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Objective: The objective of this study was to decipher chemical interactions between Danshen and Danggui using liquid chromatography–mass spectrometry (LC-MS) and explore the mechanisms of Danshen–Danggui against stroke using network pharmacology and molecular docking. Materials and Methods: First, the chemical compounds of Danshen–Danggui were profiled using ultra-high-performance liquid chromatography (HPLC)-quadrupole time-of-flight MS. Accurately characterized compounds in various proportions of Danshen–Danggui were quantified using HPLC combined with triple quadrupole electrospray tandem MS. Network pharmacology was used to uncover the essential mechanisms of action of Danshen–Danggui against stroke. Discovery Studio Software was used for the molecular docking verification of key active chemicals and stroke-related targets. Results: A total of 53 compounds were characterized, and 22 accurately identified constituents (10 phenolic acids, 8 phthalides, and 4 tanshinones) were quantified in 15 proportions of Danshen–Danggui. The quantification results showed that Danggui significantly increased the dissolution of most phenolic acids (compounds from Danshen), whereas Danshen promoted the dissolution of most phthalides (compounds from Danggui). Overall, the combination of Danshen and Danggui at a 1:1 ratio resulted in the maximum total dissolution rate. Further network pharmacology and molecular docking results indicated that Danshen–Danggui exerted anti-stroke effects mainly by regulating inflammation-related (tumor necrosis factor, hypoxia-inducible factor, and toll-like receptor) signaling pathways, which ranked among the top three pathways based on Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis. Conclusion: The chemical compounds in Danshen–Danggui could interact with each other to increase the dissolution of the most active compounds, which could provide a solid basis for uncovering the compatibility mechanisms of Danshen–Danggui and Danshen–Danggui-based formulae.

Abstract Rammed earth is a kind of cleaning material, widely used in all kinds of buildings in the world. The Great Wall of ancient China is a typical world cultural site built from rammed earth. The rammed earth Great Wall of Shanhaiguan is close to Bohai Bay, which has suffered from long-term erosion by rain, causing a series of problems such as soil loss, collapse and gully flushing. The protection materials of the rammed earth site have always puzzled scholars. However, during the rainy season, it was found that some of the walls at Xiaowan Gouge and Nantuzhuang Gouge in the Shanhaiguan Great Wall had unwashed traces, the soil surface of the walls was intact, and the anti-erosion ability of the walls was significantly higher than that of other places. In order to explore the reasons for its strong anti-erosion ability in the natural state of rammed earth wall, guide the protection of rammed earth Great Wall, and carry out different experimental tests to explore its anti-erosion reasons and internal mechanisms. Firstly, the characteristics of rammed soil were understood through the composition test of rammed soil, and the indoor and outdoor erosion test was carried out to determine that the anti-erosion reason was the protection of gray-green soil crust. The property and composition of soil crust were determined through the immersion test and genome sequencing. Finally, the protection mechanism of soil crust was analyzed by scanning electron microscopy.

Abstract Fluoropyrimidine-based combination chemotherapy plus targeted therapy is the standard initial treatment for unresectable metastatic colorectal cancer (mCRC), but the prognosis remains poor. This phase 3 trial (ClinicalTrials.gov: NCT03950154) assessed the efficacy and adverse events (AEs) of the combination of PD-1 blockade-activated DC-CIK (PD1-T) cells with XELOX plus bevacizumab as a first-line therapy in patients with mCRC. A total of 202 participants were enrolled and randomly assigned in a 1:1 ratio to receive either first-line XELOX plus bevacizumab (the control group, n = 102) or the same regimen plus autologous PD1-T cell immunotherapy (the immunotherapy group, n = 100) every 21 days for up to 6 cycles, followed by maintenance treatment with capecitabine and bevacizumab. The main endpoint of the trial was progression-free survival (PFS). The median follow-up was 19.5 months. Median PFS was 14.8 months (95% CI, 11.6–18.0) for the immunotherapy group compared with 9.9 months (8.0–11.8) for the control group (hazard ratio [HR], 0.60 [95% CI, 0.40–0.88]; p = 0.009). Median overall survival (OS) was not reached for the immunotherapy group and 25.6 months (95% CI, 18.3–32.8) for the control group (HR, 0.57 [95% CI, 0.33–0.98]; p = 0.043). Grade 3 or higher AEs occurred in 20.0% of patients in the immunotherapy group and 23.5% in the control groups, with no toxicity-associated deaths reported. The addition of PD1-T cells to first-line XELOX plus bevacizumab demonstrates significant clinical improvement of PFS and OS with well tolerability in patients with previously untreated mCRC.

