal squamous cell carcinoma.

Esophageal squamous cell carcinoma (ESCC) is a poor-prognostic cancer type with extensive intra- and inter-patient heterogeneity in both genomic variations and tumor microenvironment (TME). However, the patterns and drivers of spatial genomic and microenvironmental heterogeneity of ESCC remain largely unknown. Here, we generated a spatial multi-omic atlas by whole-exome, transcriptome, and methylome sequencing of 507 tumor samples from 103 patients. We identified a novel tumor suppressor PREX2, accounting for 22% of ESCCs with frequent somatic mutations or hyper-methylation, which promoted migration and invasion of ESCC cells in vitro. Analysis of the TME and quantification of subclonal expansion indicated that ESCCs undergo spatially directed evolution, where subclones mostly originated from the tumor center but had a biased clonal expansion to the upper direction of the esophagus. Interestingly, we found upper regions of ESCCs often underwent stronger immunoediting with increased selective fitness, suggesting more stringent immune selection. In addition, distinct TMEs were associated with variable genomic and clinical outcomes. Among them, hot TME was associated with high immune evasion and subclonal heterogeneity. We also found that immunoediting, instead of CD8+ T cell abundance, acts as an independent prognostic factor of ESCCs. Importantly, we found significant heterogeneity in previously considered potential therapeutic targets, as well as BRCAness characteristics in a subset of patients, emphasizing the importance of focusing on heterogeneity in ESCC targeted therapy. Collectively, these findings provide novel insights into the mechanisms of the spatial evolution of ESCC and inform precision therapeutic strategies.

AIGO-DTI: Predicting Drug-Target Interactions Based on Improved Drug Properties Combined with Adaptive Iterative Algorithms.

Artificial intelligence-based methods for predicting drug-target interactions (DTIs) aim to explore reliable drug candidate targets rapidly and cost-effectively to accelerate the drug development process. However, current methods are often limited by the topological regularities of drug molecules, making them difficult to generalize to a broader chemical space. Additionally, the use of similarity to measure DTI network links often introduces noise, leading to false DTI relationships and affecting the prediction accuracy. To address these issues, this study proposes an Adaptive Iterative Graph Optimization (AIGO)-DTI prediction framework. This framework integrates atomic cluster information and enhances molecular features through the design of functional group prompts and graph encoders, optimizing the construction of DTI association networks. Furthermore, the optimization of graph structure is transformed into a node similarity learning problem, utilizing multihead similarity metric functions to iteratively update the network structure to improve the quality of DTI information. Experimental results demonstrate the outstanding performance of AIGO-DTI on multiple public data sets and label reversal data sets. Case studies, molecular docking, and existing research validate its effectiveness and reliability. Overall, the method proposed in this study can construct comprehensive and reliable DTI association network information, providing new graphing and optimization strategies for DTI prediction, which contribute to efficient drug development and reduce target discovery costs.

Etiological diagnostic performance of probe capture-based targeted next-generation sequencing in bloodstream infection.

Background: A rapid and precise etiological diagnosis is crucial for the effective treatment of bloodstream infection (BSI). In this study, the performance of probe capture-based targeted next-generation sequencing (tNGS) was compared to that of blood culture and metagenomic next-generation sequencing (mNGS) in detecting potential pathogens in patients with BSI. Methods: A total of 80 patients with suspected BSI were prospectively enrolled from 24 November 2023 to 30 December 2023 at Zhongshan Hospital, Shanghai, China. All 80 participants underwent simultaneous blood culture, blood mNGS, and blood tNGS after admission when febrile, and the results were compared. Results: Among the 80 participants, 11 were clinically diagnosed with noninfectious fever, and 69 were diagnosed with BSI. Blood tNGS had a higher sensitivity for the diagnosis of BSI than blood culture (91.3% vs. 23.2%, P<0.001) and blood mNGS (91.3% vs. 69.6%, P=0.001). There was no significant difference in specificity between blood mNGS and tNGS (81.8% vs. 100.0%, P=0.13). Blood tNGS demonstrated a faster turnaround time than blood culture and blood mNGS. In 22 (31.9%) patients with BSI, targeted adjustment of the anti-infectious therapy according to the blood tNGS results resulted in clinical improvement. Conclusions: Blood tNGS may be a promising tool for detecting potential pathogens in patients with BSI. The application of blood tNGS for BSI could guide anti-infectious treatment strategies and might improve clinical outcomes.

