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Abstract Background Zuogui Wan (ZGW) is a traditional herbal formula used to treat chronic kidney and bone diseases. Previous research has shown that ZGW slows down the aging process of bone marrow mesenchymal stem cells (BMSCs) and improves bone metabolism. However, its role in treating postmenopausal osteoporosis (PMOP) has not yet been fully investigated. Therefore, we investigated the therapeutic effects of ZGW and its potential mechanisms in an ovariectomy (OVX)-induced osteoporosis rat model. Results We observed significant improvements in bone loss and the osteoporotic phenotype in OVX rats treated with ZGW. These findings were confirmed with micro-computed tomography (micro-CT) and histomorphological analysis. We also discovered that ZGW reversed the macrophage imbalance, which in turn inhibited osteoclast differentiation and bone resorption. Furthermore, RNA-Seq results revealed the active expression of CD51 in BMSCs before and after ZGW therapy, which is associated with macrophage polarization and osteoblastic differentiation. The results also showed that ZGW decreased CD51 + BMSCs levels, which is closely related to the inhibition of osteoblast differentiation and promotion of osteoclast resorption. Conclusions Our study demonstrated that ZGW may improve postmenopausal osteoporosis by restoring macrophage polarization and down-regulating CD51 + BMSCs. In addition, ZGW promoted osteoblast formation and inhibited osteoclast resorption.

Abstract Four new isoquinoline alkaloids, hypecotumines A-D (1–4), were isolated and identified from the whole herbs of Hypecoum erectum L. Their structures were determined by a combination of HRESIMS, NMR, and X-ray diffraction analysis methods. Compounds 1–4 were characterized by a terminal double bond at C-9 and their plausible biosynthetic pathway was hypothesized. Since PCSK9 plays a key role in the development of cardiovascular disease (CVD), exploration of PCSK inhibitors from natural products are beneficial for drug discovery of CVD treatment. SPR and Western blot assays showed compound 4 had PCSK9 inhibition activity with KD value of 59.9 µM and thus elevated the LDLR level. Further molecular docking studies demonstrated that 4 and PCSK9 could form stable interactions via key hydrogen bonds. Graphical Abstract

Ovarian cancer is a common gynecologic malignancy. In clinical practice, recurrent ovarian cancer is mainly classified into two categories on the basis of platinum-free interval, platinum-resistant and platinum-sensitive, corresponding to different treatment modalities and prognoses. The treatment of platinum-resistant ovarian cancer is challenging. Some scholars have pointed out limitations in the binary classification of platinum-free interval. In this article, the classification of recurrent ovarian cancer, the treatment challenges of platinum-resistant ovarian cancer, the limitations of the platinum-free interval binary classification, and new classification perspectives were reviewed to help physicians enhance their understanding on the research progress in ovarian cancer classification and develop more effective treatment strategies.

Abstract Background The aim of this study was to analyze the influence of the positioning of the components of total hip arthroplasty (THA) evaluated by the acetabular anteversion (AA) and femoral anteversion (FA) angle on postoperative gait in patients with symptomatic hip osteoarthritis secondary to hip dysplasia undergoing THA. Methods Between May 2023 and May 2024, patients with symptomatic hip osteoarthritis secondary to hip dysplasia (Crowe Type I and IV) who underwent THA were enrolled in the study. The AA angle and FA angle were measured by computer tomography (CT). Gait data were determined by using the Dynamic Right Gait & Posture analysis system. The relationship between FA, AA and gait data was analyzed by Pearson correlation test, subgroup Pearson correlation test, multiple linear regression. Results A total of 40 patients (45hips) were included in the study. Compared with preoperative, the patient’s postoperative foot progression angle, foot contact angle, plantarflexion velocity, swing foot speed, gait velocity, cadence, stride length were significantly improved. Preoperative FA is significantly different from postoperative FA (P

Abstract By analyzing e + e − annihilation data corresponding to an integrated luminosity of 2.93 fb −1 collected at a center-of-mass energy of 3.773 GeV with the BESIII detector, the first observation of the semileptonic decays D 0 → K S 0 π − π 0 e + ν e $$ {D}^0\to {K}_S^0{\pi}^{-}{\pi}^0{e}^{+}{\nu}_e $$ and D + → K S 0 π + π − e + ν e $$ {D}^{+}\to {K}_S^0{\pi}^{+}{\pi}^{-}{e}^{+}{\nu}_e $$ is reported. In the hypothesis that all events correspond to K 1(1270) decays, the branching fractions are measured to be B D 0 → K 1 1270 − → K S 0 π − π 0 e + ν e = 1.69 − 0.46 + 0.53 ± 0.15 × 10 − 4 $$ \mathcal{B}\left({D}^0\to {K}_1{(1270)}^{-}\left(\to {K}_S^0{\pi}^{-}{\pi}^0\right){e}^{+}{\nu}_e\right)=\left({1.69}_{-0.46}^{+0.53}\pm 0.15\right)\times {10}^{-4} $$ and B D + → K ¯ 1 1270 0 → K S 0 π + π − e + ν e = 1.47 − 0.40 + 0.45 ± 0.14 × 10 − 4 $$ \mathcal{B}\left({D}^{+}\to {\overline{K}}_1{(1270)}^0\left(\to {K}_S^0{\pi}^{+}{\pi}^{-}\right){e}^{+}{\nu}^e\right)=\left({1.47}_{-0.40}^{+0.45}\pm 0.14\right)\times {10}^{-4} $$ with statistical significance of 5.4σ and 5.6σ, respectively. When combined with measurements of the K 1(1270) → K + π − π decays, the absolute branching fractions are determined to be B D 0 → K 1 1270 − e + ν e = 1.08 − 0.13 − 0.10 + 0.14 + 0.08 ± 0.21 × 10 − 3 $$ \mathcal{B}\left({D}^0\to {K}_1{(1270)}^{-}{e}^{+}{\nu}_e\right)=\left({1.08}_{-0.13-0.10}^{+0.14+0.08}\pm 0.21\right)\times {10}^{-3} $$ and B D + → K ¯ 1 1270 0 e + ν e = 1.70 − 0.23 + 0.26 ± 0.13 ± 0.35 × 10 − 3 $$ \mathcal{B}\left({D}^{+}\to {\overline{K}}_1{(1270)}^0{e}^{+}{\nu}_e\right)=\left({1.70}_{-0.23}^{+0.26}\pm 0.13\pm 0.35\right)\times {10}^{-3} $$ . The first and second uncertainties are statistical and systematic, respectively, and the third uncertainties originate from the assumed branching fractions of the K 1(1270) → Kππ decays.

