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Abstract Targeted alpha (α) therapy (TAT) is an emerging therapeutic strategy for cancer treatment. To evaluate the safety and efficacy of targeted α‐therapy, the biodistribution and internal radiation dose of α‐emitting radionuclides should be determined. In vivo imaging of these radionuclides often involves the detection of gamma rays, X‐rays, and positrons generated during their complex decay processes. This review aims to classify the α‐emitting radionuclides (astatine‐211, actinium‐225, radium‐223, bismuth‐212, bismuth‐213, thorium‐227, and terbium‐149) according to their imageable signals. Additionally, this study summarizes various imaging modalities, including gamma camera imaging, single‐photon emission computed tomography, positron emission tomography, Compton imaging, bremsstrahlung imaging, and Cerenkov luminescence imaging, which hold potential for imaging α‐emitting radionuclides, to explore their biomedical applications in qualitative nuclide tracing and diagnosis, quantifying pharmacokinetics, and assessing prognosis and response to therapy.

Abstract Background Currently, the synthesis pathway of metal nuclide-labeled radiopharmaceuticals is mainly divided into two steps: first, connecting the chelator with the target molecule, and second, labeling the metal nuclide to the chelator. However, the second step of the reaction to label the metal nuclide requires high temperature (90–100 °C), which tends to denature and inactivate the target molecule, leading to loss of biological activities, especially the targeting ability. A feasible solution may be the click chemistry labeling method, which consists of reacting a metal nuclide with a chelating agent to generate an intermediate and then synthesizing a radiopharmaceutical agent via the click chemistry intermediate and the target molecule-alkyne compound. In this study, through the click chemistry of 177Lu-DOTA-N3 with prostate-specific membrane antigen (PSMA)-alkyne compound, 177Lu-labeled PSMA-targeted molecular probe was synthesized and evaluated for its potential to be cleared from the bloodstream and rapidly distributed to tissues and organs, achieving a high target/non-target ratio. 177Lu-PSMA-617 was utilized as an analogue for comparison in terms of synthesizing efficiency and PSMA-targeting ability. Results A novel 177Lu-labeled PSMA radioligand was successfully synthesized through the click chemistry of 177Lu-DOTA-N3 with PSMA-alkyne compound, and abbreviated as 177Lu-DOTA-CC-PSMA, achieving a radiochemical yield of 77.07% ± 0.03% (n = 6) and a radiochemical purity of 97.62% ± 1.49% (n = 6) when purified by SepPak C18 column. Notably, 177Lu-DOTA-CC-PSMA was characterized as a hydrophilic compound that exhibited stability at room temperature and commendable pharmacokinetic properties, such as the superior uptake (19.75 ± 3.02%ID/g at 0.5 h) and retention (9.14 ± 3.16%ID/g at 24 h) within xenografts of 22Rv1 tumor-bearing mice. SPECT/CT imaging indicated that radioactivity in both kidneys and bladder was essentially eliminated after 24 h, while 177Lu-DOTA-CC-PSMA was further enriched and retained in PSMA-expressing tumors, resulting in the high target/non-target ratio. Conclusion This study demonstrated the potential of click chemistry to unify the synthesis of metal radiopharmaceuticals, and 177Lu-DOTA-CC-PSMA was found for rapid clearance and appropriate chemical stability as a PSMA-targeted radioligand.

Abstract Stroke is a leading cause of mortality and long-term disability globally, with acute ischemic stroke (AIS) being the most common subtype. Despite significant advances in reperfusion therapies, their limited time window and associated risks underscore the necessity for novel treatment strategies. Stem cell-derived extracellular vesicles (EVs) have emerged as a promising therapeutic approach due to their ability to modulate the post-stroke microenvironment and facilitate neuroprotection and neurorestoration. This review synthesizes current research on the therapeutic potential of stem cell-derived EVs in AIS, focusing on their origin, biogenesis, mechanisms of action, and strategies for enhancing their targeting capacity and therapeutic efficacy. Additionally, we explore innovative combination therapies and discuss both the challenges and prospects of EV-based treatments. Our findings reveal that stem cell-derived EVs exhibit diverse therapeutic effects in AIS, such as promoting neuronal survival, diminishing neuroinflammation, protecting the blood-brain barrier, and enhancing angiogenesis and neurogenesis. Various strategies, including targeting modifications and cargo modifications, have been developed to improve the efficacy of EVs. Combining EVs with other treatments, such as reperfusion therapy, stem cell transplantation, nanomedicine, and gut microbiome modulation, holds great promise for improving stroke outcomes. However, challenges such as the heterogeneity of EVs and the need for standardized protocols for EV production and quality control remain to be addressed. Stem cell-derived EVs represent a novel therapeutic avenue for AIS, offering the potential to address the limitations of current treatments. Further research is needed to optimize EV-based therapies and translate their benefits to clinical practice, with an emphasis on ensuring safety, overcoming regulatory hurdles, and enhancing the specificity and efficacy of EV delivery to target tissues. Graphical Abstract

Background: Remote ischemic conditioning (RIC) is considered a promising non-pharmacological therapeutic strategy to mitigate ischemic injury. Although the precise mechanisms of RIC's protective effects remain elusive, existing data suggest that exosomes contribute significantly to these processes through cell-to-cell communication Objective: This review aims to elucidate the role of exosomes in RIC-mediated multi-organ protection. Methods: We systematically searched multiple databases through October 2023 for preclinical studies evaluating the effect of exosomes in ischemic models using RIC procedures. Key outcomes, such as improved organ function and reduced infarct size, were recorded. Articles were selected and data were extracted by independent pairs of reviewers. Findings: A total of 16 relevant studies were identified in this review, showing that circulating exosomes derived from the plasma of RIC-treated animals exhibited protective effects akin to those of the RIC procedure itself. Exosome concentrations were measured in eight studies, six of which reported significant increases in the RIC group. Additional findings indicated that RIC might primarily modulate the expression of miRNAs and bioactive molecules delivered by exosomes, rather than directly altering circulating exosome levels. Notably, the expression of 11 distinct exosomal miRNAs was altered after RIC intervention, potentially involving multiple pathways. Conclusion: Exosomes appear to play a pivotal role in the protective effects induced by RIC. Clarifying their function in RIC under different pathological situations represents a grand challenge for future research.