H2O-Mg2+ Waltz-Like Shuttle Enables High-Capacity and Ultralong-Life Magnesium-Ion Batteries.

Mg-ion batteries (MIBs) are promising next-generation secondary batteries, but suffer from sluggish Mg2+ migration kinetics and structural collapse of the cathode materials. Here, an H2O-Mg2+ waltz-like shuttle mechanism in the lamellar cathode, which is realized by the coordination, adaptive rotation and flipping, and co-migration of lattice H2O molecules with inserted Mg2+, leading to the fast Mg2+ migration kinetics, is reported; after Mg2+ extraction, the lattice H2O molecules rearrange to stabilize the lamellar structure, eliminating structural collapse of the cathode. Consequently, the demo cathode of Mg0.75V10O24·nH2O (MVOH) exhibits a high capacity of 350 mAh g-1 at a current density of 50 mA g-1 and maintains a capacity of 70 mAh g-1 at 4 A g-1. The full aqueous MIB based on MVOH delivers an ultralong lifespan of 5000 cycles The reported waltz-like shuttle mechanism of lattice H2O provides a novel strategy to develop high-performance cathodes for MIBs as well as other multivalent-ion batteries.

A Multiplex Recombinase-Aided qPCR Assay for Highly Sensitive and Rapid Detection of khe, blaKPC -2, and blaNDM -1 Genes in Klebsiella pneumoniae.

OBJECTIVE: This study aimed to establish a highly sensitive and rapid single-tube, two-stage, multiplex recombinase-aided qPCR (mRAP) assay to specifically detect the khe, blaKPC-2, and blaNDM-1 genes in Klebsiella pneumoniae. METHODS: mRAP was carried out in a qPCR instrument within 1 h. The analytical sensitivities of mRAP for khe, blaKPC-2, and blaNDM-1 genes were tested using recombinant plasmids and dilutions of reference strains. A total of 137 clinical isolates and 86 sputum samples were used to validate the clinical performance of mRAP. RESULTS: mRAP achieved the sensitivities of 10, 8, and 14 copies/reaction for khe, blaKPC-2, and blaNDM-1 genes, respectively, superior to qPCR. The Kappa value of qPCR and mRAP for detecting khe, blaKPC-2, and blaNDM-1 genes was 1, 0.855, and 1, respectively (p < 0.05). CONCLUSION: mRAP is a rapid and highly sensitive assay for potential clinical identification of khe, blaKPC-2, and blaNDM-1 genes in K. pneumoniae.

High spatial resolution elevation change dataset derived from ICESat-2 crossover points on the Tibetan Plateau.

Understanding elevation changes on the Tibetan Plateau is crucial to comprehend the changes in topography, landscape, climate, environmental conditions, and water resources. However, some of the current products that track elevation changes only cover specific surface types or limited areas, and others have low spatial resolution. We propose an algorithm to extract ICESat-2 crossover points dataset for the Tibetan Plateau, and form a dataset. The crossover points dataset has a density of 2.015 groups/km², and each group of crossover points indicates the amount of change in elevation before and after a period of time over an area of approximately 17 meters in diameter. Comparing ICESat-2 crossover points data with existing studies on glaciers and lakes, we demonstrated the reliability of the derived elevation changes. The ICESat-2 crossover points provide a refined data source for understanding high-spatial-resolution elevation changes on the Tibetan Plateau. This dataset can provide validation data for various studies that require high-precision or high-resolution elevation change data on the Tibetan Plateau.

An improved differential evolution algorithm for multi-modal multi-objective optimization.