Deformation twins (DTs) and stacking faults (SFs) are rarely found in Cu-20Ni-20Mn alloy, which limits further strengthening of alloy. Here, we report ultra-strong Cu-20Ni-20Mn alloy prepared by introducing a high density of coherent nanoprecipitates. The ultimate tensile strength (UTS) of alloy can be largely enhanced to 1624.7 ± 14.7 MPa, while maintaining an acceptable elongation of 7.3 ± 0.5%. We find that the coherent nanoprecipitates contribute to an ultra-high true stress up to about 1740 MPa, which facilitate the formation of DTs. The strength and ductility improvement stems from the synergistic effect of dislocations, nanoprecipitates and DTs.

Abstract Patients with advanced gastric cancer typically face a grim prognosis. This phase 1a (dose escalation) and phase 1b (dose expansion) study investigated safety and efficacy of first-line camrelizumab plus apatinib and chemotherapy for advanced gastric or gastroesophageal junction adenocarcinoma. The primary endpoints included maximum tolerated dose (MTD) in phase 1a and objective response rate (ORR) across phase 1a and 1b. Phase 1a tested three dose regimens of camrelizumab, apatinib, oxaliplatin, and S-1. Dose regimen 1: camrelizumab 200 mg on day 1, apatinib 250 mg every other day, oxaliplatin 100 mg/m² on day 1, and S-1 40 mg twice a day on days 1–14. Dose regimen 2: same as dose regimen 1, but oxaliplatin 130 mg/m². Dose regimen 3: same as dose regimen 2, but apatinib 250 mg daily. Thirty-four patients were included (9 in phase 1a, 25 in phase 1b). No dose-limiting toxicities occurred so no MTD was identified. Dose 3 was set for the recommended phase 2 doses and administered in phase 1b. The confirmed ORR was 76.5% (95% CI 58.8–89.3). The median progression-free survival was 8.4 months (95% CI 5.9-not evaluable [NE]), and the median overall survival (OS) was not mature (11.6-NE). Ten patients underwent surgery after treatment and the multidisciplinary team evaluation. Among 24 patients without surgery, the median OS was 19.6 months (7.8-NE). Eighteen patients (52.9%) developed grade ≥ 3 treatment-emergent adverse events. Camrelizumab plus apatinib and chemotherapy showed favorable clinical outcomes and manageable safety for untreated advanced gastric cancer (ChiCTR2000034109).

Abstract Background Data related to the characteristics, treatments and clinical outcomes of acute exacerbation of chronic obstructive pulmonary disease (AECOPD) patients in China are limited, and sex differences are still a neglected topic. Methods The patients hospitalized for AECOPD were prospectively enrolled from ten medical centers in China between September 2017 and July 2021. Patients from some centers received follow-up for 3 years. Data regarding the characteristics, treatments and in-hospital and long-term clinical outcomes from male and female AECOPD patients included in the cohort were analyzed and compared. Results In total, 14,007 patients with AECOPD were included in the study, and 11,020 (78.7%) were males. Compared with males, female patients were older (74.02 ± 10.79 vs. 71.86 ± 10.23 years, P

