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Background: The incidence of early-onset colorectal cancer (EOCRC), which exhibits differential clinical, pathological, and molecular features compared to late-onset CRC (LOCRC), is rising globally. The potential differential effects of blood glucose on EOCRC compared to LOCRC have not been investigated. Methods: This study analyzed 374,568 participants from the UK Biobank cohort and 172,809 participants from the Kailuan cohort. The linear associations between blood glucose and EOCRC/LOCRC were estimated using Cox regression models. Restricted cubic spline (RCS) analysis and non-linear Mendelian randomization (MR) analysis using a 70-SNPs genetic instrument for fasting glucose were used to explore the potential non-linear associations. Results: Participants in the highest quintile of blood glucose had higher overall CRC risk compared to the lowest quintile (HR = 1.10 in the UK Biobank cohort, 95% CI: 1.01–1.21, P-trend = 0.012; HR = 1.23 in the Kailuan cohort, 95% CI: 1.01–1.51, P-trend = 0.036). Elevated glucose (>7.0 mmol/L) was more strongly associated with increased risk of EOCRC (HR = 1.61, 95% CI: 1.07–2.44) than with LOCRC (HR = 1.14, 95% CI: 1.02–1.27) in the UK Biobank cohort (P-heterogeneity = 0.014). Elevated glucose (>7.0 mmol/L) was associated with increased risk of LOCRC (HR = 1.25, 95% CI: 1.04–1.65) in the Kailuan cohort as well. There was no evidence for non-linear associations between blood glucose and risks of EOCRC/LOCRC. Conclusions: This study showed a positive association between blood glucose and CRC risk in a dose-response manner, particularly for EOCRC, suggesting that tighter glucose control should be a priority for younger age groups.

Background: Osteomyelitis (OM) is an inflammatory condition of bone characterized by cortical bone devascularization and necrosis. Dysregulation of bone remodelling is triggered by OM. Bone remodelling is precisely coordinated by bone resorption and formation via a reversal phase. However, the cellular and molecular mechanisms underlying bone remodelling failure after osteomyelitis remain elusive. Methods: To elucidate the cellular and molecular mechanism underlying bone healing after osteomyelitis, we employed single-cell RNA sequencing (scRNA-seq) to depict the atlas of human cortical bone in normal, infected and reconstructed states. Dimensionality reduction by t-stochastic neighbourhood embedding (t-SNE) and graph-based clustering were applied to analyse the detailed clusters of osteoclast lineages. After trajectory analysis of osteoclast lineages over pseudotime, real-time PCR and immunofluorescence (IF) staining were applied to identify marker gene expression of various osteoclast lineages in the osteoclast induction model and human bone sections, respectively. The potential function and communication of osteoclasts were analysed via gene set enrichment analysis (GSEA) and CellChat. The chemotactic ability of mesenchymal stem cells (MSCs) and osteoclast lineage cells in various differentiation states was determined by transwell assays and coculture assays. The effects of various osteoclast lineages on the osteogenic differentiation potential of MSCs were also determined by using this coculture system. A normal mouse tibia fracture model and an osteomyelitis-related tibia fracture model were generated via injection of luciferase-labelled Staphylococcus aureus to verify the relationships between a novel osteoclast lineage and MSCs. Then, the infection was detected by a bioluminescence imaging system. Finally, immunofluorescence staining was used to detect the expression of markers of MSCs and novel osteoclast lineages in different remodelling phases in normal and infected bone remodelling models. Results: In this study, we constructed a cell atlas encompassing normal, infected, and reconstructed cortical bone. Then, we identified a novel subset at the earlier stage of the osteoclast lineage that exhibited increased expression of IDO1, CCL3, and CCL4. These IDO1highCCL3highCCL4high cells, termed osteostaticytes (OSCs), were further regarded as the reservoir of osteoclasts in the reversal phase. Notably, OSCs exhibited the highest chemotactic activity, surpassing other lineage subsets. We also discovered that cells at the earlier stage of the osteoclast lineage play a significant role in recruiting mesenchymal stem cells (MSCs). Finally, the data revealed that OSCs might be positively related to the occurrence of bone MSCs and the contribution of bone remodelling. Conclusion: Collectively, our findings revealed a novel stage (OSC) within the osteoclast lineage, potentially representing elusive bone reversal cells due to its increased chemotactic ability towards MSCs and potential contribution to bone remodelling. This study provides valuable insights into the intricate mechanisms of the reversal phase during bone remodelling and unveils potential therapeutic strategies for diseases associated with bone uncoupling. Translational potential of this article: This study identified a new subset, referred to as IDO1(plus symbol) CCL3(plus symbol) CCL4(plus symbol) osteostaticytes which displayed the highest chemotactic activity among all osteoclast lineages and may serve as reversal cells in bone remodelling. These findings offer new insights and insights for understanding bone reversal-related diseases and may serve as novel therapeutic targets for conditions such as osteomyelitis and delayed bone healing.