Abstract Background Influenza remains a global public health concern. Understanding the vaccination-induced response in an aging population, which is susceptible and at high risk, is essential for disease prevention and control. Here, we report findings on the safety and immunogenicity of a quadrivalent influenza split-virion vaccine (15 µg/subtype/0.5 ml/dose) (hereinafter referred to as the “quadrivalent influenza vaccine”) in a population aged ≥ 60 years. Methods This open-label, pragmatic post-marketing trial enrolled 1399 older adults to receive one dose of an approved commercially available quadrivalent influenza vaccine manufactured by Hualan Biological Bacterin Inc. (hereinafter referred to as “Hualan Bio”). Participants with contraindications for the vaccine were excluded, while poor health condition was acceptable. All vaccinated subjects experienced adverse events collection within 30 days and serious adverse events within 180 days post-vaccination. 25% subjects, selected randomly, underwent venous blood sampling pre-vaccination and 30 days after post-vaccination, for detecting antibody titers against each subtype of influenza virus by hemagglutination inhibition assay. The incidences of adverse events and antibody titers against each subtype of influenza virus were statistically analyzed using SAS 9.4. Results No grade 3 adverse reactions occurred within 30 days post-vaccination. The incidences of overall adverse reactions, local adverse reactions and systemic adverse reactions were 3.79%, 2.86% and 1.00%, respectively. No serious adverse reactions occurred within 180 days post-vaccination. There were 350 subjects who completed venous blood sampling pre-vaccination, among whom 348 subjects completed venous blood sampling at 30 days post-vaccination for immunogenicity assessment. With respect to hemagglutination inhibition antibodies against influenza viruses H1N1, H3N2, BV and BY subtypes, at 30 days post-vaccination, the seroconversion rates were 87.64%, 75.57%, 73.28% and 78.74%, respectively; the seropositive rates were 93.97%, 98.56%, 79.31% and 95.40%, respectively; and the geometric mean increase (GMI) in post-immunization/pre-immunization antibodies was 24.80, 7.26, 10.39 and 7.39, respectively. Conclusion One 15 µg/subtype dose of the vaccine had a good safety profile and elicited favorable immunogenicity among subjects aged ≥ 60 years. The results of this study indicate that Hualan Bio quadrivalent influenza vaccine strike balance between safety and immunogenicity, supporting unnecessity to increase dosage or inoculation frequency for further enhancing immunogenicity. Trial registration Registered on ClinicalTrials.gov. Registration number: NCT06334510. Registered on 28/03/2024 (retrospectively registered).

Abstract The investigation of aberrations in lipid metabolism within tumor has become a burgeoning field of study that has garnered significant attention in recent years. Lipids can serve as a potent source of highly energetic fuel to support the rapid growth of neoplasia, in where the ER-mitochondrial membrane domains (ERMMDs) provide an interactive network for facilitating communication between ER and mitochondria as well as their intermembrane space and adjunctive proteins. In this review, we discuss fatty acids (FAs) anabolic and catabolic metabolism, as well as how CPT1A-VDAC-ACSL clusters on ERMMDs participate in FAs transport, with a major focus on ERMMDs mediated collaborative loop of FAO, Ca2+ transmission in TCA cycle and OXPHOS process. Here, we present a comprehensive perspective on the regulation of aberrant lipid metabolism through ERMMDs conducted tumor physiology might be a promising and potential target for tumor starvation therapy.

A novel insertion device is introduced, designated as the Mango wiggler, designed for synchrotron radiation (SR) imaging that provides a large field of view. This innovative device is constructed from two orthogonal planar wigglers with a small difference in their period lengths, eliciting the phase difference of the magnetic fields to incrementally transitions from 0 to π/2. Such a configuration enlarges the vertical divergence of the light source, as with the horizontal divergence. The appellation `Mango wiggler' derives from the distinctive mango-shaped contour of its radiation field. A comprehensive suite of theoretical analyses and simulations has been executed to elucidate the radiation properties of the Mango wiggler, employing SPECTRA and Mathematica as calculation tools. In conjunction with the ongoing construction of the High Energy Photon Source in Beijing a practical Mango wiggler device has been fabricated for utilization in SR imaging applications. Theoretical analyses were applied to this particular Mango wiggler to yield several theoretical conclusions, and several simulations were performed according to the measured magnetic field results.

Abstract Background The global prospective surveillance data showed the re-emergence of mycoplasma pneumoniae pneumonia (MPP) in Europe and Asia after the coronavirus disease 2019 pandemic. We sought to observe the effect of macrolide antibiotics in the treatment of MPP carrying a macrolide-resistant mutation gene and the potential of targeted next-generation sequencing (tNGS) as a front-line diagnostic in MPP patients. Methods The baseline characteristics of 91 children with MPP hospitalized from January to October 2023 were retrospectively analyzed. They were divided into two groups according to whether carrying the macrolide-resistant mutation or not. The logistic and linear regression analyses were used to determine whether the mutation was a standalone predictive predictor of the duration of fever and hospital length of stay. Results First, no patients had a fever for ≥ 7 days after macrolide treatment. But length of stay and hormone concentration were significantly different between the two groups (P

Since the approval of gemtuzumab ozogamicin, an antibody–drug conjugate (ADC) targeting CD33 in 2000, 13 ADC drugs have been approved by the FDA. Although these drugs have clearly improved the survival of patients with various types of advanced cancers, their significant toxicity has compromised their therapeutic benefits. The adverse reactions of ADC drugs are complex and include on-target and off-target toxicities, where the payload drug is a determining factor. Antibody and linker may also affect the degree of toxicity. Combination therapy becomes an important strategy in anticancer treatment because of its increased efficiency, but treatment-related adverse reactions also increase accordingly. This review comprehensively analyzes the toxicity mechanisms of current ADC drugs and proposes various optimization strategies, including but not limited to optimizing linker molecules, upgrading antibody design, and changing drug administration strategies, to improve the overall safety profile of ADC drugs.

Abstract With a sample of (10087 ± 44) × 106 J/ψ events accumulated with the BESIII detector, we analyze the decays η′ → π + π − l + l − (l = e, μ) via the process J/ψ → γη′. The branching fractions are measured to be B $$ \mathcal{B} $$ (η′ → π + π − e + e − ) = (2.45 ± 0.02(stat.) ± 0.08(syst.)) × 10 −3 and B $$ \mathcal{B} $$ (η′ → π + π − μ + μ − ) = (2.16 ± 0.12(stat.) ± 0.06(syst.)) × 10 −5, and the ratio is B η ′ → π + π − e + e − B η ′ → π + π − μ + μ − = 113.4 ± 0.9 stat . ± 3.7 syst . $$ \frac{\mathcal{B}\left({\eta}^{\prime}\to {\pi}^{+}{\pi}^{-}{e}^{+}{e}^{-}\right)}{\mathcal{B}\left({\eta}^{\prime}\to {\pi}^{+}{\pi}^{-}{\mu}^{+}{\mu}^{-}\right)}=113.4\pm 0.9\left(\textrm{stat}.\right)\pm 3.7\left(\textrm{syst}.\right) $$ . In addition, by combining the η′ → π + π − e + e − and η′ → π + π − μ + μ − decays, the slope parameter of the electromagnetic transition form factor is measured to be b η′ = 1.30 ± 0.19 (GeV/c 2) −2, which is consistent with previous measurements from BESIII and theoretical predictions from the VMD model. The asymmetry in the angle between the π + π − and l + l − decay planes, which has the potential to reveal the CP-violation originating from an unconventional electric dipole transition, is also investigated. The asymmetry parameters are determined to be A CP η ′ → π + π − e + e − = − 0.21 ± 0.73 stat . ± 0.01 syst . % $$ {\mathcal{A}}_{CP}\left({\eta}^{\prime}\to {\pi}^{+}{\pi}^{-}{e}^{+}{e}^{-}\right)=\left(-0.21\pm 0.73\left(\textrm{stat}.\right)\pm 0.01\left(\textrm{syst}.\right)\right)\% $$ and A CP η ′ → π + π − μ + μ − = 0.62 ± 4.71 stat . ± 0.08 syst . % $$ {\mathcal{A}}_{CP}\left({\eta}^{\prime}\to {\pi}^{+}{\pi}^{-}{\mu}^{+}{\mu}^{-}\right)=\left(0.62\pm 4.71\left(\textrm{stat}.\right)\pm 0.08\left(\textrm{syst}.\right)\right)\% $$ , implying that no evidence of CP-violation is observed at the present statistics. Finally, an axion-like particle is searched for via the decay η′ → π + π − a, a → e + e − , and upper limits of the branching fractions are presented for the mass assumptions of the axion-like particle in the range of 0 − 500 MeV/c 2.