We report on the metal-free and rapid catalytic conversion of carbon dioxide into cyclic carbonates under solventless conditions utilizing novel bifunctional fluoroalcohol-based ionic liquids (FBILs) as catalsyts. In the presence of 2.5 mol% 4-(1,1,1,3,3,3-hexafluoro-2-hydroxyisopropyl) phenyl trimethylammonium iodide (FBIL-1), under 0.1 MPa and 90 °C, excellent yield of propylene carbonate(>95%) was achieved in 1 h, which significantly shortens the reaction time, compared with the conventional catalysts. DFT calculations reveal that FBILs with fluorine-substituted hydroxyl groups exhibit stronger hydrogen bonding with epoxides compared to ILs lacking fluorine substitutions. The hydrogen bond length for ILF/PO is 1.658 Å, shorter than that for IL/PO (1.813 Å). This characteristic contributes to reducing the activation energy for the ring-opening reaction of epoxides. In the ILF/PO system, the reaction barrier is 88.72 kJ·mol−1, lower than the 101.46 kJ·mol−1 barrier for IL/PO, allowing the former to more rapidly facilitate the fixation of carbon dioxide into cyclic carbonates. Besides high catalytic efficiency, these FBILs have the characteristics of a facile synthesis route and easy post-reaction recovery.

In this work, SiCp reinforced Al–Si–Mg matrix composites were prepared by stirring casting with different SiCp sizes. The effect of SiCp sizes on the microstructure and mechanical properties was investigated, and different strengthening effects were systematically calculated and analyzed. With the decrease of SiCp sizes, the microstructure of composites is refined and the plasticity is improved significantly. The refined SiCp also leads to a more intense grain refinement strengthening and thermal expansion mismatch strengthening. However, an abnormal decrease of yield strength is discovered with the refinement of SiCp, which is due to the influence of SiCp on GP zones strengthening in the matrix. As SiCp sizes decreasing, the increased SiCp/Al interfaces capture more Mg atoms, and then inhibits the formation of GP zones in the α-Al. Therefore, the refined SiCp weaken the precipitation strengthening in composites. These acicular Mg–Si GP zones exhibit a preferentially growing direction along Al and present a same structure as α-Al with coherent interfaces which pin dislocations and provide precipitation strengthening. The high density of GP zones also increases nano-hardness and elastic modulus of α-Al, which improves the wear resistance of SiCp/Al–Si–Mg composites. Therefore, it is suggested that the interaction between the SiCp and precipitates in matrix should also be considered to obtain a suitable strengthening effect in the design of SiCp/Al alloy composites.

Abstract Interactions between oncogenic proteins contribute to the phenotype and drug resistance. Here, EZH2 (enhancer of zest homolog 2) is identified as a crucial factor that mediates HIF‐1 (hypoxia‐inducible factor) inhibitor resistance. Mechanistically, targeting HIF‐1 enhanced the activity of EZH2 through transcription activation of SUZ12 (suppressor of zest 12 protein homolog). Conversely, inhibiting EZH2 increased HIF‐1α transcription, but not the transcription of other HIF family members. Additionally, the negative feedback regulation between EZH2 and HIF‐1α is confirmed in lung cancer patient tissues and a database of cell lines. Moreover, molecular prediction showed that a newly screened dual‐target compound, DYB‐03, forms multiple hydrogen bonds with HIF‐1α and EZH2 to effectively inhibit the activity of both targets. Subsequent studies revealed that DYB‐03 could better inhibit migration, invasion, and angiogenesis of lung cancer cells and HUVECs in vitro and in vivo compared to single agent. DYB‐03 showed promising antitumor activity in a xenograft tumor model by promoting apoptosis and inhibiting angiogenesis, which could be almost abolished by the deletion of HIF‐1α and EZH2. Notably, DYB‐03 could reverse 2‐ME2 and GSK126‐resistance in lung cancer. These findings clarified the molecular mechanism of cross‐regulation of HIF‐1α and EZH2, and the potential of DYB‐03 for clinical combination target therapy.

Summary: Drug resistance is the leading problem in non-small-cell lung cancer (NSCLC) therapy. The contribution of histone methylation in mediating malignant phenotypes of NSCLC is well known. However, the role of histone methylation in NSCLC drug-resistance mechanisms remains unclear. Here, our data show that EZH2 and G9a, two histone methyltransferases, are involved in the drug resistance of NSCLC. Gene manipulation results indicate that the combination of EZH2 and G9a promotes tumor growth and mediates drug resistance in a complementary manner. Importantly, clinical study demonstrates that co-expression of both enzymes predicts a poor outcome in patients with NSCLC. Mechanistically, G9a and EZH2 interact and promote the silencing of the tumor-suppressor gene SMAD4, activating the ERK/c-Myc signaling pathway. Finally, SU08, a compound targeting both EZH2 and G9a, is demonstrated to sensitize resistant cells to therapeutic drugs by regulating the SMAD4/ERK/c-Myc signaling axis. These findings uncover the resistance mechanism and a strategy for reversing NSCLC drug resistance.

Interfacial bonding has attracted extensive attention because it essentially affects the performance of SiC reinforced Al matrix composites. To investigate the impact of Ni and Cu inherent in the Al matrix on the interfacial bonding of the composite, Al–Si–Mg/oxidized SiC composite and Al–Si–Cu–Ni–Mg/unoxidized SiC composite were fabricated by semisolid stir casting. Our study demonstrated that several intermetallics can nucleate and grow on the surface of SiC in Al–Si–Cu–Ni–Mg/unoxidized SiC composite during solidification, forming the intermetallic/unoxidized SiC interface and Al-intermetallic-SiC transition structure. The bonding of the Al3CuNi/unoxidized SiC interface is stronger than the conventional Al/oxidized SiC interface. The Al3CuNi/unoxidized SiC interface is functional in impeding crack propagation and withstanding loading during deformation. Moreover, the Al-intermetallic-SiC transition structure can alleviate the agglomeration of SiC particles, improve the overall coherency and coordinate the deformation of the composite. The extraordinary interface and structure strengthen the composite to a certain extent both at room and high temperatures.