Currently, the efficacy of albumin-bound paclitaxel (PTX@Alb) is still limited due to the impaired PTX@Alb accumulation in tumors partly mediated by the dense collagen distribution. Meanwhile, acquired immune resistance always occurs due to the enhanced programmed cell death-ligand 1 (PD-L1) expression after PTX@Alb treatment, which then leads to immune tolerance. To fill these gaps, we newly revealed that tamoxifen (TAM), a clinically widely used adjuvant therapy for breast cancer with mitochondrial metabolism blockade capacity, could also be used as a novel effective PD-L1 and TGF-β dual-inhibitor via inducing the phosphorylation of adenosine 5ʹ-monophosphate-activated protein kinase (AMPK) protein. Following this, to obtain a more significant effect, TPP-TAM was prepared by conjugating mitochondria-targeted triphenylphosphine (TPP) with TAM, which then further self-assembled with albumin (Alb) to form TPP-TAM@Alb nanoparticles. By doing this, TPP-TAM@Alb nanoparticles effectively decreased the expression of collagen in vitro, which then led to the enhanced accumulation of PTX@Alb in 4T1 tumors. Besides, TPP-TAM@Alb also effectively decreased the expression of PD-L1 and TGF-β in tumors to better sensitize PTX@Alb-mediated chemo-immunotherapy by enhancing T cell infiltration. All in all, we newly put forward a novel mitochondrial metabolism blockade strategy to inhibit PTX@Alb-resistant tumors, further supporting its better clinical application.

Viruses often manipulate ubiquitination pathways to facilitate their replication and pathogenesis. CUL2ZYG11B known as the substrate receptor of cullin-2 RING E3 ligase, is bound by SARS-CoV-2 ORF10 to increase its E3 ligase activity, leading to degradation of IFT46, a protein component of the intraflagellar transport (IFT) complex B. This results in dysfunctional cilia, which explains certain symptoms that are specific to COVID-19. However, the precise molecular mechanism of how ORF10 recognizes CUL2ZYG11B remains unknown. Here, we determined the crystal structure of CUL2ZYG11B complexed with the N-terminal extension (NTE) of SARS-CoV-2 ORF10 (2.9 Å). The structure reveals that the ORF10 N-terminal heptapeptide (NTH) mimics the Gly/N-degron to bind CUL2ZYG11B. Mutagenesis studies identified key residues within ORF10 that are key players in its interaction with CUL2ZYG11B both in ITC assay and in vivo cells. In addition, we prove that enhancement of CUL2ZYG11B activity for IFT46 degradation by which ORF10-mediated correlates with the binding affinity between ORF10 and CUL2ZYG11B. Finally, we used a Global Protein Stability system to show that the NTH of ORF10 mimics the Gly/N-degron motif, thereby binding competitively to CUL2ZYG11B and inhibiting the degradation of target substrates bearing the Gly/N-degron motif. Overall, this study sheds light on how SARS-CoV-2 ORF10 exploits the ubiquitination machinery for proteasomal degradation, and offers valuable insights for optimizing PROTAC-based drug design based on NTH CUL2ZYG11B interaction, while pinpointing a promising target for the development of treatments for COVID-19.

Despite the promising prospects of nanoparticles in oral drug delivery, the process of oral administration involves a complex transportation pathway that includes cellular uptake, intracellular trafficking, and exocytosis by intestinal epithelial cells, which are necessary steps for nanoparticles to enter the bloodstream and exert therapeutic effects. Current researchers have identified several crucial factors that regulate the interaction between nanoparticles and intestinal epithelial cells, including surface properties such as ligand modification, surface charge, hydrophilicity/hydrophobicity, intestinal protein corona formation, as well as holistic properties like particle size, shape, and rigidity. Understanding these properties is essential for enhancing transepithelial transport efficiency and designing effective oral drug delivery systems. Therefore, this review provides a comprehensive overview of the surface and holistic properties that influence the transepithelial transport of nanoparticles, elucidating the underlying principles governing their impact on transepithelial transport. The review also outlines the chosen of parameters to be considered for the subsequent design of oral drug delivery systems.