Abstract We measured the Born cross sections for the process e + e − → ωη′ at 22 center-of-mass energies from 2.000 to 3.080 GeV with the BESIII detector at the BEPCII collider. We observed a resonant structure with a statistical significance of 9.6σ. A Breit-Wigner fit determines its mass to be M R = (2153 ± 30 ± 31) MeV/c 2 and its width to be Γ R = (167 ± 77 ± 7) MeV, where the first uncertainties are statistical and the second are systematic.

Abstract The influence of precipitated nanophases on the mechanical properties of Fe-based amorphous nanocrystalline alloys is an urgent issue to be explored. Two amorphous nanocrystalline alloys, i.e., (Fe0.9Ni0.1)86B14 and (Fe0.7Ni0.3)86B14 containing nanophase of the body-centered cubic and face-centered cubic structures, respectively, were selected to investigate the effect of the structure and volume fraction of nanophase on their mechanical properties. The results of nanoindentation experiments and the calculation of the volume and size of the shear transition zone reveal that the two alloys show different mechanical properties. When the volume fraction of the nanophase in (Fe0.9Ni0.1)86B14 is larger than 50%, the elastic modulus is increased suddenly and the volume and size of the shear transition zone is decreased dramatically, while no dramatic change occurs in (Fe0.7Ni0.3)86B14. Moreover, it was found by using molecular dynamics simulations that the main reason for these abnormal mechanical properties is the change of cluster type in the system due to the incorporation of nanophases with different structures.

The effect of the volume fraction of nanocrystals on the macroscopic mechanical properties and microscopic atomic structure of Fe-based nanocrystalline alloys, as well as the relationship between the two, is an urgent issue to be explored. Seven nanocrystalline alloys with different volume fractions of nanocrystals were formed by annealing treatment of (Fe0·9Ni0.1)86B14 amorphous precursor. Through hardness, flat plate bending, and nanoindentation experiments, it is found that when the volume fraction of nanocrystals reaches the range of 45–55 %, there is an abrupt change in the macroscopic mechanical properties. Specifically, when the volume fraction is less than this range, the properties inherit the amorphous matrix, however, larger than this range, the properties are dominated by precipitated nanocrystalline phases. Meanwhile, based on the molecular dynamics simulation method, seven Fe90Ni10 amorphous nanocrystalline models with different volume fractions of body-centered cubic nanocrystals are established, and the deformation mechanism of models and the evolution of their microstructures during the nanoindentation process are obtained intuitively. Moreover, it is further revealed that the significant changes in the Voronoi polyhedral index, which represents the microscopic atomic structure in this range of nanocrystal volume fractions, are the main reason for the abrupt changes in the mechanical properties at the macroscopic level.

Flowering time is important for adaptation of soybean (Glycine max) to different environments. Here, we conducted a genome-wide association study of flowering time using a panel of 1490 cultivated soybean accessions. We identified three strong signals at the qFT02-2 locus (Chr02: 12037319–12238569), which were associated with flowering time in three environments: Gongzhuling, Mengcheng, and Nanchang. By analyzing linkage disequilibrium, gene expression patterns, gene annotation, and the diversity of variants, we identified an AP1 homolog as the candidate gene for the qFT02-2 locus, which we named GmAP1d. Only one nonsynonymous polymorphism existed among 1490 soybean accessions at position Chr02:12087053. Accessions carrying the Chr02:12087053-T allele flowered significantly earlier than those carrying the Chr02:12087053-A allele. Thus, we developed a cleaved amplified polymorphic sequence (CAPS) marker for the SNP at Chr02:12087053, which is suitable for marker-assisted breeding of flowering time. Knockout of GmAP1d in the ‘Williams 82’ background by gene editing promoted flowering under long-day conditions, confirming that GmAP1d is the causal gene for qFT02-2. An analysis of the region surrounding GmAP1d revealed that GmAP1d was artificially selected during the genetic improvement of soybean. Through stepwise selection, the proportion of modern cultivars carrying the Chr02:12087053-T allele has increased, and this allele has become nearly fixed (95%) in northern China. These findings provide a theoretical basis for better understanding the molecular regulatory mechanism of flowering time in soybean and a target gene that can be used for breeding modern soybean cultivars adapted to different latitudes.

This is an article in the field of mineral processing engineering. Copper is an important non-ferrous metal resource. With the increasing reduction of easily processed copper sulfide, the development and utilization of copper oxide is an important content of research in the mining field. Flotation is the main method to treat copper oxide. This paper summarizes the relevant research progress of copper oxide flotation in recent years, details the development status of direct flotation, sulfide flotation and other flotation methods, analyzes the flotation reagents, and discusses the future development direction of copper oxide flotation, aiming to provide an important theoretical basis for efficient separation of copper oxide.

Abstract Background Pediatric-type diffuse high-grade glioma (pHGG) is the most frequent malignant brain tumor in children and can be subclassified into multiple entities. Fusion genes activating the MET receptor tyrosine kinase often occur in infant-type hemispheric glioma (IHG) but also in other pHGG and are associated with devastating morbidity and mortality. Methods To identify new treatment options, we established and characterized two novel orthotopic mouse models harboring distinct MET fusions. These included an immunocompetent, murine allograft model and patient-derived orthotopic xenografts (PDOX) from a MET-fusion IHG patient who failed conventional therapy and targeted therapy with cabozantinib. With these models, we analyzed the efficacy and pharmacokinetic properties of three MET inhibitors, capmatinib, crizotinib and cabozantinib, alone or combined with radiotherapy. Results Capmatinib showed superior brain pharmacokinetic properties and greater in vitro and in vivo efficacy than cabozantinib or crizotinib in both models. The PDOX models recapitulated the poor efficacy of cabozantinib experienced by the patient. In contrast, capmatinib extended survival and induced long-term progression-free survival when combined with radiotherapy in two complementary mouse models. Capmatinib treatment increased radiation-induced DNA double-strand breaks and delayed their repair. Conclusions We comprehensively investigated the combination of MET inhibition and radiotherapy as a novel treatment option for MET-driven pHGG. Our seminal preclinical data package includes pharmacokinetic characterization, recapitulation of clinical outcomes, coinciding results from multiple complementing in vivo studies, and insights into molecular mechanism underlying increased efficacy. Taken together, we demonstrate the groundbreaking efficacy of capmatinib and radiation as a highly promising concept for future clinical trials.

Type I interferon (IFN) inhibits a wide spectrum of viruses through stimulating the expression of antiviral proteins. As an IFN-induced protein, myxovirus resistance B (MXB) protein was reported to inhibit multiple highly pathogenic human viruses. It remains to be determined whether MXB employs a common mechanism to restrict different viruses. Here, we find that IFN alters the subcellular localization of hundreds of host proteins, and this IFN effect is partially lost upon MXB depletion. The results of our mechanistic study reveal that MXB recognizes vimentin (VIM) and recruits protein kinase B (AKT) to phosphorylate VIM at amino acid S38, which leads to reorganization of the VIM network and impairment of intracellular trafficking of virus protein complexes, hence causing a restriction of virus infection. These results highlight a new function of MXB in modulating VIM-mediated trafficking, which may lead towards a novel broad-spectrum antiviral strategy to control a large group of viruses that depend on VIM for successful replication.