Abstract Background The evolutionarily conserved protein FBXO9 acts as a substrate receptor for the SKP1-cullin-1-RBX1 ubiquitin ligase and is implicated in cancer, exhibiting either tumor-suppressive or oncogenic effects depending on the specific tumor type. However, their role in lung cancer metastasis remains unclear. Methods Lentiviral vectors carrying miRNA-based shRNA sequences for gene-specific knockdown were generated, and Lenti-CRISPR-Cas9 vectors containing gene-specific sgRNA sequences were designed. Gene overexpression was achieved using doxycycline-inducible lentiviral constructs, while gene knockdown or knockout cells were generated using shRNA and CRISPR-Cas9, respectively. Functional assays included migration, clonogenic survival assays, tumor sphere assays, and protein interaction studies using mass spectrometry, immunoprecipitation, and immunoblot analysis. Results This study identified FBXO9 as a crucial regulator that suppresses lung cancer cell migration, tumor sphere growth and restricts metastasis. We showed that FBXO9 facilitates the ubiquitination of the catalytic subunit A (ATP6V1A) of the Vacuolar-type H+-ATPase (V-ATPase), resulting in its interaction with the cytoplasmic chaperone HSPA8 and subsequent sequestration within the cytoplasm. This process hinders the assembly of functional V-ATPase, resulting in reduced vesicular acidification. In contrast, depletion of FBXO9 reduced ATP6V1A ubiquitination, resulting in increased V-ATPase assembly and vesicular acidification, thus promoting pro-metastatic Wnt signaling and metastasis of lung cancer cells. Furthermore, we demonstrated the effectiveness of inhibitors targeting V-ATPase in inhibiting lung cancer metastasis in a mouse model. Finally, we established a correlation between lower FBXO9 levels and poorer survival outcomes in patients with lung cancer. Conclusion These findings collectively elucidate the critical role of FBXO9 in regulating V-ATPase assembly and provide a molecular basis for FBXO9’s function in inhibiting lung cancer metastasis. This highlights the potential therapeutic opportunities of FBXO9 supplementation.

Abstract Abnormal lipid metabolism is an essential hallmark of glioblastoma. Hormone sensitive lipase (HSL), an important rate-limiting enzyme contributed to lipolysis, which was involved in aberrant lipolysis of glioblastoma, however, its definite roles and the relevant regulatory pathway have not been fully elucidated. Our investigations disclosed high expression of HSL in glioblastoma. Knock-down of HSL restrained proliferation, migration, and invasion of glioblastoma cells while adding to FAs could significantly rescue the inhibitory effect of si-HSL on tumor cells. Overexpression of HSL further promoted tumor cell proliferation and invasion. Bioinformatics analysis and dual-luciferase reporter assay were performed to predict and verify the regulatory role of ncRNAs on HSL. Mechanistically, hsa_circ_0021205 regulated HSL expression by sponging miR-195-5p, which further promoted lipolysis and drove the malignant progression of glioblastoma. Besides, hsa_circ_0021205/miR-195-5p/HSL axis activated the epithelial-mesenchymal transition (EMT) signaling pathway. These findings suggested that hsa_circ_0021205 promoted tumorigenesis of glioblastoma through regulation of HSL, and targeting hsa_circ_0021205/miR-195-5p/HSL axis can serve as a promising new strategy against glioblastoma.

Abstract Purpose Point-of-care ultrasound (POCUS) instruction is prevalent in medical schools but not in pediatric residency programs, even though the majority of pediatric residents desire POCUS instruction. Virtual ultrasound instruction with affordable handheld ultrasound devices may help remedy this deficiency by allowing qualified instructors to circumvent geographic and financial limitations to reach this population. This study sought to determine if virtual ultrasound instruction is an effective alternative to traditional in-person instruction in a cohort of pediatric residents for the extended Focused Assessment with Sonography in Trauma (eFAST) exam. Methods Pediatric residents were randomized to receive either in-person or virtual instruction to learn the eFAST exam using a Sonosite Edge (Sonosite, Inc., Bothell, WA) or Butterfly iQ (Butterfly Network, Inc., Guilford, CT), respectively. After the instructional session, the participants completed a timed assessment in which all required images for the eFAST exam were obtained on the same anatomic model. The content and quality of the images were then scored by expert faculty. Results There were no significant differences in assessment scores (65.8% and 61.8%, p = 0.349) and assessment duration (482.6 s and 432.6 s, p = 0.346) between pediatric residents who received in-person instruction and those who received virtual instruction. Conclusion Virtual ultrasound instruction appears to be an effective alternative to traditional in-person instruction.