This work investigated the influence of cooling rate (0.04, 0.87, 15.2 and 156.2 K/s) on the microstructure and compressive properties of Al–4Cu–3Li-0.7 Mg–1Zn alloys fabricated by several casting molds. The experiment results revealed that the microstructure cooled at low cooling rates of 0.04, 0.87 and 15.2 K/s is composed of α-Al, α(Al)+T2, θ (Al2Cu), T1 phases and core-shell configuration (Al13Fe4/Al7Cu2Fe phase). This core-shell structure is observed for the first time in an Al–Cu–Li alloy. However, T1 and core-shell configuration vanish at the high cooling rate of 156.2 K/s due to the insufficient diffusion time of Cu, Li and Fe elements. As the cooling rate increases, the average secondary dendrite arm spacing (SDAS) decreases significantly from 110.3 to 7.5 μm and the relationship between SDAS and cooling rate has been established. The average diameter/thickness of the α(Al)+T2, Al2Cu and Al13Fe4/Al7Cu2Fe phases decreases dramatically from 16.9 to 1.0 μm, 8.1 to 0.8 μm and 7.5 to 0.7 μm with the increase of cooling rate, respectively. Fine spherical Al13Fe4/Al7Cu2Fe and Al2Cu phases are beneficial to the improvement of comprehensive compressive properties. Additionally, the solute concentration in the matrix decreases, while the hot-tear resistance and volume fraction of secondary phases increase with increasing cooling rate. The empirical equations are established between (compressive properties, SDAS) and cooling rate. The fracture failure is responsible for the initial hot tearing at low cooling rates, the α(Al)+T2 or Al2Cu or Al13Fe4/Al7Cu2Fe phases at the moderate cooling rate, and the α(Al)+T2 phase at the high cooling rate.

This study investigated the effect of astragalus polysaccharide (APS, an ingredient with hypoglycemic function in a traditional Chinese herbal medicine) on gut microbiota and metabolites of type 2 diabetes mellitus (T2DM) patients using a simulated fermentation model in vitro. The main components of APS were isolated, purified, and structure characterized. APS fermentation was found to increase the abundance of Lactobacillus and Bifidobacterium and decrease the Escherichia-Shigella level in the fecal microbiota of T2DM patients. Apart from increasing propionic acid, APS also caused an increase in all-trans-retinoic acid and thiamine (both have antioxidant properties), with their enrichment in the KEGG pathway associated with thiamine metabolism, etc. Notably, APS could also enhance fecal antioxidant properties. Correlation analysis confirmed a significant positive correlation of Lactobacillus with thiamine and DPPH-clearance rate, suggesting the antioxidant activity of APS was related to its ability to enrich some specific bacteria and upregulate their metabolites.

Cartilage destruction caused by inflammation is a clinical challenge. Many studies have investigated cartilage destruction in adults, but little research was conducted on children. In this study, the protective effect of gold nanoparticles (AuNPs) on the cartilage of children was realized by counteracting chondrocyte apoptosis and extracellular matrix (ECM) degradation in a young mouse model of lipopolysaccharide (LPS)-induced growth plate (GP) cartilage damage. Initially, engineered AuNPs can be efficiently absorbed by chondrocytes, approximately 20 times the amount absorbed by macrophages, resulting in a 29% ± 0.05% increase in chondrocyte viability. Then, AuNPs exposure significantly reduced the release of inflammatory cytokines and secretion of ECM degradation factors induced by LPS. Subsequently, AuNPs were applied to resist LPS-induced cartilage destruction in young mice. AuNPs inhibited the formation of gaps, without chondrocytes and extracellular matrix, between the proliferative and hypertrophy zones of the GP cartilage, and the gaps were noticeable in the LPS group. This finding can be attributed to the capability of AuNPs to reduce the LPS-induced apoptosis rate of mouse chondrocytes by 72.38% and the LPS-induced ECM degradation rate by 70.89%. Further analysis demonstrated that remission is partly due to AuNPs’ role in maintaining the balance of catabolic and anabolic factors in the ECM. Altogether, these findings indicate that AuNPs can partially protect the cartilage of children from inflammatory damage by suppressing chondrocyte apoptosis and ECM degradation.

The microstructure and properties of stirred cast SiCP/A359 composites under different cooling rates were studied. The strengthening mechanism of the composite material under three cooling rates was analyzed, and the failure mechanism of the composite material was elucidated by means of in-situ tension and EBSD testing. The results showed that increasing the cooling rate simultaneously refined the grains, secondary dendrites, and eutectic silicon, resulting in improved distribution uniformity of SiC and the stacking fault density of eutectic silicon. Additionally, the relationship between the secondary dendrite arm spacing (SDAS) and cooling rate (v) of the SiCP/A359 composite was described using the equation SDAS = 56.02v^(-0.3). There was a positive correlation between cooling rate and yield strength, with particle strengthening being the main contributor to the strength of composites with high cooling rates, resulting in significantly higher strength than samples with low cooling rates. The geometrically necessary dislocations (GND) density at the eutectic Si-Al boundary was found to be higher than other positions after the material was loaded, and the main crack propagated mainly along the eutectic region. Secondary cracks, including SiC cracking, eutectic silicon cracking, interface separation, and shrinkage cracking, may become part of the main crack by bridging.

Low-dose computed tomography (LDCT) can effectively reduce radiation exposure in patients. However, with such dose reductions, large increases in speckled noise and streak artifacts occur, resulting in seriously degraded reconstructed images. The non-local means (NLM) method has shown potential for improving the quality of LDCT images. In the NLM method, similar blocks are obtained using fixed directions over a fixed range. However, the denoising performance of this method is limited. In this paper, a region-adaptive NLM method is proposed for LDCT image denoising. In the proposed method, pixels are classified into different regions according to the edge information of the image. Based on the classification results, the adaptive searching window, block size and filter smoothing parameter could be modified in different regions. Furthermore, the candidate pixels in the searching window could be filtered based on the classification results. In addition, the filter parameter could be adjusted adaptively based on intuitionistic fuzzy divergence (IFD). The experimental results showed that the proposed method performed better in LDCT image denoising than several of the related denoising methods in terms of numerical results and visual quality.