Cyanobacterial blooms pose a serious threat to the survival of fish because of the hepatotoxicity of microcystins produced by toxic cyanobacteria such as Microcystis. Many studies have investigated the hepatotoxicity of microcystins in common carp, a freshwater fish distributed worldwide, but the hepatotoxicity mechanism has not been fully clarified. The present study aimed to investigate the mechanism underlying the hepatic inflammatory response and hepatocyte apoptosis induced by acute microcystin-LR exposure via intraperitoneal injection (71 μg/kg and 119 μg/kg) or gavage (357.08 μg/kg) and chronic exposure to toxic Microcystis blooms. The results of acute exposure revealed that microcystin-LR caused an increase in serum transaminase activity and increased the levels of inflammatory factors and inflammatory mediators, inducing a significant inflammatory response in the liver of common carp. Moreover, biochemical detection revealed that hepatocyte apoptosis occurred in the fish. Moreover, chronic toxic Microcystis exposure also caused hepatic inflammation and subsequent apoptosis mediated by the tumour necrosis factor-α (TNF-α) pathway and the mitochondrial pathway similar to acute exposure. Therefore, our study suggests that the inflammatory response induced by microcystin-LR exacerbates apoptosis, likely mediated by TNF-α. In summary, both acute microcystin-LR exposure and chronic toxic Microcystis exposure can cause inflammation in the liver of common carp, which subsequently triggers hepatocyte apoptosis mediated by the TNF-α pathway and the mitochondrial pathway. This study helps elucidate the mechanism of liver damage induced by cyanobacterial blooms in natural water.

Background: Our previous research has shown that LKB1 in amniotic mesenchymal stem cells (MSCs) serves as a vital regulator of regulatory T cell differentiation and T cell proliferation, which may have a similar role in bone marrow MSCs (BMMSCs). Therefore, we investigated the role of LKB1 in BMMSCs for regulating CD4+ T cell proliferation in the bone micro-environment of AML. Methods: RT-PCR was used to assessed LKB1 expression in BMMSCs derived from AML patients and healthy controls. Subsequently, LKB1 was knocked down in the BMMSCs line HS-5 (HS-5-LKB1KD). Co-cultures in vitro were established to analyze the effect of HS-5-LKB1KD on CD4+ T cell. Flow cytometry was employed to measure PD-L1 and CD4+ T cell proliferation levels. Western blot was utilized to detect related proteins. Results: The expression of LKB1 in BMMSCs derived from AML patients was decreased. Knockdown of LKB1 in HS-5 resulted in upregulation of PD-L1 expression. Co-culture of peripheral blood CD4+ T cell with HS-5-LKB1KD exhibited reduced CD4+ T cell proliferation compared to co-culture with HS-5-LKB1con. Furthermore, blocking PD-L1 in the co-culture conditions could restore the reduced CD4+ T cell proliferation. Additionally, it was found that upregulation of the Wnt signaling pathway-related proteins following LKB1 knockdown in HS-5, indicating that downregulating LKB1 could promote PD-L1 expression through activation of the Wnt signaling pathway. Conclusions: The decreased expression of LKB1 in BMMSCs may activate the Wnt signaling pathway, leading to increased PD-L1 expression. This inhibited CD4+ T cell proliferation, which might lead to impaired anti-tumor immunity in AML patients and promote AML progression.

The liver is the largest solid organ in the body and is primarily composed of hepatocytes (HCs), endothelial cells (ECs), Kupffer cells (KCs), and hepatic stellate cells (HSCs), which spatially interact and cooperate with each other to maintain liver homeostasis. However, the complexity and molecular mechanisms underlying the crosstalk between these different cell types remain to be revealed. Here, we generated mice with conditional deletion of Gdf2 (also known as Bmp9) and Bmp10 in different liver cell types and demonstrated that HSCs were the major source of GDF2 and BMP10 in the liver. Using transgenic ALK1 (receptor for GDF2 and BMP10) reporter mice, we found that ALK1 is expressed on KCs and ECs other than HCs and HSCs, and GDF2 and BMP10 secreted by HSCs promote the differentiation of KCs and ECs and maintain their identity. Pdgfb expression was significantly upregulated in KCs and ECs after Gdf2 and Bmp10 deletion, ultimately leading to HSCs activation and liver fibrosis. ECs express several angiocrine factors, such as BMP2, BMP6, Wnt2, and Rspo3, to regulate HC iron metabolism and metabolic zonation. We found that these angiocrine factors were significantly decreased in ECs from Gdf2/Bmp10HSC-KO mice, which further resulted in liver iron overload and disruption of HC zonation. In summary, we demonstrated that HSCs play a central role in mediating liver cell-cell crosstalk via the production of GDF2 and BMP10, highlighting the important role of intercellular interaction in organ development and homeostasis.

Abstract Dedicator of cytokinesis 8 (DOCK8) deficiency is a primary immunodeficiency disease caused by mutations in exon 45 of the DOCK8 gene. The clinical signs primarily consist of increased serum IgE levels, eczema, repeated skin infections, allergies, and upper respiratory tract infections. Using CRISPR/Cas9 technology, we generated a DOCK8 exon 45 mutation in mice, mirroring the mutation found in patients. The results indicated that DOCK8 mutation impairs peripheral T cell homeostasis, disrupts regulatory T cells (Tregs) development, increases ICOS expression in Tregs within peripheral lymph nodes (pLn), and promotes Th17 cell differentiation within the spleen and pLn. Upon virus infection, DOCK8 mutation CD4+ T cells have a Th2 effector fate. RNA‐bulk sequencing data revealed alternations in the mTOR pathway of DOCK8 mutant CD4+ T cells. We observed that DOCK8 mutation upregulates the glycolysis levels in CD4+ T cells, which is related to the Akt/mTOR/S6/HIF‐1α pathway. In summary, our research elucidates that DOCK8 regulates the differentiation of helper T cells by modulating the glycolytic pathway in CD4+ T cells, thereby advancing the comprehension and offering potential treatment of diseases in DOCK8‐deficient patients.

Hepatocellular carcinoma (HCC) remains the fourth leading cause of cancer-associated death globally with a lack of efficient therapy. The pathogenesis of HCC is a complex and multistep process, highly reliant on de novo lipogenesis, from which tumor cells can incorporate fatty acids to satisfy the necessary energy demands of rapid proliferation and provide survival advantages. Triptolide (TP) is a bioactive ingredient exhibiting potent abilities of anti-proliferation and lipid metabolism regulation, but its clinical application is constrained because of its toxicity and non-specific distribution. The present study has developed galactosylated bovine serum albumin nanoparticles loaded with TP (Gal-BSA-TP NPs) to alleviate systemic toxicity and increase tumor-targeting and antitumor efficacy. Furthermore, Gal-BSA-TP NPs could inhibit de novo lipogenesis via the p53-SREBP1C-FASN pathway to deprive the fuel supply of HCC, offering a specific strategy for HCC treatment. In general, this study provided a biocompatible delivery platform for targeted therapy for HCC from the perspective of de novo lipogenesis.

The estimation of State of Health (SOH) for battery packs used in Electric Vehicles (EVs) is a complex task with significant importance, accompanied by several challenges. This study introduces a data-fusion model approach to estimate the SOH of battery packs. The approach utilizes dual Gaussian Process Regressions (GPRs) to construct a data-driven and non-parametric aging model based on charging-based Aging Features (AFs). To enhance the accuracy of the aging model, a noise model is established to replace the random noise. Subsequently, the state-space representation of the aging model is incorporated. Additionally, the Particle Filter (PF) is introduced to track the unknown state in the aging model, thereby developing the data-fusion-model for SOH estimation. The performance of the proposed method is validated through aging experiments conducted on battery packs. The simulation results demonstrate that the data-fusion model approach achieves accurate SOH estimation, with maximum errors less than 1.5%. Compared to conventional techniques such as GPR and Support Vector Regression (SVR), the proposed method exhibits higher estimation accuracy and robustness.