Abstract Background The morbidity and mortality among hospital inpatients with AECOPD and CVDs remains unacceptably high. Currently, no risk score for predicting mortality has been specifically developed in patients with AECOPD and CVDs. We therefore aimed to derive and validate a simple clinical risk score to assess individuals’ risk of poor prognosis. Study design and methods We evaluated inpatients with AECOPD and CVDs in a prospective, noninterventional, multicenter cohort study. We used multivariable logistic regression analysis to identify the independent prognostic risk factors and created a risk score model according to patients’ data from a derivation cohort. Discrimination was evaluated by the area under the receiver-operating characteristic curve (AUC), and calibration was assessed by the Hosmer–Lemeshow goodness-of-fit test. The model was validated and compared with the BAP-65, CURB-65, DECAF and NIVO models in a validation cohort. Results We derived a combined risk score, the ABCDMP score, that included the following variables: age > 75 years, BUN > 7 mmol/L, consolidation, diastolic blood pressure ≤ 60 mmHg, mental status altered, and pulse > 109 beats/min. Discrimination (AUC 0.847, 95% CI, 0.805–0.890) and calibration (Hosmer‒Lemeshow statistic, P = 0.142) were good in the derivation cohort and similar in the validation cohort (AUC 0.811, 95% CI, 0.755–0.868). The ABCDMP score had significantly better predictivity for in-hospital mortality than the BAP-65, CURB-65, DECAF, and NIVO scores (all P

Abstract Background Cardiovascular diseases (CVDs) are the leading cause of death around the world. Most CVDs-related death can be prevented by the optimal management of risk factors such as unhealthy diet and physical inactivity. Clinical practice guidelines (CPGs) for CVDs, provide some evidence-based recommendations which help healthcare professionals to achieve the best care for patients with CVDs. This systematic review aims to appraise the methodological quality of CPGs systematically and summarize the recommendations of self-managed non-pharmacological interventions for the prevention and management of CVDs provided by the selected guidelines. Methods A comprehensive electronic literature search was conducted via six databases (PubMed, Medline, The Cochrane Library, Embase, CINAHL, and Web of Science), seven professional heart association websites, and nine guideline repositories. The Appraisal of Guidelines, Research and Evaluation II (AGREE II) instrument was adopted to critically appraise the methodological quality of the selected guidelines. Content analysis was used to summarise recommended self-managed non-pharmacological interventions for CVDs. Results Twenty-three CPGs regarding different CVDs were included, in which four guidelines of CVDs, three for coronary heart diseases, seven for heart failure, two for atrial fibrillation, three for stroke, three for peripheral arterial disease, and one for hypertrophic cardiomyopathy. Twenty CPGs were appraised as high quality, and three CPGs as moderate quality. All twenty-three CPGs were recommended for use with or without modification. The domain of “Editorial Independence” had the highest standardized percentage (93.47%), whereas the domain of “Applicability” had the lowest mean domain score of 75.41%. The content analysis findings summarised some common self-managed non-pharmacological interventions, which include healthy diet, physical activity, smoking cessation, alcohol control, and weight management. Healthy diet and physical acidity are the most common and agreed on self-managed interventions for patients with CVDs. There are some inconsistencies identified in the details of recommended interventions, the intervention itself, the grade of recommendation, and the supported level of evidence. Conclusion The majority of the summarized non-pharmacological interventions were strongly recommended with moderate to high-quality levels of evidence. Healthcare professionals and researchers can adopt the results of this review to design self-managed non-pharmacological interventions for patients with CVDs.