Abstract Objective The incidence of non-virus-related hepatocellular carcinoma (NV-HCC) in hepatocellular carcinoma (HCC) is steadily increasing. The aim of this study was to establish a prognostic model to evaluate the overall survival (OS) of NV-HCC patients. Methods Overall, 261 patients with NV-HCC were enrolled in this study. A prognostic model was developed by using LASSO-Cox regression analysis. The prognostic power was appraised by the concordance index (C-index), and the time-dependent receiver operating characteristic curve (TD-ROC). Kaplan–Meier (K–M) survival analysis was used to evaluate the predictive ability in the respective subgroups stratified by the prognostic model risk score. A nomogram for survival prediction was established by integrating the prognostic model, TNM stage, and treatment. Results According to the LASSO-Cox regression results, the number of nodules, lymphocyte-to-monocyte ratio (LMR), prognostic nutritional index (PNI), alkaline phosphatase (ALP), aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ratio (SLR) and C-reactive protein (CRP) were included for prognostic model construction. The C-index of the prognostic model was 0.759 (95% CI 0.723–0.797) in the development cohort and 0.796 (95% CI 0.737–0.855) in the validation cohort, and its predictive ability was better than TNM stage and treatment. The TD-ROC showed similar results. K–M survival analysis showed that NV-HCC patients with low risk scores had a better prognosis (P

Using directional solidification technique, a series of Nb–Si in situ composites with nominal compositions of Nb–16Si–23Ti–4Cr–2Al-2Hf-xRe (x = 0, 0.1, 0.4, 0.6, at.%) were manufactured to investigate the phase constituent, microstructural evolution and room temperature fracture toughness. These four different alloys all consisted of Nbss, αNb5Si3 and γNb5Si3, while Rhenium was primarily partitioned in Nbss matrix. With further addition content of Re, the silicide got refinement firstly, its average size minimized to 4.68 μm in 0.4Re alloy; but that coarsened again in 0.6Re alloy which resulting in the maximum micro-hardness of 1627 HV. The ductile Nbss matrix in 0.4Re alloy exhibited best continuity and its volume fraction rose to 63.1%; that triggered more obvious microcrack, fracture step and crack bifurcation, especially interface decohesion during loading process, thus increasing the room temperature fracture toughness from 8.4 MPa m1/2 to 13.1 MPa m1/2. But the 0.6Re alloy had an adverse effect on room temperature plasticity due to higher proportion and larger size of silicide, then exerted perceptible constraint for ductile Nbss matrix. In order to better optimize the mechanical performance of Nb–Si based alloys, the alloying amount of Rhenium should be properly selected to circumvent its concentration-sensitive effect.

Abstract Background Magnetosomes (BMPs) are organelles of magnetotactic bacteria (MTB) that are responsible for mineralizing iron to form magnetite. In addition, BMP is an ideal biomaterial that is widely used in bio- and nano-technological applications, such as drug delivery, tumor detection and therapy, and immunodetection. The use of BMPs to create multifunctional nanocomposites would further expand the range of their applications. Results In this study, we firstly demonstrate that the extracted BMP can remineralize in vitro when it is exposed to AgNO3 solution, the silver ions (Ag+) were transported into the BMP biomembrane (MM) and mineralized into a silver crystal on one crystal plane of Fe3O4. Resulting in the rapid synthesis of an Ag-Fe3O4 hybrid BMP (BMP-Ag). The synergy between the biomembrane, Fe3O4 crystal, and unmineralized iron enabled the remineralization of BMPs at an Ag+ concentration ≥ 1.0 mg mL−1. The BMP-Ag displayed good biocompatibility and antibacterial activity. At a concentration of 2.0 mg/mL, the BMP-Ag and biomembrane removed Ag-Fe3O4 NPs inhibited the growth of gram-negative and gram-positive bacteria. Thus using BMP-Ag as a wound dressing can effectively enhance the contraction of infected wounds. Conclusions This study represents the first successful attempt to remineralize organelles ex vivo, realizing the biosynthesis of hybrid BMP and providing an important advancement in the synthesis technology of multifunctional biological nanocomposites. Graphical abstract

ABSTRACT Prediction of susceptibility to pyrazinamide (PZA) directly from sputum has been challenging. The MeltPro MTB/PZA assay, based on melting curve analysis, can simultaneously detect Mycobacterium tuberculosis and the resistance to PZA from sputum. We aimed to evaluate the MeltPro MTB/PZA assay to predict PZA resistance among rifampin-resistant tuberculosis (RR-TB) patients. We prospectively enrolled RR-TB patients in the registered trials, and their baseline sputum samples were obtained to perform the assay and culture. DNA sequencing of culture isolates was analyzed and used as the reference standard. Sanger sequencing was performed for samples with discrepant results between next-generation sequencing (NGS) and the investigational assay. The main analysis was conducted in the population of patients with interpretable results by both NGS and the assay. A total of 239 patients with RR-TB were screened, and 220 underwent the MeltPro MTB/PZA assay. The assay provided no information for 25 of 220 patients (11.4%). Among the remaining 195 patients, 13 had negative culture or insufficient raw NGS sequencing data, and 15 had indeterminate assay results. A total of 167 patients were included in the main analysis. Against DNA sequencing, the sensitivity, specificity, and negative predictive value of the assay for detecting resistance to PZA were 91.4% (95% confidence interval [CI], 87.1% to 95.6%), 89.9% (95% CI, 85.3% to 94.5%), and 95.2% (95% CI, 91.9% to 98.4%), respectively. In conclusion, the MeltPro MTB/PZA assay is a fast semiautomatic molecular platform to rapidly predict resistance to PZA from sputum and holds promise as a screening tool with satisfactory sensitivity. IMPORTANCE This study evaluated the accuracy of the MeltPro MTB/PZA assay at detecting the presence of PZA resistance through registered clinical trials. Compared to DNA sequencing, the assay had high sensitivity and negative predictive value, suggesting its potential utility as a screening tool in clinical practice. The assay could serve as an ideal primary screening tool in low PZA-resistant M. tuberculosis prevalence settings and could be used as an additional test to identify PZA resistance rapidly and initially in the RR-TB population.