Paclitaxel plus carboplatin is the most common regimen for the treatment of ovarian cancer. While generally effective, these chemotherapy agents can cause adverse events such as myelotoxicity, nausea, vomiting, and rarely, hepatotoxicity. Paclitaxel is associated with mild elevations in serum aminotransferase levels, but significant hepatotoxicity is uncommon, particularly in patients without prior liver disease. We present a patient with ovarian cancer who developed significant elevation of serum aminotransferases up to 12 times the upper limit of normal after the first cycle of paclitaxel plus carboplatin chemotherapy. Extensive evaluations excluded other potential causes of liver injury and the diagnosis of paclitaxel-induced liver injury was confirmed. The patient was treated with liver protective medications and a reduced dose of paclitaxel (135 mg/m 2 ) for subsequent cycles. Her liver function tests stabilized within 2 to 3 times the upper limit of normal, allowing continuation of chemotherapy and achieving a favorable outcome.

Heavy metal (HM) contamination affects the composition and structure of soil microbial communities, but there are few studies on the assembly process and co-occurrence network of soil microbial community succession driven by Cd in volcanic ecosystem. To address this gap in knowledge, we collected and analyzed soil samples from the Nvshan Volcanic area to understand the microbial characteristics in primary succession soil (PS) and secondary succession soil (SS). We found that the soil was contaminated with different levels of Cd (PS > SS), resulting in obvious heterogeneity of microorganisms. The absolute abundance of bacteria (16S rRNA gene copies) varied significantly between the two successions (P < 0.0001). The co-occurrence networks analysis showed that the number of nodes in bacterial communities was lower in PS compared to SS (1002 vs. 1004), indicating that heavy metal contamination would reduce the number of soil microbial communities. Compared with PS, bacterial communities exhibited stronger competitiveness in SS (positive: negative, P/N: 25.69 vs. 64.22), whereas fungal communities were closer symbiotic relationships (positive/negative, P/N: 15.85 vs. 14.29). The neutral community model (NCM) analysis revealed that stochastic processes predominantly governed the microbial assembly process (bacterial R2: 0.657, fungal R2: 0.686). The Mantel test analysis revealed that Cd was negatively associated with cbbLR, amoA, and phoD. The results of the Sankey diagram showed that fungi were more resistant than bacteria (27 vs. 13). This study contributes to understanding the process of soil microbial succession under Cd stress and identifying microbial strains with potential for Cd remediation.

Abstract Macrophage-orchestrated inflammation contributes to multiple diseases including sepsis. However, the underlying mechanisms remain to be defined clearly. Here, we show that macrophage TP53-induced glycolysis and apoptosis regulator (TIGAR) is up-regulated in murine sepsis models. When myeloid Tigar is ablated, sepsis induced by either lipopolysaccharide treatment or cecal ligation puncture in male mice is attenuated via inflammation inhibition. Mechanistic characterizations indicate that TIGAR directly binds to transforming growth factor β-activated kinase (TAK1) and promotes tumor necrosis factor receptor-associated factor 6-mediated ubiquitination and auto-phosphorylation of TAK1, in which residues 152-161 of TIGAR constitute crucial motif independent of its phosphatase activity. Interference with the binding of TIGAR to TAK1 by 5Z-7-oxozeaenol exhibits therapeutic effects in male murine model of sepsis. These findings demonstrate a non-canonical function of macrophage TIGAR in promoting inflammation, and confer a potential therapeutic target for sepsis by disruption of TIGAR-TAK1 interaction.

Photocatalysis offers a sustainable means for the oxidative removal of low concentrations of NOx (NO, NO2, N2O, N2O5, etc.) from the atmosphere. Layered double hydroxides (LDHs) are promising candidate photocatalysts owing to their unique layered and tunable chemical structures and abundant surface hydroxide (OH−) moieties, which are hydroxyl radical (·OH) precursors. However, the practical applications of LDHs are limited by their poor charge-separation ability and insufficient active sites. Herein, we developed a facile N2H4-driven etching approach to introduce dual Ni2+ and OH− vacancies (Niv and OHv, respectively) into NiFe-LDH nanosheets (hereafter referred to as NiFe-LDH-et) to facilitate improved charge-carrier separation and active Lewis acidic site (Fe3+ and Ni2+ exposed at OHv) formation. In contrast to inert pristine LDH, NiFe-LDH-et actively removed NO under visible-light illumination. Specifically, Ni76Fe24-LDH-et etched with 1.50 mmol·L−1 N2H4 solution removed 32.8% of the NO in continuously flowing air (NO feed concentration: ∼500 parts per billion (ppb)) under visible-light illumination, thereby outperforming most reported catalysts. Experimental and theoretical data revealed that the dual vacancies promoted the production of reactive oxygen species (O2·− and ·OH) and the adsorption of NO on the LDH. In situ spectroscopy demonstrated that NO was preferentially adsorbed at Lewis acidic sites, particularly exposed Fe3+ sites, converted into NO+, and subsequently oxidized to NO3− without the notable formation of the more toxic intermediate NO2, thereby alleviating risks associated with its production and emission.

Abstract Using e + e − collision data collected at the BESIII detector at center-of-mass energies between 4.128 and 4.226 GeV, corresponding to an integrated luminosity of 7.33 fb −1, we determine the absolute branching fractions of fifteen hadronic D s + $$ {D}_s^{+} $$ decays with a double-tag technique. In particular, we make precise measurements of the branching fractions B D s + → K + K − π + = 5.49 ± 0.04 ± 0.07 % $$ \mathcal{B}\left({D}_s^{+}\to {K}^{+}{K}^{-}{\pi}^{+}\right)=\left(5.49\pm 0.04\pm 0.07\right)\% $$ , B D s + → K S 0 K + = 1.50 ± 0.01 ± 0.01 % $$ \mathcal{B}\left({D}_s^{+}\to {K}_S^0{K}^{+}\right)=\left(1.50\pm 0.01\pm 0.01\right)\% $$ and B D s + → K + K − π + π 0 = 5.50 ± 0.05 ± 0.11 % $$ \mathcal{B}\left({D}_s^{+}\to {K}^{+}{K}^{-}{\pi}^{+}{\pi}^0\right)=\left(5.50\pm 0.05\pm 0.11\right)\% $$ , where the first uncertainties are statistical and the second ones are systematic. The CP asymmetries in these decays are also measured and all are found to be compatible with zero.

Abstract Objectives The progression of knee osteoarthritis (OA) can be defined as either radiographic progression or pain progression. This study aimed to construct models to predict radiographic progression and pain progression in patients with knee OA. Methods We retrieved data from the FNIH OA Biomarkers Consortium project, a nested case-control study. A total of 600 subjects with mild to moderate OA (Kellgren-Lawrence grade of 1, 2, or 3) in one target knee were enrolled. The patients were classified as radiographic progressors (n = 297), non-radiographic progressors (n = 303), pain progressors (n = 297), or non-pain progressors (n = 303) according to the change in the minimum joint space width of the medial compartment and the WOMAC pain score during the follow-up period of 24–48 months. Initially, 376 variables concerning demographics, clinical questionnaires, imaging measurements, and biochemical markers were included. We developed predictive models based on multivariate logistic regression analysis and visualized the models with nomograms. We also tested whether adding changes in predictors from baseline to 24 months would improve the predictive efficacy of the models. Results The predictive models of radiographic progression and pain progression consisted of 8 and 10 variables, respectively, with area under curve (AUC) values of 0.77 and 0.76, respectively. Incorporating the change in the WOMAC pain score from baseline to 24 months into the pain progression predictive model significantly improved the predictive effectiveness (AUC = 0.86). Conclusions We identified risk factors for imaging progression and pain progression in patients with knee OA over a 2- to 4-year period, and provided effective predictive models, which could help identify patients at high risk of progression.