Abstract The sparsity of a direct record for the moment of subduction zone initiation has led to various models describing the infancy and evolution of modern oceanic subduction systems. Recently, with increases in available samples and geochemical data for subduction zone initiation-to-mature-arc lavas, better constraints on subduction evolution are possible. Here, by systemically modeling the time-space pattern and geochemical characters of forearc magmas with forward numerical modeling, we attempt to search for a best-fit geodynamic scenario where Izu-Bonin-Mariana-type subduction tends to develop. Our modeling and geochemical constraints have identified a necessary and possibly transitory pre-subduction zone initiation trenchward contraction consistent with observed Izu-Bonin-Mariana forearc magma geochemistry. Our results also reveal a typical maturation process for Izu-Bonin-Mariana-type oceanic subductions, controlled by the pace of the upper plate’s rifting and solidification.

The present study aimed to investigate the ameliorative effects of lysolecithin on fish stearin oil, meanwhile comparing the application of two different forms (lysolecithin powder and lysolecithin oil) and three inclusion levels (0.25, 0.75, 1.25 g kg−1) in largemouth bass. The entire study consisted of a 28-day digestibility trial and a consequent 68-day feeding experiment. Eight iso-nitrogenous (∼ 500 g kg−1) and iso-energetic (∼ 22 MJ kg−1) diets with high lipid level (∼ 170 g kg−1) were formulated to contain the same level of two different types of lysolecithin, and namely WFO (130 g kg−1 winterized fish oil), FSO (130 g kg−1 fish stearin oil), LLP (FSO + 1 g kg−1 lysolecithin powder, purity 250 g kg−1), MLP (FSO + 3 g kg−1 lysolecithin powder), HLP (FSO + 5 g kg−1 lysolecithin powder), LLO (FSO + 0.625 g kg−1 lysolecithin oil, purity 400 g kg−1), MLO (FSO + 1.875 g kg−1 lysolecithin oil) and HLO (FSO + 3.125 g kg−1 lysolecithin oil), respectively. Largemouth bass fed FSO showed lower apparent digestibility coefficients (ADCs) of nutrients (total fat, crude protein, gross energy, total amino acid, total essential amino acid) than the WFO. Without considering the lysolecithin type, medium and high doses (0.75, 1.25 g kg−1) significantly increased ADCs of nutrients compared with the 0.25 g kg−1 supplementation level. Lysolecithin oil significantly increased ADCs of nutrients than the lysolecithin powder. Thus, lysolecithin oil was chosen for 68-day feeding trial, and results showed the highest FBW, FI, WGR and SGR were recorded in diet HLO, and significantly higher than the FSO, LLO and MLO. Diet MLO significantly decreased lipid and energy in whole-body and lipid retention compared with the FSO, LLO and HLO. In addition, activity and mRNA expression of adipose triglyceride lipase significantly increased, while glycerol-3-phosphate acyltransferase 4 decreased in diet HLO.

Plankton, as an important part of the food chain in the river ecosystem, is sensitive to changes in the environment. To investigate the influence of plankton community structure on the aquatic ecosystem and further verify the applicability of biomanipulation, the midstream of the Jialing River was selected as the study area. A total of 149 species (varieties) from 7 phyla, 18 orders, 34 families, and 72 genera were identified for phytoplankton. A total of 48 species were found for zooplankton. The mean density of phytoplankton was 2.09 × 106 cells/L, and the mean density of zooplankton was 27.1 ind./L. Moreover, the mean values of the Shannon–Wiener diversity index (H′), Pielou homogeneity index (J′), and Margalef abundance index (D) for phytoplankton were 3.17, 0.76, and 4.47, respectively. The mean values of the Shannon–Wiener diversity index (H′), Pielou homogeneity index (J′), and Margalef abundance index (D) for zooplankton were 2.64, 0.92, and 5.07, respectively. Based on the diversity indices, the water quality was evaluated as oligo pollution to β-medium pollution level. Redundancy analysis (RDA) was used to explore the relationship between dominant plankton species and environmental factors. The RDA results show that the main environmental factors affecting the community structure of phytoplankton and zooplankton were water temperature (WT), electrical conductivity (EC), pH, total phosphorus (TP), and transparency (Secchi depth; SD). There were 17 functional groups in phytoplankton, which are X1, S1, Y, Y2, and so on. In zooplankton, there were six functional groups, which are Pmsl, Prsu, Pfif, Pmip, Lrsf and Lmic. Many articles have demonstrated the feasibility of using biological manipulation to control algae. The number of piscivorous fish in the midstream of the Jialing River had increased, and phytoplankton density in this survey was significantly decreased. The results show that traditional biomanipulation can be applied to this region, which can provide better scientific support for the future management of the aquatic environment in the Jialing River basin.