Abstract For hypereutectic Nb-Si based alloys, primary Nb5Si3 phases typically grow in a faceted mode during equilibrium or near-equilibrium solidification, which damages the ductility and toughness. To address this issue, here we artificially manipulate the growth morphology of Nb5Si3 using electron beam surface melting (EBSM) and subsequent annealing treatments. Results show that such a non-equilibrium solidification pathway enables the transition from faceted growth to non-faceted dendritic growth of Nb5Si3, along with evident microstructure refinement, generation of metastable β-Nb5Si3 phases and elimination of chemical segregation. The transformation from β-Nb5Si3 to α-Nb5Si3 and Nb solid solution (Nbss) particles is triggered by the annealing treatment at 1450 °C for 5 h. Also, we find the annealing-mediated formation of inherited Nb5Si3 dendrites that maintain the dendritic morphology of the original as-solidified β-Nb5Si3 dendrites. This work thus provides a feasible routine to obtain thermally stable and refined α-Nb5Si3 dendrites in hypereutectic Nb-Si based alloys.

Abstract Background Lung cancer is a kind of malignancy with high morbidity and mortality worldwide. Paclitaxel (PTX) is the main treatment for non-small cell lung cancer (NSCLC), and resistance to PTX seriously affects the survival of patients. However, the underlying mechanism and potential reversing strategy need to be further explored. Methods We identified ALDH2 as a PTX resistance-related gene using gene microarray analysis. Subsequently, a series of functional analysis in cell lines, patient samples and xenograft models were performed to explore the functional role, clinical significance and the aberrant regulation mechanism of ALDH2 in PTX resistance of NSCLC. Furthermore, the pharmacological agents targeting ALDH2 and epigenetic enzyme were used to investigate the diverse reversing strategy against PTX resistance. Results Upregulation of ALDH2 expression is highly associated with resistance to PTX using in vitro and in vivo analyses of NSCLC cells along with clinicopathological analyses of NSCLC patients. ALDH2-overexpressing NSCLC cells exhibited significantly reduced PTX sensitivity and increased biological characteristics of malignancy in vitro and tumor growth and metastasis in vivo. EHMT2 (euchromatic histone lysine methyltransferase 2) inhibition and NFYA (nuclear transcription factor Y subunit alpha) overexpression had a cooperative effect on the regulation of ALDH2. Mechanistically, ALDH2 overexpression activated the RAS/RAF oncogenic pathway. NSCLC/PTX cells re-acquired sensitivity to PTX in vivo and in vitro when ALDH2 was inhibited by pharmacological agents, including the ALDH2 inhibitors Daidzin (DZN)/Disulfiram (DSF) and JIB04, which reverses the effect of EHMT2. Conclusion Our findings suggest that ALDH2 status can help predict patient response to PTX therapy and ALDH2 inhibition may be a promising strategy to overcome PTX resistance in the clinic.

Childhood emotional neglect (CEN) has a relatively high incidence rate and substantially adverse effects. Many studies have found that CEN is closely related to emotion regulation and depression symptoms. Besides, the functional activity of the prefrontal lobe may also be related to them. However, the relationships between the above variables have not been thoroughly studied. This study recruited two groups of college students, namely, those with primary CEN (neglect group) and those without childhood trauma (control group), to explore the relationships among CEN, adulthood emotion regulation, depressive symptoms, and prefrontal resting functional connections. The methods used in this study included the Childhood Trauma Questionnaire (CTQ), Emotion Regulation Questionnaire (ERQ), Beck Depression Inventory-II (BDI-II) and resting-state functional magnetic resonance imaging (rs-fMRI). The results showed that compared with the control group, the neglect group utilized the reappraisal strategy less frequently and displayed more depressive symptoms. The prefrontal functional connections with other brain regions in the neglect group were more robust than those in the control group using less stringent multiple correction standards. Across the two groups, the functional connection strength between the right orbitofrontal gyrus and the right middle frontal gyrus significantly negatively correlated with the ERQ reappraisal score and positively correlated with the BDI-II total score; the ERQ reappraisal score wholly mediated the relationship between the functional connection strength and the BDI-II total score. It suggests that primary CEN may closely correlate with more depressive symptoms in adulthood. Furthermore, the more robust spontaneous activity of the prefrontal lobe may also be closely associated with more depressive symptoms by utilizing a reappraisal strategy less frequently.

Cadmium (Cd), as one of the seventh most toxic heavy metal pollutants, widely persisted in the environment, leading to osteoblast dysfunction and ultimately Cd-related skeletal disease. However, the damaging effects of Cd on cellular functions and the potential pathogenic mechanisms are still unclear. In our study, Cd is believed to induce mitochondrial dysfunction and endoplasmic reticulum stress (ERS) in a dose-dependent manner, thereby leading to apoptosis, as evident by elevated Drp1, Fis1, GRP78, CHOP, ATF4, P-EIF2α, P-PERK, BAX, cleaved caspase 3 proteins expression and ROS levels, and decreased the levels of Mfn2, OPA1, Bcl2, and intracellular Collagen I, B-ALP, RUNX2, and BGP genes. Additionally, when the exogenous addition of NAC and 4-PBA was added, it was found that NAC and 4-PBA had a positive moderating effect on Cd-induced cell dysfunction. Mechanistically, Cd-induced oxidative stress and apoptosis by upregulating the PERK-EIF2α-ATF4-CHOP signaling pathway and inhibiting the Nrf2/NQO1 pathway. In conclusion, we found that Cd was involved in mitochondrial dysfunction, ERS, and apoptosis in MC3T3-E1 cells, While NAC and 4-PBA relieved ERS and attenuated cell apoptosis.

Drug delivery systems with high-targeted doses can minimize excipients, reduce side effects, and improve efficacy. Human blood circulation is a complex circulatory system, and the motion control of microrobots in the static flow field in vitro is completely different from in vivo. How to achieve precise counterflow motion for targeted drug delivery without vascular blockage and immune rejection is the biggest challenge for micro-nano robots. Here, we propose a control method that enables vortex-like paramagnetic nanoparticle swarm (VPNS) to move upstream against the flow. By mimicking the clustering motion of wild herring schools and the rolling of leukocytes, VPNS are incredibly stable even when subjected to high-intensity jet impacts in the blood environment, can travel upstream, anchor at the target location, and dissipate when the magnetic field is withdrawn, which greatly reduces the risk of thrombosis. VPNS can also upstream along the vessel wall without an additional energy source and has a marked targeted therapeutic effect on subcutaneous tumors.