Abstract Using 24.1 fb −1 of e + e − collision data collected with the BESIII detector at the BEPCII collider, the Born cross sections and effective form factors of the e + e − → Σ + Σ ¯ − $$ {e}^{+}{e}^{-}\to {\Sigma}^{+}{\overline{\Sigma}}^{-} $$ reaction are measured. The measurements are performed at center-of-mass energies ranging from 3.510 to 4.951 GeV. No significant evidence for the decay of the charmonium(-like) states, ψ(3770), ψ(4040), ψ(4160), Y(4230), Y(4360), ψ(4415), and Y(4660), into a Σ + Σ ¯ − $$ {\Sigma}^{+}{\overline{\Sigma}}^{-} $$ final state is observed. Consequently, upper limits for the products of the branching fractions and the electronic partial widths at the 90% confidence level are reported for these decays.

Abstract Tumors desmoplastic microenvironments are characterized by abundant stromal cells and extracellular matrix (ECM) deposition. Cancer-associated fibroblasts (CAFs), as the most abundant of all stromal cells, play significant role in mediating microenvironments, which not only remodel ECM to establish unique pathological barriers to hinder drug delivery in desmoplastic tumors, but also talk with immune cells and cancer cells to promote immunosuppression and cancer stem cells-mediated drug resistance. Thus, CAFs mediated desmoplastic microenvironments will be emerging as promising strategy to treat desmoplastic tumors. However, due to the complexity of microenvironments and the heterogeneity of CAFs in such tumors, an effective deliver system should be fully considered when designing the strategy of targeting CAFs mediated microenvironments. Engineered exosomes own powerful intercellular communication, cargoes delivery, penetration and targeted property of desired sites, which endow them with powerful theranostic potential in desmoplastic tumors. Here, we illustrate the significance of CAFs in tumors desmoplastic microenvironments and the theranostic potential of engineered exosomes targeting CAFs mediated desmoplastic microenvironments in next generation personalized nano-drugs development. Graphical Abstract

Abstract Using (27.12 ± 0.14) × 108 ψ(3686) events collected with the BESIII detector at BEPCII, the decay of ψ(3686) → Ω − K + Ξ ¯ 0 $$ {\varOmega}^{-}{K}^{+}{\overline{\Xi}}^0 $$ + c.c. is observed for the first time. The branching fraction of this decay is measured to be B ψ 3686 → Ω − K + Ξ ¯ 0 + c . c . $$ {\mathcal{B}}_{\psi (3686)\to {\varOmega}^{-}{K}^{+}{\overline{\Xi}}^0+\textrm{c}.\textrm{c}.} $$ = (2.78 ± 0.40 ± 0.18) × 10 −6, where the first uncertainty is statistical and the second is systematic. Possible baryon excited states are searched for in this decay, but no evident intermediate state is observed with the current sample size.

Abstract Solution-state self-assemblies of block copolymers to form nanostructures are tremendously attractive for their tailorable morphologies and functionalities. While incorporating moieties with strong ordering effects may introduce highly orientational control over the molecular packing and dictate assembly behaviors, subtle and delicate driving forces can yield slower kinetics to reveal manifold metastable morphologies. Herein, we report the unusually convoluted self-assembly behaviors of a liquid crystalline block copolymer bearing triphenylene discotic mesogens. They undergo unusual multiple morphological transitions spontaneously, driven by their intrinsic subtle liquid crystalline ordering effect. Meanwhile, liquid crystalline orderedness can also be built very quickly by doping the mesogens with small-molecule dopants, and the morphological transitions are dramatically accelerated and various exotic micelles are produced. Surprisingly, with high doping levels, the self-assembly mechanism of this block copolymer is completely changed from intramolecular chain shuffling and rearrangement to nucleation-growth mode, based on which self-seeding experiments can be conducted to produce highly uniform fibrils.

Background: Nitrate, a key component of saliva, has been shown widely physiological functions in the human body. But its function on bone metabolism remains unclear. The aim of this study was to investigate the function and mechanism of saliva nitrate on osteoporosis and the function of bone marrow mesenchymal stem cells (BMSCs). Methods: Saliva nitrate removal or supplemental interventions were performed for 1 month in ovariectomized (OVX) osteopenia mice. The nitrate levels in saliva and serum were detected. The bone formation and bone microarchitecture in the OVX mouse model were investigated by quantitative Micro--computed tomography imaging, histological staining and serum bone biomarker analysis. The effects of nitrate on the functional homeostasis of BMSCs in OVX mice were explored by Ki67 immunofluorescence staining, Ki67 flow staining, alizarin red staining, qPCR and western blotting. Finally, downstream signaling pathways were screened by proteomics and verified by western blotting. Results: The results showed that nitrate deficiency exacerbated osteoporosis, while nitrate administration prevent osteoporosis in OVX mice. Nitrate increased the expression of PINP, a biomarker of bone formation, in OVX mice. Besides, nitrate enhanced the proliferative capacity and osteogenic function of BMSCs in OVX mice in vitro and in vivo. In addition, nitrate upregulated the expression levels of osteogenesis-related genes ALP, Run2 and OPN of BMSCs. EGFR and mTOR signaling were screened as the key downstream of nitrate, and phosphorylated protein levels of its subfamily members AKT, ERK and S6K were significantly upregulated by nitrate. Conclusion: The present results showed saliva nitrate preventively protects against osteoporosis through enhances the proliferation and osteogenic differentiation potential of BMSCs. The effects of nitrate on bone homeostasis are closely related to the EGFR/AKT/ERK and mTOR/S6K signaling axes. The translational potential of this article: Our study provides experimental evidence for the use of saliva nitrate as an effective candidate for the prevention of osteoporosis and maintenance of bone homeostasis.

Abstract The hemorrhagic progression of a contusion (HPC) after Traumatic brain injury (TBI) is one of the important causes of death in trauma patients. The purpose of this meta-analysis was to evaluate the predictive effect of imaging features of Computed tomography (CT) on HPC after TBI. A comprehensive systematic search was performed using PubMed, EMBASE, and WEB OF SCIENCE databases to identify all relevant literature. A total of 8 studies involving 2543 patients were included in this meta-analysis. Meta-analysis showed that subarachnoid hemorrhage (OR 3.28; 95% CI 2.57–4.20), subdural hemorrhage (OR 4.35; 95% CI 3.29–5.75), epidural hemorrhage (OR 1.47;95% CI 1.15–1.89), contrast extravasation (OR 11.81; 95% CI 4.86–28.71) had a predictive effect on the occurrence of HPC. Skull fracture (OR 1.64; 95% CI 0.84–3.19) showed no statistical significance, and midline displacement > 5 mm (OR 4.66; 95% CI 1.87–11.62) showed high heterogeneity. The results of this meta-analysis showed that some imaging features were effective predictors of HPC after TBI. Well-designed prospective studies are needed to more accurately assess the effective predictors of HPC after TBI.