AbstractReliable landslide susceptibility maps are essential for geohazard risk management. However, the selection of models and methods in the landslide susceptibility modeling (LSM) process is subjective and can lead to uncertainties in susceptibility outcomes. This paper introduces a framework for LSM and uncertainty analysis that leverages multiple models in key steps. The framework dynamically operates and combines models at each LSM step to generate susceptibility evaluation results from various method combinations. The uncertainty of different model combinations is then analyzed by comparing these results. The framework’s effectiveness is validated using Baoji City as a case study, examining the impact of different attribute interval numbers (AIN), non-landslide negative sample selection methods, and prediction models on susceptibility prediction outcomes. The results of each group show that the highest AUC value is 0.963 (AIN = 12, buffer-controlled sampling, Random forest) is about 0.26 higher than the lowest (no AIN, low-slope controlled sampling, Support vector machine). The findings suggest that the combinations involving larger AIN values, buffer-controlled sampling, XGBoost, or Random forest model yield relatively high AUC accuracy and relatively low uncertainty in the susceptibility index.

Background We aimed to compare the cardiovascular events and mortality in patients who underwent either physician-oriented or patient-oriented kidney replacement therapy (KRT) conversion due to discontinuation of peritoneal dialysis (PD).Methods Patients with end-stage kidney disease who were receiving PD and required a switch to an alternative KRT were included. They were divided into physician-oriented group or patient-oriented group based on the decision-making process. Logistic regression analysis was used to explore the influencing factors related to KRT conversion in PD patients. The association of physician-oriented or patient-oriented KRT conversion with outcomes after the conversion was assessed by using Cox proportional hazards models.Results A total of 257 PD patients were included in the study. The median age at catheterization was 35 years. 69.6% of the participants were male. The median duration of PD was 20 months. 162 participants had patient-oriented KRT conversion, while 95 had physician-oriented KRT conversion. Younger patients, those with higher education levels, higher income, and no diabetes were more likely to have patient-oriented KRT conversion. Over a median follow-up of 39 months, 40 patients experienced cardiovascular events and 16 patients died. Physician-oriented KRT conversion increased nearly 3.8-fold and 4.0-fold risk of cardiovascular events and death, respectively. After adjusting for confounders, physician-oriented KRT conversion remained about a 3-fold risk of cardiovascular events.Conclusion Compared to patient-oriented KRT conversion, PD patients who underwent physician-oriented conversion had higher risks of cardiovascular events and all-cause mortality. Factors included age at catheterization, education level, annual household income, and history of diabetes mellitus.

ABSTRACTObjective It was to assess the efficacy of preoperative guidance using cone beam computed tomography (CBCT) and the application of autologous concentrated growth factors (CGF) for implantation in maxillary teeth with inadequate bone mass.Methods An eigenvector-based multimodal elasticity algorithm was developed. Eighty patients with insufficient bone mass in the maxillary dental region were rolled into control group (n = 40, Bio-Oss bone powder treatment) and observation group (n = 40, autologous CGF and Bio-Oss bone powder treatment). The scale-invariant feature transform (SIFT) algorithm and the hierarchical attribute matching mechanism for elastic registration (HAMMER) were introduced, whose registration time and mutual information value were compared. Therapeutic outcomes of patients were also compared.Results The eigenvector-based multimodal elastic algorithm exhibited a significantly shorter registration time versus SIFT and HAMMER algorithms, and superior accuracy, sensitivity, and specificity (p