Macrophage inflammation promotes insulin resistance during diet-induced obesity. Here the authors show that macrophage NOC4L is decreased in humans and mice with obesity, that macrophage NOC4L deficiency aggravated high-fat diet induced inflammation and insulin resistance, and that NOC4L interacts with toll-like receptor 4, to inhibit endocytosis, and thus blocks TLF4/TRIF inflammatory signaling.

Osteoarthritis (OA) is a common chronic musculoskeletal disease reported in veterinary clinics that severely reduces the quality of life of animals. The natural product, bilobalide, has positive effects on chondroprotection but its exact mechanism of action is unclear. This study aimed to investigate the antioxidant and anti-matrix degradation activities of bilobalide in a rabbit model of OA and its protective effects on joints. We also investigated the possible mechanisms underlying these effects. The rabbit OA model was established by intra-articular injection of 4% papain. Thirty healthy male New Zealand rabbits were randomly divided into control, untreated OA, Cel (100 mg/kg celecoxib intervention as a positive control), BB-L and BB-H (40 mg /kg and 80 mg /kg bilobalide gavage treatment, respectively) groups. Two weeks after surgical induction, bilobalide or celecoxib was administered by gavage daily for 8 weeks. After 8 weeks of bilobalide intervention, cartilage macroscopic observation and histopathological images showed alleviation of cartilage damage after bilobalide treatment, and the Osteoarthritis Research Society International (OARSI) score was significantly lower than that in the OA group. Bilobalide reduced the expression of metalloproteinase 3 (MMP-3) and MMP-13 in cartilage tissue of OA rabbits and reversed the levels of serum C-telopeptides of type II collagen (CTX-II), cartilage oligomeric matrix protein (COMP), interleukin 1(IL-1), and tumor necrosis factor (TNF-α). Bilobalide (80 mg/kg) could improve the biomechanical properties and microstructural changes in subchondral bone in the early stage of OA in rabbits, thereby delaying subchondral bone damage. Mechanistically, bilobalide exerted antioxidant and anti-matrix degradation effects by upregulating the oxidative stress signaling Nrf2/HO-1 pathway and inhibiting cartilage degeneration in rabbit OA. We thus speculate that bilobalide supplements recovery from OA damage.

Osteoarthritis (OA) is driven by chronic low-grade inflammation and subsequent cartilage degradation. OA is the most prevalent degenerative joint disease worldwide, and its treatment remains a challenge. The aim of this study was to explore the potential effects and mechanism underlying the anti-OA properties of ginkgolide C (GC). Protective effects of GC on hydrogen peroxide (H2O2)-treated rat chondrocytes were evaluated using ELISA, qPCR, western blot analysis, flow cytometry, ROS detection and immunofluorescence in vitro. Ameliorating effects of GC on cartilage degeneration in rats were evaluated through behavioral assays, microcomputed tomography, histopathological analysis, western blot analysis and ELISA in vivo. In vitro, GC treatment inhibited the release of pro-apoptotic factors induced by H2O2 and promoted the release of the anti-apoptotic proteins. In addition, GC decreased the expression of matrix metalloproteinase (MMP3 and MMP13), thrombospondin motifs 4 (ADAMTS4), and inflammatory mediators inducible nitric oxide synthase (iNOS), cyclooxygenase (COX-2), and SOX9 thereby inhibiting extracellular matrix (ECM) degradation. Mechanistically, GC exerts its anti-apoptotic and anti-inflammatory effects by upregulating the oxidative stress signaling Nrf2/HO-1 pathway and preventing p65 from binding to DNA. Similarly, In a rat model with post-traumatic OA (PTOA) induced by anterior cruciate ligament transection (ACLT), GC inhibited joint pain, cartilage destruction, and abnormal bone remodeling of subchondral bone. GC inhibited H2O2-induced chondrocyte apoptosis through Nrf2/HO-1 and NF-κB axis, exerted anti-inflammatory effects, and inhibited cartilage degeneration in rat OA. Our findings advanced the concept that GC may contribute to cartilage metabolism through anti-inflammatory and anti-apoptotic effects, and the identified GC is a potential therapeutic agent for the treatment of OA.

In this work, mechanisms of two different deformation and fracture modes at 1250 °C of directional solidified Nb-Si-Ti based multi-alloys are investigated to explore the influence of element Zr on the high temperature properties. The 5Zr alloy exhibits the least drop of tensile strength and it shows the best comprehensive property of the plasticity and the tensile strength. Zr reduces α-Nb5Si3 and weakens the load-carrying capacity at high temperatures. Meanwhile, γ-Nb5Si3 are introduced by the addition of Zr which improve the plasticity and provides a significant work hardening to recover the tensile strength at 1250 °C. New super-dislocations are discovered for the first time with a slip system of (112¯0) in γ-Nb5Si3 which significantly improve the plasticity and promotes a coordinated deformation between Nb solid solutions and γ-Nb5Si3. Due to the different phase compositions, two models are derived to discuss the deformation mechanisms at high temperatures. In order to achieve an enough tensile strength at high temperatures, it is suggested that microstructures consisting of two phases is more beneficial to provide a good load-carrying capacity (Nbss/α) or a significant work hardening (Nbss/γ) at high temperatures.

Abstract The ongoing pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) and its variants has posed a serious global public health emergency. Therapeutic interventions or vaccines are urgently needed to treat and prevent the further dissemination of this contagious virus. This study described the identification of neutralizing receptor‐binding domain (RBD)‐specific antibodies from mice through vaccination with a recombinant SARS‐CoV‐2 RBD. RBD‐targeted monoclonal antibodies (mAbs) with distinct function and epitope recognition were selected to understand SARS‐CoV‐2 neutralization. High‐affinity RBD‐specific antibodies exhibited high potency in neutralizing both live and pseudotype SARS‐CoV‐2 viruses and the SARS‐CoV‐2 pseudovirus particle containing the spike protein S‐RBDV367F mutant (SARS‐CoV‐2(V367F)). These results demonstrated that these antibodies recognize four distinct groups (I–IV) of epitopes on the RBD and that mAbs targeting group I epitope can be used in combination with mAbs recognizing groups II and/or IV epitope to make mAb cocktails against SARS‐CoV‐2 and its mutants. Moreover, structural characterization reveals that groups I, III, and IV epitopes are closely located to an RBD hotspot. The identification of RBD‐specific antibodies and cocktails may provide an effective therapeutic and prophylactic intervention against SARS‐CoV‐2 and its isolates.