Abstract Background The objective of the current study was to investigate the correlation between trajectories of maternal perinatal depression (PND) spanning from early pregnancy to one year postpartum and developmental delays observed in one-year-old children. Methods The dataset under examination encompassed 880 women who took part in a mother-child birth study conducted in China. Latent class growth analysis (LCGA) was employed to identify patterns in Edinburgh Postnatal Depression Scale (EPDS) scores of women, spanning from early pregnancy to one year postpartum. To assess the neurodevelopment of one-year-old children, a Chinese version of the Bayley Scale of Infant Development (BSID-CR) was employed. Logistic regression was employed to explore the association between PND trajectories and developmental delays in children, with appropriate covariate adjustments. Results The trajectories of maternal PND identified in this study included a minimal-stable symptom group (n = 155), low-stable symptom group (n = 411), mild-stable symptom group (n = 251), and moderate-stable symptom group (n = 63). Logistic regression analysis revealed that mothers falling into the moderate-stable symptom group exhibited a notably heightened risk of having a child with psychomotor developmental delays at the age of one year. Conclusions The findings drawn from a representative sample in China provide compelling empirical evidence that bolsters the association between maternal PND and the probability of psychomotor developmental delays in children. It is imperative to develop tailored intervention strategies and meticulously design mother-infant interactive intervention programs for women with PND.

Abstract The development of algorithms and the spread of digital infrastructure have contributed significantly to the productivity of the digital economy. Data has come to be known as the “oil of the digital economy”. At the same time, data has begun to participate more deeply in the production activities of the global sports industry chain, and the international discussion on how to protect the rights of sports event data has been increasing. Based on the configurational theory and fuzzy-set qualitative comparative analysis, this study discusses the factors affecting the protection of sports event data rights. The study found three configuration paths for achieving high enterprise data protection effectiveness and two for achieving low enterprise data protection effectiveness. The results of this study provide theoretical support for governments to address the issue of sports event data rights. They will also facilitate the safe use of data in sports, promote the global sports industry and humanitarian action development, and contribute to international sustainable development.

Abstract Background N6-methyladenosine (m6A) is dysregulated in various cancers, including colorectal cancer (CRC). Herein, we assess the diagnostic potential of peripheral blood (PB) m6A levels in CRC. Methods We collected PB from healthy controls (HCs) and patients with CRC, analyzed PB RNA m6A levels and the expression of m6A-related demethylase genes FTO and ALKBH5, cocultured CRC cells with PB mononuclear cells (PBMCs), and constructed an MC38 cancer model. Results PB RNA m6A levels were higher in the CRC than that in HCs. The area under the curve (AUC) of m6A levels (0.886) in the CRC was significantly larger compared with carbohydrate antigen 199 (CA199; 0.666) and carcinoembryonic antigen (CEA; 0.834). The combination of CEA and CA199 with PB RNA m6A led to an increase in the AUC (0.935). Compared with HCs, the expression of FTO and ALKBH5 was decreased in the CRC. After coculturing with CRC cells, the PBMCs RNA m6A were significantly increased, whereas the expression of FTO and ALKBH5 decreased. Furthermore, m6A RNA levels in the PB of MC38 cancer models were upregulated, whereas the expression of FTO and ALKBH5 decreased. Conclusions PB RNA m6A levels are a potential diagnostic biomarker for patients with CRC.

ABSTRACTThe United Nations reported that the mortality risk of Corona Virus Disease 2019 (COVID-19) is five times higher in the elderly than the global average. Although the COVID-19 vaccine effectively prevents infections and reduce mortality among the elderly, vaccine hesitancy among the Chinese elderly poses a significant threat. This study, utilizing the “Confidence, Convenience and Complacency (3 Cs)” vaccine hesitancy model, aimed to explore factors contributing to vaccine hesitancy among the Chinese elderly and assess national countermeasures and potential improvement approaches. Thirteen elderly with vaccine hesitancy and eleven vaccine-related staff participated in semi-structured interviews. Thematic analysis revealed three key determinants of vaccine hesitancy among the elderly: perceived low threat of COVID-19, lack of confidence in COVID-19 vaccine, and poor accessibility to vaccination. China has implemented strategies, including advocacy through diverse channels, joint multi-sectoral promotion vaccination, and enhancing ongoing vaccination services. Recommendations from the vaccine-related staff emphasize improving vaccine awareness among the elderly, and prioritizing the vaccination environment and process. The study underscores the importance of targeted vaccination promotion programs addressing hesitation reasons to improve vaccination rates. Furthermore, existing countermeasures can serve as a foundation for enhancing vaccination strategies, including improved publicity, administration, and management approaches.

Abstract Currently, cancer is still a leading cause of human death globally. Tumor deterioration comprises multiple events including metastasis, therapeutic resistance and immune evasion, all of which are tightly related to the phenotypic plasticity especially epithelial–mesenchymal plasticity (EMP). Tumor cells with EMP are manifest in three states as epithelial–mesenchymal transition (EMT), partial EMT, and mesenchymal–epithelial transition, which orchestrate the phenotypic switch and heterogeneity of tumor cells via transcriptional regulation and a series of signaling pathways, including transforming growth factor‐β, Wnt/β‐catenin, and Notch. However, due to the complicated nature of EMP, the diverse process of EMP is still not fully understood. In this review, we systematically conclude the biological background, regulating mechanisms of EMP as well as the role of EMP in therapy response. We also summarize a range of small molecule inhibitors, immune‐related therapeutic approaches, and combination therapies that have been developed to target EMP for the outstanding role of EMP‐driven tumor deterioration. Additionally, we explore the potential technique for EMP‐based tumor mechanistic investigation and therapeutic research, which may burst vigorous prospects. Overall, we elucidate the multifaceted aspects of EMP in tumor progression and suggest a promising direction of cancer treatment based on targeting EMP.

The distribution of heat absorption and the mechanisms of conductive, convective, and radiative heat transfers between cold particle clusters (Tp = 300 K) and high-temperature surfaces (Tw = 1173 K) in fluidized beds were investigated through numerical simulations using the MFiX-DEM approach. The influence of cluster characteristics (εc and Dc), restitution coefficients (ep and ew), and particle properties (dp, ρp, kp, and cp) on heat absorption and various heat transfers was examined. The simulations indicate that convection predominantly governed the heat transfer behavior during the process of mesoscale clusters impacting the surfaces. A significant increase in heat transfer can be attained by reducing the cluster volume fraction, cluster size, particle diameter, and particle density. Besides, decreasing the restitution coefficients allowed for a relatively small enhancement of heat absorption. The maximum difference in ep was 2.11 kW/kg, while the maximum difference in ew was 0.99 kW/kg. The specific heat capacity and thermal conductivity of the particle had little influence on the distribution of heat absorption and heat transfer with a maximum relative error of up to 5.8 %. Finally, the mathematical correlation during surface-to-cluster heat transfer was established. This work introduces a novel application of the MFiX-DEM approach to analyze surface-to-cluster heat transfer at the particle scale, providing valuable insights for optimizing fluidized bed systems.

Ferroptosis is an iron-dependent programmed cell death (PCD) enforced by lipid peroxidation accumulation. Transferrin receptor (TFRC), one of the signature proteins of ferroptosis, is abundantly expressed in hepatocellular carcinoma (HCC). However, post-translational modification (PTM) of TFRC and the underlying mechanisms for ferroptosis regulation remain less understood. In this study, we found that TFRC undergoes O-GlcNAcylation, influencing Erastin-induced ferroptosis sensitivity in hepatocytes. Further mechanistic studies found that Erastin can trigger de-O-GlcNAcylation of TFRC at serine 687 (Ser687), which diminishes the binding of ubiquitin E3 ligase membrane-associated RING-CH8 (MARCH8) and decreases polyubiquitination on lysine 665 (Lys665), thereby enhancing TFRC stability that favors labile iron accumulation. Therefore, our findings report O-GlcNAcylation on an important regulatory protein of ferroptosis and reveal an intriguing mechanism by which HCC ferroptosis is controlled by an iron metabolism pathway.