Multi-modal multi-objective problems (MMOPs) have gained much attention during the last decade. These problems have two or more global or local Pareto optimal sets (PSs), some of which map to the same Pareto front (PF). This article presents a new affinity propagation clustering (APC) method based on the Multi-modal multi-objective differential evolution (MMODE) algorithm, called MMODE_AP, for the suit of CEC'2020 benchmark functions. First, two adaptive mutation strategies are adopted to balance exploration and exploitation and improve the diversity in the evolution process. Then, the affinity propagation clustering method is adopted to define the crowding degree in decision space (DS) and objective space (OS). Meanwhile, the non-dominated sorting scheme incorporates a particular crowding distance to truncate the population during the environmental selection process, which can obtain well-distributed solutions in both DS and OS. Moreover, the local PF membership of the solution is defined, and a predefined parameter is introduced to maintain of the local PSs and solutions around the global PS. Finally, the proposed algorithm is implemented on the suit of CEC'2020 benchmark functions for comparison with some MMODE algorithms. According to the experimental study results, the proposed MMODE_AP algorithm has about 20 better performance results on benchmark functions compared to its competitors in terms of reciprocal of Pareto sets proximity (rPSP), inverted generational distances (IGD) in the decision (IGDX) and objective (IGDF). The proposed algorithm can efficiently achieve the two goals, i.e., the convergence to the true local and global Pareto fronts along with better distributed Pareto solutions on the Pareto fronts.

Dual-Defect Engineering Strategy Enables High-Durability Rechargeable Magnesium-Metal Batteries.

Rechargeable magnesium-metal batteries (RMMBs) are promising next-generation secondary batteries; however, their development is inhibited by the low capacity and short cycle lifespan of cathodes. Although various strategies have been devised to enhance the Mg2+ migration kinetics and structural stability of cathodes, they fail to improve electronic conductivity, rendering the cathodes incompatible with magnesium-metal anodes. Herein, we propose a dual-defect engineering strategy, namely, the incorporation of Mg2+ pre-intercalation defect (P-Mgd) and oxygen defect (Od), to simultaneously improve the Mg2+ migration kinetics, structural stability, and electronic conductivity of the cathodes of RMMBs. Using lamellar V2O5·nH2O as a demo cathode material, we prepare a cathode comprising Mg0.07V2O5·1.4H2O nanobelts composited with reduced graphene oxide (MVOH/rGO) with P-Mgd and Od. The Od enlarges interlayer spacing, accelerates Mg2+ migration kinetics, and prevents structural collapse, while the P-Mgd stabilizes the lamellar structure and increases electronic conductivity. Consequently, the MVOH/rGO cathode exhibits a high capacity of 197 mAh g-1, and the developed Mg foil//MVOH/rGO full cell demonstrates an incredible lifespan of 850 cycles at 0.1 A g-1, capable of powering a light-emitting diode. The proposed dual-defect engineering strategy provides new insights into developing high-durability, high-capacity cathodes, advancing the practical application of RMMBs, and other new secondary batteries.

Spatiotemporal transcriptomic changes of human ovarian aging and the regulatory role of FOXP1.

Limited understanding exists regarding how aging impacts the cellular and molecular aspects of the human ovary. This study combines single-cell RNA sequencing and spatial transcriptomics to systematically characterize human ovarian aging. Spatiotemporal molecular signatures of the eight types of ovarian cells during aging are observed. An analysis of age-associated changes in gene expression reveals that DNA damage response may be a key biological pathway in oocyte aging. Three granulosa cells subtypes and five theca and stromal cells subtypes, as well as their spatiotemporal transcriptomics changes during aging, are identified. FOXP1 emerges as a regulator of ovarian aging, declining with age and inhibiting CDKN1A transcription. Silencing FOXP1 results in premature ovarian insufficiency in mice. These findings offer a comprehensive understanding of spatiotemporal variability in human ovarian aging, aiding the prioritization of potential diagnostic biomarkers and therapeutic strategies.

Enhancement of antitumor response of staphylococcal enterotoxin C2 mutant 2M-118 by promoting cell-mediated antitumor immunity.

BACKGROUND: Staphylococcal enterotoxin C2 (SEC2) is used as an immunotherapeutic drug in China. However, SEC2 are limited due to its immunosuppressive and toxic effects. A SEC2 2M-118 (H118A/T20L/G22E) mutant generated by site-directed mutagenesis was studied to elucidate the underlying antitumor mechanism. METHODS: The effects of 2M-118 on mouse fibrosarcoma (Meth-A) cells and cytokine responses were tested in vitro using a transwell assay and ELISA, respectively. 2M-118 effect on immune function in tumor-bearing mice was tested. Cytokine levels and antitumor responses were measured using ELISA and flow cytometry, respectively. TUNEL staining and immunohistochemistry were employed to detect the tumor apoptosis and CD4+ and CD8+ tumor infiltrating lymphocytes (TILs) in tumor tissue. RESULTS: 2M-118 demonstrated the growth inhibition on tumor cells, increase of cytokines production (IL-2, IFN-γ, and TNF-α) and splenocyte proliferation in vitro. 2M-118 effectively inhibited tumor development and increased lymphocytes and cytokines in a tumor-bearing mouse model. Additionally, 2M-118 regulated the tumormicroenvironment by reducing the number of myeloid-derived suppressor cells (MDSCs), increasing the number of TILs, and inducing tumorcell apoptosis. CONCLUSION: 2M-118 promotes immune function and enhances antitumor response. This indicates that 2M-118 could potentially be developed as a novel anti-tumor drug with-highefficiencyandlowtoxicity.