Background: In 2022, the American Association for Thoracic Surgery (AATS) and the European Society of Thoracic Surgeons (ESTS) published joint guidelines regarding the timing, duration, and choice of agent for perioperative venous thromboembolism prophylaxis for thoracic cancer patients. Now, 1 year after their release, we looked to assess practices and general adherence to these recommendations. Methods: We conducted a survey among board-certified/board-eligible thoracic surgeons in the United States, between July and October 2023. Results: A total of 103 board-certified thoracic surgeons responded to the survey. Over half of the surgeons reported using preoperative chemical thromboprophylaxis routinely for lobectomy/sublobar resections (56.3%), pneumonectomy/extended lung resections (64.1%), and esophagectomy (67%). Over two thirds of thoracic surgeons limited the duration of postoperative chemical thromboprophylaxis to the patient’s length of hospital stay and never administered chemoprophylaxis post-discharge. Among surgeons who always continued chemical thromboprophylaxis post-discharge, low-molecular-weight heparin (LMWH) was the most commonly used agent (>70%), followed by direct oral anticoagulants (13.8%-16.7%). Only 33.3% of surgeons prescribing post-discharge chemical thromboprophylaxis after lobectomy/sublobar resections continued prophylaxis up to 4 weeks postoperatively. Conclusions: Contrary to the 2022 joint AATS/ESTS guidelines, the majority of surveyed thoracic surgeons in the United States do not routinely prescribe postoperative thromboprophylaxis after lung and esophageal cancer resections. The dogma of routine extended thromboprophylaxis must be reevaluated as modern minimally invasive thoracic surgery allows for very earlier ambulation and enhanced recovery. There is a need for randomized controlled trials exploring the utility of extended thromboprophylaxis and newer agents such as direct oral anticoagulants.

Nickel-base alloy is a type of metal material with excellent properties and is widely used in many fields. However, in the harsh environment of the acid solution, corrosion causes the reduction of the service life of the alloys, thereby limiting the alloys' use and development. In this paper, the effect of Chromium (Cr) content on the microstructure and corrosion behavior of nickel-based alloys in hydrochloric acid (HCl) was studied by scanning electron microscopy (SEM), energy dispersive spectrum (EDS), electron backscatter diffraction (EBSD) and electrochemical workstation. Meanwhile, X-ray photoelectron spectroscopy (XPS) was used to investigate the composition and properties of the surface passive films. For the Cr20 and Cr30 alloys with a single face-centered cubic (FCC) structure, the Cr2O3 content in the passive films increased with the Cr content, effectively improving the corrosion resistance. As the Cr content continued to increase, the second phases having a body-centered cubic (BCC) lattice were precipitated both in the Cr40 and Cr50 samples, inducing microgalvanic corrosion, thus deteriorating the corrosion resistance. XPS results showed that, in the Cr30 alloy, the relative content of Cr2O3 and the bound water were the highest, indicating that its passive film had the best corrosion resistance. For the passive film, the pitting resistance was related to Cr content, appropriate Cr content improved the corrosion resistance.

Evolution mechanism of interfacial multi-layer intermetallic compounds (IMCs) and their impact on failure behavior in Al–Au wire bonding after thermal storage and thermal cycle process are investigated. Microstructural analysis shows that multi-layer IMCs form between the Al wire and barrier layer. After thermal storage and thermal cycle process, the Au8Al3 layer transforms into AuAl2, and Au pad transforms to a thicker layer containing Au2Al and AuAl. Thermodynamic analysis indicates that Au8Al3, Au2Al, AuAl, and AuAl2 have increasing stability. Small-size, equiaxed AuAl2 grains form due to high stored energy, while large-size, columnar Au2Al and AuAl grains result from slower reaction rate and limited recrystallization. The stack-like formation of AuAl2 grains is attributed to the balance between driving force and interfacial energy resistance. During thermal storage, thicker IMC layers cause cracking between IMC layers and Au pad, and micro voids form near the IMC layers/barrier layer interface due to Kirkendall effect. Thermal stress results show that plastic deformation of the Al layer slightly affects the thermal stress in other layers during the thermal cycle process. The cyclic stress at the interface with initial cracks ranges from −157 MPa to 114 MPa, facilitating crack propagation. Additionally, micro void grows under cyclic thermal input, weakening interface adhesion. Therefore, bond strength decreases and frequency of bonding lift-off with cracking along the IMC layers/barrier layer interface increases after thermal storage and thermal cycle process. These results provide the guidance for regulating the interfacial IMCs and predicting the thermal stress in Al–Au wire bonding.