Melon seeds have received considerable attention in recent years because of their high protein content, but they have not yet been fully used. The modification of melon seed protein (MSP) using ultrasound-assisted pH-shifting treatment was investigated in this study by analyzing structural characteristics and functional properties. The particle size, free sulfhydryl content, surface hydrophobicity, solubility, secondary structure, water-holding capacity, oil-holding capacity, emulsification activity index, and emulsification stability index of MSP were determined. MSP treated with ultrasound-assisted, pH-shifting had a smaller particle size, lower free sulfhydryl content, higher surface hydrophobicity, and solubility increased from 43.67 % to 89.12 %. The secondary structure of MSP was affected by ultrasonic treatment, manifesting as an α-helix increase and β-helix, β-turn, and random coil content decrease, which may be the reason why the protein structure became more compact after treatment. The water and oil holding capacities of MSP increased from 2.74 g/g and 3.14 g/g in untreated samples to 3.19 g/g and 3.97 g/g for ultrasound-treated samples, and further increased to 3.97 g/g and 5.02 g/g for ultrasound-assisted, pH-shifting treatment at pH 9.0, respectively. The emulsification activity index of MSP was 21.11 m2/g before treatment and reached a maximum of 32.34 m2/g after ultrasound-assisted, pH-shifting treatment at pH 9.0. The emulsification stability of MSP was maximized by ultrasonic treatment at pH 7.0. Ultrasound-assisted, pH-shifting treatment can effectively improve the functional properties of MSP by modifying the protein structure, which improves the potential application of melon seed protein in the food industry.

Abstract Objective Immunotherapy, specifically immune checkpoint inhibitors (ICIs), has revolutionized cancer treatment. However, it can also cause immune‐related adverse events (irAEs). This study aimed to develop a clinically practical animal model of irAEs using BALB/c mice. Methods Subcutaneous tumors of mouse breast cancer 4T1 cells were generated in inbred BALB/c mice. The mice were treated with programmed death‐1 (PD‐1) and cytotoxic t‐lymphocyte antigen 4 (CTLA‐4) inhibitors once every 3 days for five consecutive administration cycles. Changes in tumor volume and body weight were recorded. Lung computed tomography (CT) scans were conducted. The liver, lungs, heart, and colon tissues of the mice were stained with hematoxylin–eosin (H&E) staining to observe inflammatory infiltration and were scored. Serum samples were collected, and enzyme‐linked immunosorbent assay (ELISA) was used to detect the levels of ferritin, glutamic‐pyruvic transaminase (ALT), tumor necrosis factor‐α (TNF‐α), interferon‐gamma (IFN‐γ), and interleukin‐6 (IL‐6). Mouse liver and lung cell suspensions were prepared, and changes in macrophages, T cells, myeloid‐derived suppressor cells (MDSCs), and regulatory (Treg) cells were detected by flow cytometry. Results Mice treated with PD‐1 and CTLA‐4 inhibitors showed significant reductions in tumor volume and body weight. The tissue inflammatory scores in the experimental group were significantly higher than those in the control group. Lung CT scans of mice in the experimental group showed obvious inflammatory spots. Serum levels of ferritin, IL‐6, TNF‐α, IFN‐γ, and ALT were significantly elevated in the experimental group. Flow cytometry analysis revealed a substantial increase in CD3+T cells, Treg cells, and macrophages in the liver and lung tissues of mice in the experimental group compared with the control group, and the change trend of MDSCs was opposite. Conclusions The irAE‐related animal model was successfully established in BALB/c mice using a combination of PD‐1 and CTLA‐4 inhibitors through multiple administrations with clinical translational value and practical. This model offers valuable insights into irAE mechanisms for further investigation.

This article provides an overview of the development history and advantages and disadvantages of measurement methods for soft tissue properties of the plantar foot. The measurement of soft tissue properties is essential for understanding the biomechanical characteristics and function of the foot, as well as for designing and evaluating orthotic devices and footwear. Various methods have been developed to measure the properties of plantar soft tissues, including ultrasound imaging, indentation testing, magnetic resonance elastography, and shear wave elastography. Each method has its own strengths and limitations, and choosing the most appropriate method depends on the specific research or clinical objectives. This review aims to assist researchers and clinicians in selecting the most suitable measurement method for their specific needs.