Due to global warming, high temperature stress severely impacts maize growth and development, especially during the early filling stage. Supplemental irrigation is an effective measure to mitigate high temperature stress in maize. However, the underlying mechanism for alleviating transient high temperature stress during the early grain-filling stage is still unclear. A two-year field experiment involving high temperature during the early filling stage (HT), supplemental irrigation under high temperature stress (HTW), supplemental irrigation under control condition (W), and control treatment (CK) by using heat-tolerant variety ZD958 and heat-sensitive variety XY335 was conducted. Compared with the CK treatment, the HT treatment significantly decreased the activities of superoxide dismutase (SOD), peroxidase (POD), and catalase (CAT). HT also significantly reduced the Pn, soluble sugar content in stem, and dry matter accumulation, thus reducing kernel number per ear and yield by 11.2–17.6% and 23.4–23.7% in the both variety, respectively. However, compared with HT, the HTW treatment reduced the daily mean canopy temperature of ZD958 and XY335 by 2.6 °C and 2.8 °C, respectively. Accordingly, HTW increased SPAD value, photosynthetic performance, starch and soluble sugars content in stems and leaves, and antioxidant enzymes activities, but reduced the malondialdehyde (MDA). Moreover, HTW increased the grain sink capacity, prolonged the effective filling days by 1.4–6.5 d, and increased the average filling rate by 14.8–41.0% compared with HT. Finally, grain yield of HTW was increased by 15.8–22.3% compared with HT. Therefore, supplemental irrigation could effectively enhanced maize heat resistance by reduce canopy temperature. This study provides important insights into enhancing maize resistance and yield stability under a warming climate.

ObjectiveThe study aims to investigate the protective effect of Mingjing granule (MG) in a fibrovascular membrane rat model of neovascular age-related macular degeneration (nAMD) and explore the underlying mechanism.MethodsThe nAMD fibrovascular membrane model was established by two-stage laser photocoagulation. BN rats were randomly divided into four groups: the model group was gavaged with distilled water, the anti-VEGF group was given an intravitreous injection of ranibizumab, the MG + anti-VEGF group was gavaged with MG combined with an intravitreous injection of ranibizumab, and the normal group not modeled only fed conventionally. Lesions were evaluated by color fundus photograph, optical coherence tomography, fundus fluorescein angiography, and retinal pigment epithelial–choroid–sclera flat mount. The changes in the retinal structure were observed by histopathology. The expression of inflammatory cell markers F4/80, Iba-1, and glial fibrillary acidic protein (GFAP); the fibrosis-related factors collagen-1, fibronectin, α-smooth muscle actin (α-SMA), and transforming growth factor-beta (TGF-β); and the complement system-related factors C3a and C3aR in the retina were detected by immunofluorescence or qRT-PCR.ResultsThe current study revealed that MG + anti-VEGF administration more significantly reduced the thickness of fibrovascular lesions, suppressed vascular leakage (exudation area and mean density value), inhibited the area of fibrovascular lesions, and restrained the formation of the fibrovascular membrane than the anti-VEGF agent alone in the two-stage laser-induced rat model. The fluorescence intensities of F4/80, Iba-1, collagen-1, fibronectin, TGF-β, and C3aR showed more significant inhibition in MG + anti-VEGF-treated rats than the anti-VEGF agent alone. The mRNA expression levels of F4/80, Iba-1, GFAP, collagen-1, fibronectin, α-SMA, TGF-β, and C3a showed lower levels in rats treated with MG + anti-VEGF than the anti-VEGF agent alone.ConclusionCombining MG with anti-VEGF treatment inhibits the growth of the fibrovascular membrane more effectively than using anti-VEGF treatment alone. The mechanism underlying this effect may involve limiting inflammatory cell aggregation, controlling complement system activation, and decreasing the expression of the fibrotic protein.

Knee osteoarthritis (KOA) is one of the most common degenerative joint diseases in the elderly worldwide. The primary lesion in patients with KOA is the degeneration of articular cartilage. This study aimed to observe the biological effects of cyclic negative pressure on C28/I2 chondrocytes and to elucidate the underlying molecular mechanisms. We designed a bi-directional intelligent micro-pressure control device for cyclic negative pressure intervention on C28/I2 chondrocytes. Chondrocyte vitality and proliferation were assessed using Cell Counting Kit-8 (CCK-8) and 5-ethynyl-2'-deoxyuridine (EdU) assays. The extracellular matrix was analyzed using real-time fluorescence quantitative polymerase chain reaction (PCR) and western blot, while the molecular mechanism of the chondrocyte response to cyclic negative pressure was explored through mRNA sequencing. Experimental data demonstrated that cyclic negative pressure promoted chondrocyte proliferation and upregulated the expression of chondrocyte-specific protein, namely the collagen type II alpha 1 chain (COL2A1) protein, and the transcription factor SRY-box transcription factor 9 (SOX9). Additionally, RNA sequencing analysis revealed that the gene levels of insulin-like growth factor 2 (IGF-II) and early growth response 1 (EGR-1) were significantly elevated in the cyclic negative pressure group. This study demonstrates that cyclic negative pressure stimulates the proliferation of C28/I2 chondrocytes by promoting the expression of EGR-1 and IGF-II. This new discovery may provide novel insights into cartilage health and KOA prevention.

In this paper the integration of international understanding into design education will be discussed. Through an exposition of UNESCO's concept of Education for international understanding. I will discuss the fundamental goal of promoting world peace and the artistic vision of “understanding”. It will discuss what positive educational explorations and practices design education can undertake to expand the humanistic connotations of international understanding, promote intercultural understanding, and peaceful and friendly development, and what basic qualities it should cultivate.

BackgroundClear cell renal cell carcinoma (ccRCC) is a metabolic disorder characterized by abnormal lipid accumulation in the cytoplasm. Lipid metabolism-related genes may have important clinical significance for prognosis prediction and individualized treatment.MethodsWe collected bulk and single-cell transcriptomic data of ccRCC and normal samples to identify key lipid metabolism-related prognostic signatures. qPCR was used to confirm the expression of signatures in cancer cell lines. Based on the identified signatures, we developed a lipid metabolism risk score (LMRS) as a risk index. We explored the potential application value of prognostic signatures and LMRS in precise treatment from multiple perspectives.ResultsThrough comprehensive analysis, we identified five lipid metabolism-related prognostic signatures (ACADM, ACAT1, ECHS1, HPGD, DGKZ). We developed a risk index LMRS, which was significantly associated with poor prognosis in patients. There was a significant correlation between LMRS and the infiltration levels of multiple immune cells. Patients with high LMRS may be more likely to respond to immunotherapy. The different LMRS groups were suitable for different anticancer drug treatment regimens.ConclusionPrognostic signatures and LMRS we developed may be applied to the risk assessment of ccRCC patients, which may have potential guiding significance in the diagnosis and precise treatment of ccRCC patients.

With the advancements of IoT and blockchain, a novel era has emerged in the domain of smart building systems. At the same time, it also brings some problems and challenges. Most traditional solutions typically utilize the fully-replicated storage strategy that results in high storage costs, while recent solutions like coded blockchain may compromise query efficiency. Moreover, traditional reputation-based consensus schemes do not consider dynamic situations, limiting scalability. To handle these problems, we propose a novel hierarchical message aggregation scheme and a classified storage method under Reed–Solomon (RS) coding to minimize storage overhead while ensuring data recoverability and query performance. Additionally, we introduce a dynamic incentive reputation consensus mechanism to tackle scalability challenges such as preventing node monopolies, promoting new node integration, and enhancing fault tolerance. Through theoretical analysis and experimental simulation, the proposed scheme demonstrates a high degree of decentralization and scalability. Our scheme achieves a 20% reduction in the Gini coefficient compared to other approaches. Furthermore, our scheme can save 19 of storage overhead compared to traditional solutions while maintaining high query performance.