The development of pipeline steels with exceptional cryogenic toughness is deemed imperative for their applications in various engineering fields. In this work, API X65 steel with lamellar grain (LG) structure is constructed through warm deformation techniques. Comparative analysis with raw API X65 steel revealed notable enhancements in both yield strength (YS) and ultimate strength (UTS), exhibiting increments of 315 MPa and 164 MPa, respectively, while retaining substantial fracture toughness (KIc = 251.14 MPa m0.5). Remarkably, the LG steel exhibits a distinct absence of a ductile-brittle transition behavior over a wide temperature range, maintaining an exceptionally high impact energy from room temperature (RT) to liquid nitrogen temperature (LNT), and the Charpy impact energy exceeding 330 J at LNT, nearly 16 times higher than the raw API X65 steel. This performance can be primarily attributed to the superior plastic deformation capability, coupled with the delamination toughening mechanism. The resultant tortuous path of crack propagation effectively facilitates the absorption of substantial energy, decreases notch tip sensitivity depending on the temperature, stress triaxiality, and strain rate, thereby fostering excellent cryogenic toughness.

Background: Emerging evidence suggests that cell deaths are involved in tumorigenesis and progression, which may be treated as a novel direction of cancers. Recently, a novel type of programmed cell death, disulfidptosis, was discovered. However, the detailed biological and clinical impact of disulfidptosis and related regulators remains largely unknown. Methods: In this work, we first enrolled pancancer datasets and performed multi-omics analysis, including gene expression, DNA methylation, copy number variation and single nucleic variation profiles. Then we deciphered the biological implication of disulfidptosis in clear cell renal cell carcinoma (ccRCC) by machine learning. Finally, a novel agent targeting at disulfidptosis in ccRCC was identified and verified. Results: We found that disulfidptosis regulators were dysregulated among cancers, which could be explained by aberrant DNA methylation and genomic mutation events. Disulfidptosis scores were depressed among cancers and negatively correlated with epithelial mesenchymal transition. Disulfidptosis regulators could satisfactorily stratify risk subgroups in ccRCC, and a novel subtype, DCS3, owning with disulfidptosis depression, insensitivity to immune therapy and aberrant genome instability were identified and verified. Moreover, treating DCS3 with NU1025 could significantly inhibit ccRCC malignancy. Conclusion: This work provided a better understanding of disulfidptosis in cancers and new insights into individual management based on disulfidptosis.

The negative impacts of greenhouse gas emissions, particularly CO2 emissions, have garnered widespread attention. Various old residential areas in China, built more than 20 years ago, have been undergoing urgent transformation to improve citizens’ quality of life, which may significantly reduce carbon emissions. This study developed a carbon emissions accounting framework for residential areas to account the emissions impact of residential transformation. The framework addressed the inventory classifications of landscape greening, residential buildings, water resources, solid waste, infrastructure and transportation. The consumption-based calculation model and bottom-up data collection methods were used. The results show that the transformation of two old residential areas achieved considerable carbon reductions of 17.16% and 33.37% in South and North China, respectively. The macro guidance of local policies, specifically those regarding local urban infrastructure construction, significantly aided the carbon emissions reductions. Based on the calculation results, a list of recommended technologies was proposed to reduce carbon emissions, and four measures (adding greening, improving the garbage recovery rate, separating rain and sewage and transforming envelope structures for energy savings in northern China) were recommended to promote low carbon development in residential areas.