BackgroundAlternative and complementary therapies play an imperative role in the clinical management of Type 2 diabetes mellitus (T2DM), and exploring and utilizing natural products from a genetic perspective may yield novel insights into the mechanisms and interventions of the disorder.MethodsTo identify the therapeutic target of baicalin for T2DM, we conducted a Mendelian randomization study. Druggable targets of baicalin were obtained by integrating multiple databases, and target-associated cis-expression quantitative trait loci (cis-eQTL) originated from the eQTLGen consortium. Summary statistics for T2DM were derived from two independent genome-wide association studies available through the DIAGRAM Consortium (74,124 cases vs. 824,006 controls) and the FinnGen R9 repository (9,978 cases vs. 12,348 controls). Network construction and enrichment analysis were applied to the therapeutic targets of baicalin. Colocalization analysis was utilized to assess the potential for the therapeutic targets and T2DM to share causative genetic variations. Molecular docking was performed to validate the potency of baicalin. Single-cell RNA sequencing was employed to seek evidence of therapeutic targets’ involvement in islet function.ResultsEight baicalin-related targets proved to be significant in the discovery and validation cohorts. Genetic evidence indicated the expression of ANPEP, BECN1, HNF1A, and ST6GAL1 increased the risk of T2DM, and the expression of PGF, RXRA, SREBF1, and USP7 decreased the risk of T2DM. In particular, SREBF1 has significant interaction properties with other therapeutic targets and is supported by strong colocalization. Baicalin had favorable combination activity with eight therapeutic targets. The expression patterns of the therapeutic targets were characterized in cellular clusters of pancreatic tissues that exhibited a pseudo-temporal dependence on islet cell formation and development.ConclusionThis study identified eight potential targets of baicalin for treating T2DM from a genetic perspective, contributing an innovative analytical framework for the development of natural products. We have offered fresh insights into the connections between therapeutic targets and islet cells. Further, fundamental experiments and clinical research are warranted to delve deeper into the molecular mechanisms of T2DM.

Abstract This article proposes a hierarchical distributed voltage control (HDVC) scheme for active distribution networks (ADNs) with high penetration of photovoltaics based on distributed model predictive control (DMPC) and alternating direction method of multipliers (ADMM). The reactive power outputs of several photovoltaic clusters (PVCs) and photovoltaic (PV) units within each PVC are optimally coordinated to keep PV terminal voltages and the voltages of all critical buses of ADNs within the feasible range and mitigate voltage fluctuations. In the ADN layer, a distributed reactive power control scheme based on DMPC is designed for the PVC, which regulates the voltages of all critical buses to be closed to the rated value and mitigates the reactive power variations. In the PVC layer, the reactive power outputs of PV units are optimized based on ADMM to minimize the voltage deviation of each PV terminal and track the reactive power reference from the PVC control. The proposed HDVC scheme requires communication only between neighboring PVC controller, while each PV controller only communicates with the corresponding PVC controller. This regulates the voltages in a completely decentralized manner and effectively reduces the computation burden of the PVC and PV controllers. A modified Finnish distribution network with 10 PVCs was used to validate the control performance of the proposed HDVC scheme.

Summary: Colorectal cancer (CRC) is a prevalent cancer with intraperitoneal free cancer cells (IFCCs) playing a significant role in prognosis, especially during surgeries. The identification of IFCCs is crucial for determining the stage and treatment of patients with CRC. Existing methods for IFCC detection, such as conventional cytology, immunocytochemistry (ICC), and polymerase chain reaction (PCR), have limitations in sensitivity and specificity. This study investigates the potential of long noncoding RNA (lncRNA) SNHG1 as a biomarker for detecting IFCCs in patients with CRC. Testing on a cohort of 91 patients with CRC and 26 patients with gastrointestinal benign disease showed that SNHG1 outperformed CEA in distinguishing CRC cells and detecting IFCCs across different disease stages. SNHG1 demonstrated higher sensitivity (76.1% vs. 43.1%) and specificity (68.4% vs. 52.3%) than CEA for IFCC detection in patients with CRC, suggesting its promising role as a clinical method for identifying IFCCs in CRC.