Abstract Background We aimed to develop and validate a predictive model for the overall survival (OS) of patients with nasopharyngeal carcinoma (NPC). Methods Overall, 519 patients were retrospectively reviewed in this study. In addition, a random forest model was used to identify significant prognostic factors for OS among NPC patients. Then, calibration plot and concordance index (C-index) were utilized to evaluate the predictive accuracy of the nomogram model. Results We used a random forest model to select the three most important features, dNLR, HGB and EBV DNA, which were significantly associated with the OS of NPC patients. Furthermore, the C-index of our model for OS were 0.733 (95% CI 0.673 ~ 0.793) and 0.772 (95% CI 0.691 ~ 0.853) in the two cohorts, which was significantly higher than that of the TNM stage, treatment, and EBV DNA. Based on the model risk score, patients were divided into two groups, associated with low-risk and high-risk. Kaplan–Meier curves demonstrated that the two subgroups were significantly associated with OS in the primary cohort, as well as in the validation cohort. The nomogram for OS was established using the risk score, TNM stage and EBV DNA in the two cohorts. The nomogram achieved a higher C-index of 0.783 (95% CI 0.730 ~ 0.836) than that of the risk score model 0.733 (95% CI 0.673 ~ 0.793) in the primary cohort (P = 0.005). Conclusions The established risk score model and nomogram resulted in more accurate prognostic prediction for individual patient with NPC.

As a reversible and dynamic epigenetic modification, N6-methyladenosine (m6A) modification is ubiquitous in eukaryotic cells. m6A methylation is prevalent in almost all RNA metabolism processes that affect the fate of cells, including cancer development. As indicated by the available evidence, targeting m6A regulators may play a crucial role in tumor therapy and multidrug resistance. Currently, many questions remain uncovered. Here, we review recent studies on m6A modification in various aspects of tumor progression, tumor immunity, multidrug resistance, and therapeutic targets to provide new insight into the m6A methylation process.

Insects have the phenomenon of immune priming by which they can have enhanced protection against reinfection with the same pathogen, and this immune protection can be passed on to their offspring, which is defined as “trans-generational immune priming (TGIP).” But whether housefly possesses TGIP is still unclear. Therefore, we used the housefly as the insect model and Candida albicans as the pathogen to explore whether the housefly is capable of eliciting TGIP, and RNA sequencing (RNA-seq) was performed to explore the molecular mechanism of TGIP of the housefly. We found that the housefly possesses TGIP, and adults pre-exposed to heat-killed C. albicans could confer protection to itself and its offspring upon reinfection with a lethal dose of C. albicans. RNA-seq results showed that 30 and 154 genes were differentially expressed after adults were primed with heat-killed C. albicans (CA-A) and after offspring larvae were challenged with a lethal dose of C. albicans (CA-CA-G), respectively. Among the differentially expressed genes (DEGs), there were 23 immune genes, including 6 pattern recognition receptors (PRRs), 7 immune effectors, and 10 immunoregulatory molecules. More importantly, multiple DEGs were involved in the Toll signaling pathway and phagosome signaling pathway, suggesting that the Toll signaling pathway and phagocytosis might play important roles in the process of TGIP of housefly to C. albicans. Our results expanded on previous studies and provided parameters for exploring the mechanism of TGIP.

Osteoarthritis (OA) is a degenerative disease that seriously affects an individual's quality of life. Oleanolic acid (OLA) is widely present in food and medicinal plants and has various pharmacological activities. Autophagy is an intracellular protective mechanism, and this study aimed to investigate the potential role of OLA targeting the autophagy pathway in the pathogenesis of OA. A rat OA model was established in vivo by intra-articular injection of Monosodium Iodoacetate (MIA), followed by ELISA, Western blot analysis, and behavioral assays. The results showed that OLA improved OA pain symptoms and inhibit cartilage degeneration. In vitro, OLA inhibited the secretion of inflammatory factors and matrix metalloproteinases in ATDC5 cells after induction with IL-1β (10 ng/mL). Meanwhile, Dansylcadaverine (MDC) staining, transmission electron microscopy (TEM), mRFP-GFP-LC3 immunofluorescence, Western blot analysis and RT-qPCR confirmed that OLA activates autophagy by inhibiting the PI3K/AKT/mTOR signaling pathway. In conclusion, OLA shows promise in the treatment of OA.

This study used a person-centered approach to identify reading motivation profiles of 514 Chinese adolescents in seventh- to ninth-grade, based on dimensions of intrinsic reading motivation (curiosity and involvement) and extrinsic reading motivation (grades and competition). Furthermore, the effects of each profile on outcome variables (reading amount for enjoyment and for school) were investigated. Latent profile analyses revealed three reading motivation profiles: high quantity (high on all four dimensions), high intrinsic (high on curiosity and involvement, low on grades, and competition), and moderate quantity (moderate on all four dimensions). The high-intrinsic and high-quantity profiles proved to be equally successful in terms of amount of reading for enjoyment and for school, and both significantly exceeded the moderate-quantity profile. The current findings emphasize the importance of intrinsic reading motivation and the importance of quality of motivation, compared with its quantity.