Urban form contributes to crime prevention. However, most studies not only simplify the relationship between urban form and crime, they also fail to reflect the geographic structure of urban areas. This study first measured a comprehensive multidimensional urban form indicator for 1486 counties in the United States, which was used to characterize the size and geospatial structure of urban areas. Specifically, it described urban form as consisting of three components: 1) size and population distribution; 2) built environment; and 3) landscape environment. Then, generalized additive mixed models were then used to explore linear or nonlinear associations between urban form indicators and different crime types (violent and property crime). This study's main findings were that 1) the relationship between urban form and crime is not only linear but may also be nonlinear; 2) urban size, fragmentation, connectivity, forest mixing, and shrub mixing are associated with all crime types; 3) population distribution and agricultural mixing are associated with violent crime; and 4) urban patch complexity and water mixing are associated with property crime. Overall, the results of this study can provide guidance for long-term planning of urban geographic structures, contributing to the safe and sustainable development of urban areas.

The integration of TiCN particles into superalloy composites for laser powder bed fusion (LPBF) and the construction of Triply Periodic Minimal Surface (TPMS) lattice structures have been understudied. This research systematically examines the microstructure and mechanical properties of LPBF-processed 10 vol% micron sized TiCN particle reinforced Inconel 718 (IN718) composites. The compressive behavior of the resultant TPMS lattice structures, derived from the TiCN-IN718 composite, was scrutinized through a combination of experimental testing and Finite Element (FE) simulation. The micro-sized TiCN reinforcement is demonstrated to notably augment the hardness, tensile strength, and wear resistance of the LPBFed TiCN-IN718 composite. Furthermore, the application of homogenization-solution-aging (HSA) heat treatment is shown to provide additional enhancements to the composite's mechanical behavior. Both the TiCN reinforcement and the HSA heat treatment are identified as pivotal factors influencing the compressive response of the TPMS lattice structures. Experimental findings indicate that the HSA-treated D-structure attains the highest compressive strength, reaching 122 MPa, outperforming both the G- and P-structures. During quasi-static compression testing, the D- and G-structures undergo a layer-by-layer collapse, while the P-structure exhibits tilt shear band behavior. The congruence between FE simulation results and experimental data substantiates the simulation's reliability and its capacity to accurately evaluate the mechanical behavior of TPMS lattice structures.

Rapidly obtaining the coverage characteristics of leaching solution in In-situ Leaching Area of Sandstone Uranium Mines is a necessary condition for optimizing well locations reasonably. In the presented study, the improved algorithm of the Fast Marching Method (FMM) was studied for rapidly solving coverage characteristics to replace the groundwater numerical simulator. First, the effectiveness of the FMM was verified by simulating diffusion characteristics of the leaching solution in In-situ Leaching Area. Second, based on the radial flow pressure equation and the interaction mechanism of the front diffusion of production and injection well flow field, an improved FMM which is suitable for In-situ Leaching Mining, was developed to achieve the co-simulation of production and injection well. Finally, the improved algorithm was applied to engineering practice to guide the design and production. The results show that the improved algorithm can efficiently solve the coverage characteristics of leaching solution, which is consistent with those obtained from traditional numerical simulators. In engineering practice, the improved FMM can be used to rapidly analyze the leaching process, delineate Leaching Blind Spots, and evaluate the rationality of well pattern layout. Furthermore, it can help to achieve iterative optimization and rapid decision-making of production and injection well locations under large-scale mining area models.

Introduction: Global warming is increasing interest in how aquatic animals can adjust their physiological performance and cope with temperature changes. Therefore, understanding the behavioral changes and molecular underpinnings in fish under warming is crucial for both the individual and groups survival. This could provide experimental evidence and resource for evaluating the impact of global warming. Objective: Three genetic families of common carp (Cyprinus carpio) were generated. These juveniles were constructed short-term (4 days) and long-term (30 days) warming groups to investigate the effects of warming on behavioral responses and to elucidate the potential underlying mechanisms of warming-driven behavior. Methods: Behavioral tests were used to explore the effects of short- and long-term exposure to warming on the swimming behavior of C. carpio. Brain transcriptome combined with measurement of nervous system activity was used to further investigated the comprehensive neuromolecular mechanisms under warming. Results: Long-term warming groups had a more significant impact on the decline of swimming behavior in juvenile C. carpio. Furthermore, brain comparative transcriptomic analysis combined with measurement of nervous system activity revealed that genes involved in cytoskeletal organization, mitochondrial regulation, and energy metabolism are major regulators of behavior in the juvenile under warming. Importantly, especially in the long-term warming groups, enrichment analysis of associated gene expression suggested functional alterations of synaptic transmission and signal transduction leading to swimming function impairment in the central nervous system, as revealed by behavioral tests. Conclusions: Our study provides evidence of the neurogenomic mechanism underlying the decreased swimming activity in juvenile C. carpio under warming. These findings have important implications for understanding the impacts of climate change on aquatic ecosystems and the organisms that inhabit them.