Pinning-Based Neural Control for Multiagent Systems With Self-Regulation Intermediate Event-Triggered Method.

A pinning-based self-regulation intermediate event-triggered (ET) funnel tracking control strategy is proposed for uncertain nonlinear multiagent systems (MASs). Based on the backstepping framework, a pinning control strategy is designed to achieve the tracking control objective, which only uses the communication weight between the agents without additional feedback parameters. Moreover, by designing a self-regulation triggered condition based on the tracking error, the intermediate triggered signal is calculated to replace the continuous signal in the controller, so as to achieve the goal of discontinuous update of the controller signal, and this mechanism does not need to add additional compensation function to the controller signal. At the same time, the funnel method is adopted to restrict the error of step n and avoid the possible negative impact caused by control signal. Furthermore, the nonlinear noncontinuous faults are compensated by the disturbance observer. Then, the Lyapunov stability theorem is used to prove that all signals of the closed-loop system are semiglobally uniformly ultimately bounded (SGUUB). Finally, some simulation results confirm the effectiveness of the proposed control scheme.

The feasibility of dexmedetomidine-led anesthesia maintenance strategy during major abdominal surgery.

Background: Dexmedetomidine is known for its selective action on α2-adrenoceptor sites and is recognized for its neuroprotective capabilities. It can improve postoperative cognitive function. Commonly used anesthetics, such as sevoflurane and propofol, have been reported to affect postoperative cognitive function. Therefore, it could be valuable to explore dexmedetomidine-led anesthesia strategy. This study was designed to assess the performance, safety, and effective infusion rate in anesthesia maintenance, to explore a feasible dexmedetomidine-led anesthesia maintenance protocol, and to provide a foundation for potential combined anesthesia. Methods: Thirty patients aged 18-60 years, classified as ASA I or II, undergoing abdominal surgery were involved. The anesthesia maintenance was achieved with dexmedetomidine, remifentanil and rocuronium. Dixon up-and-down sequential methodology was utilized to ascertain the ED50 of dexmedetomidine for maintaining Patient State Index (PSI) 25-40 (depth of stage III anesthesia). Intraoperative HR, BP and depth of anesthesia were monitored and controlled. The wake-up time from anesthesia, the incidence of intraoperative awareness and postoperative delirium, and the patients' satisfaction were assessed. Results: The results indicated that dexmedetomidine-led anesthesia could maintain the depth of stage III anesthesia during abdominal surgery. The ED50 and ED95 of dexmedetomidine infusion rates during anesthesia maintenance were 2.298 µg/kg·h (95%CI: 2.190-2.404 µg/kg·h) and 3.765 µg/kg·h (95%CI: 3.550-4.050 µg/kg·h). Continuous infusion of dexmedetomidine and 0.1-0.3 µg/kg·min remifentanil could maintain PSI 25-40, and provide appropriate anesthesia depth for abdominal surgery. Perioperative bradycardia and hypertension could be rapidly corrected with atropine and nitroglycerin. The median wake-up time after anesthesia was 4.8 min, the perioperative maximum HR had significant correlation with wake-up time and intraoperative dexmedetomidine dose. No intraoperative awareness and postoperative delirium occurred; the patients were satisfied with dexmedetomidine-led anesthesia. Conclusions: dexmedetomidine-led strategy could maintain stable depth of anesthesia throughout surgery, and the ED50 of dexmedetomidine infusion rates was 2.298 µg/kg·h. Intraoperative HR, BP and depth of anesthesia require monitoring, the bradycardia and hypertension could be rapidly corrected.