The transformation of lung adenocarcinoma to small cell lung cancer (SCLC) is a recognized resistance mechanism and a hindrance to therapies using epidermal growth factor receptor tyrosine kinase inhibitors (TKIs). The paucity of pretranslational/posttranslational clinical samples limits the deeper understanding of resistance mechanisms and the exploration of effective therapeutic strategies. Here, we developed preclinical neuroendocrine (NE) transformation models. Next, we identified a transcriptional reprogramming mechanism that drives resistance to erlotinib in NE transformation cell lines and cell-derived xenograft mice. We observed the enhanced expression of genes involved in the EHMT2 and WNT/ß-catenin pathways. In addition, we demonstrated that EHMT2 increases methylation of the SFRP1 promoter region to reduce SFRP1 expression, followed by activation of the WNT/ß-catenin pathway and TKI-mediated NE transformation. Notably, the similar expression alterations of EHMT2 and SFRP1 were observed in transformed SCLC samples obtained from clinical patients. Importantly, suppression of EHMT2 with selective inhibitors restored the sensitivity of NE transformation cell lines to erlotinib and delayed resistance in cell-derived xenograft mice. We identify a transcriptional reprogramming process in NE transformation and provide a potential therapeutic target for overcoming resistance to erlotinib. [ABSTRACT FROM AUTHOR]

Although osteoarthritis (OA) significantly affects the quality of life of the elderly, there is still no effective treatment strategy. The standardized Ginkgo biloba L. extract preparation has been shown to have a wide range of therapeutic effects. Bilobalide, a unique ingredient of Ginkgo biloba, has anti-inflammatory and antioxidant pharmacological properties, but its mechanism of action on OA remains unknown. In this study, we investigated the effects of bilobalide on the development of OA through in vivo and in vitro experiments, as well as its potential anti-inflammatory mechanisms. The in vitro experiments demonstrated that bilobalide significantly inhibited the production of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), and matrix metalloproteinase 13 (MMP13) in ATDC5 chondrocytes induced by Interleukin-1β (IL-1β). At the molecular level, bilobalide induced chondrocyte autophagy by activating the AMPK/SIRT1/mTOR signaling pathway, which increased the expression of autophagy-related Atg genes, up-regulated the expression of LC3 protein, and reduced the expression of the p62 protein. In vivo, bilobalide exerted significant anti-inflammatory and anti-extracellular matrix (ECM) degradation effects in a rat model of post-traumatic OA (PTOA) induced by anterior cruciate ligament transection (ACLT). Bilobalide could relieve joint pain in PTOA rats, inhibit the expression of iNOS and COX-2 protein in cartilage via the AMPK/SIRT1/mTOR pathway, and reduce the level of ECM degradation biomarkers in serum. In conclusion, bilobalide exhibits vigorous anti-inflammatory activity, presenting it as an interesting potential therapeutic agent for OA.

Abstract Background Cisplatin is a first-line drug for the treatment of human non-small cell lung cancer (NSCLC); however, the majority of patients will develop drug resistance after treatment. In order to overcome cisplatin resistance, it is important to understand the mechanisms underlying the resistance. Methods A gene microarray was used to screen for genes related to cisplatin resistance in NSCLC cell lines. Subsequently, the correlation between the HDAC, RXR and HtrA1 genes, in NSCLC, were verified using gene manipulation. Immunohistochemical staining was used to detect HDAC, RXR and HtrA1 expression in NSCLC specimens. Proliferation, migration and invasion assays were performed in vitro and in vivo to determine the role of the HDAC/RXR/HtrA1 signaling axis in cisplatin resistance, and luciferase reporter analysis and ChIP assays were performed to ascertain the mechanisms by which HDAC and RXR regulate the expression of HtrA1. Furthermore, in vitro and in vivo experiments were conducted in NSCLC cisplatin-resistant NSCLC to elucidate the effect of the low molecular weight compound, DW22, which targets the NSCLC cisplatin resistance HDAC/RXR/HtrA1 signaling pathway. Results HtrA1 was identified as a cisplatin resistance-related gene in NSCLC cells. The regulation of HtrA1 by HDAC and RXR significantly decreased the efficacy of cisplatin in NSCLC cells resistant to cisplatin. Immunohistochemistry results showed a negative relationship between HDAC1 and HtrA1, and a positive relationship between RXRα and HtrA1 in NSCLC patients’ tissues. Notably, the expression of HDAC1 and HtrA1 can be considered as biomarkers for the efficacy of platinum-based drugs and prognosis in NSCLC patients. Mechanistically, the heterodimers of the nuclear receptor RXR, in combination with the enzyme, HDAC, regulate the transcription of HtrA1 in NSCLC cells. The rescue of HtrA1 expression by dual targeting of HDAC and RXR with the compound, DW22, significantly inhibited the proliferation, migration and invasion of NSCLC cells resistant to cisplatin, and induced NSCLC cell apoptosis. Conclusion Our results indicate that HtrA1, a cisplatin resistance-related gene, is synergistically regulated by HDAC and RXR in NSCLC. Targeting the HDAC/RXR/HtrA1 signaling axis can rescue HtrA1 expression and reverse cisplatin resistance in NSCLC.

Abstract Honey is thought to act against microbes and regulates microbiota balance, and this is mainly attributed to the enzymatic production of hydrogen peroxide, high osmolarity, and nonperoxidase factors, for example, lysozyme and botanical sources of nectar, while the effect of honey's probiotic is recently considered. The study of honey as source of beneficial microbes is understudied. The purpose of this study was to screen for the beneficial microorganisms in honey with antagonistic property against important pathogens and the mechanism of antimicrobial activity and thus play a beneficial role as probiotics. The results showed that one out of the fourteen bacterial isolates had antimicrobial activity and was identified as Bacillus Sp. A2 by 16S rRNA sequence and morphology. Antimicrobial activity of the isolate against C. albicans, E. coli, and S. aureus was confirmed by Agar well diffusion and liquid coculture assays, and the propagation of those microbes was significantly inhibited after treatment with the isolate Bacillus sp. A2 (p

Intuitive moral emotions play a major role in forming our opinions and moral decisions. However, it is not yet known how we perceive the subjective time of moral-related information. In this study, we compared subjective durations of phrases depicting immoral, disgust, or neutral behaviors in a duration bisection task and found that phrases depicting immoral behavior were perceived as lasting longer than the neutral and disgusting phrases. By contrast, the subjective duration of the disgusting phrase, unlike the immoral phrase, was comparable to the neutral phrase. Moreover, the lengthening effect of the immoral phrase relative to the neutral phrase was significantly correlated to the anonymously prosocial tendency of the observer. Our findings suggest that immoral phrases induce embodied moral reaction, which alters emotional state and subsequently lengthens subjective time.