In this study, nano-Nb-modified AlSi10Mg composites were fabricated using laser powder bed fusion (LPBF). The effects of Nb addition on the microstructure and mechanical properties of the AlSi10Mg alloy were systematically investigated. Compared with the as-built AlSi10Mg alloy, the microstructure along the building direction of the AlSi10Mg–Nb composites changed from coarse columnar grains to ultrafine equiaxed grains. Moreover, the preferential grain growth orientation was significantly weakened. Grain refinement occurs due to the presence of abundant in-situ Al3Nb precipitates dispersed within the grain, serving as heterogeneous nucleation inoculants. Simultaneously, the precipitation of NbSi2 particles along the eutectic network also contributed to refining the structure of the eutectic network. As a result, the LPBF-processed AlSi10Mg–Nb samples demonstrated a very high ultimate tensile strength (∼560 MPa) and good ductility (∼7%), comparable to those of high-strength aluminum alloys. The underlying mechanisms for this strength enhancement are discussed based on the improved mechanical properties. This study provides a novel perspective for the fabrication of high-performance AlSi10Mg alloys using LPBF.

For the development of new energy automobile industry and the trend of automobile lightweight have put forward a huge demand for high-strength lightweight materials, so developing high strength aluminum alloys is particularly momentous. As the most widely used aluminum alloy, 6000 series aluminum alloys (Al–Mg–Si alloys) have the advantages such as better mechanical properties, outstanding welding properties, excellent formability and fine processing capability, and therefore have obtained great attention as the structural materials. In addition, the Al–Mg–Si alloys with low density and corrosion resistance not only reduce the total weight of the car, but also extend the service life when subjected to chemical corrosion, which effectively achieve energy saving and emission reduction. This paper summarizes the research progress of 6000 series aluminum alloys, in particular, and reviews the methods of microalloying and particle strengthening, and their effects on the microstructure and properties of the alloy, thus providing a reference for the subsequent development of high-performance aluminum alloys in automobile and aerospace industries.

In general, the Ti–6.5Al–2Zr–1Mo–1V (TA15) components fabricated via laser powder bed fusion (L-PBF) exhibit high strength and low ductility. Herein, we report a novel approach to enhance the comprehensive mechanical properties of L-PBF TA15 alloy by adjusting the laser power. Samples processed using the optimal laser power exhibit a grid structure of alternating wide and narrow prior-β grains (PBGs), the inside of which is composed of a fully martensitic microstructure. The paper discusses in detail the alterations in the microstructure of samples processed at both low and high laser powers, clarifying the relationship between microstructure and mechanical properties. Thinner martensite contributes to higher strength, while a homogenous microstructure improves ductility. These findings provide valuable insights for controlling microstructure and achieving strength-ductility synergy in L-PBF additive manufacturing of titanium alloys.

Laser powder bed fusion (LPBF) enables the production of large and intricately shaped bulk metallic glasses (BMGs); however, the current strength of LPBF-fabricated BMGs is significantly lower than their cast counterparts due to defects generated during the LPBF process in the as-built BMGs. In this study, considering the viscosity characteristics of BMG melts and their impact on melt pool characteristics, we investigated the relationship between LPBF parameters, structural characteristics, and defects in a selected Cu45Zr45Al6Ti4 BMG. Our findings revealed a transition of the melt pool from conduction mode to keyhole mode and subsequently to extended mode with increasing laser power. Furthermore, we explored how melt pool characteristics influence defects such as pores, heat affected zone (HAZ), and crystalline phase in the as-built Cu45Zr45Al6Ti4 BMG. Under optimized LPBF parameters, we successfully fabricated nearly fully amorphous Cu45Zr45Al6Ti4 BMG samples with high density (>99%) and absence of cracks. The printed samples exhibited a compressive strength of 1839 MPa comparable to their cast counterparts while achieving an impressive tensile strength value of 920 MPa, currently the highest reported for CuZr-based BMGs. This study enhances our understanding of the intrinsic relationship between LPBF parameters, melt pool characteristics, defects, and mechanical properties of LPBF-fabricated BMGs while providing a new parameter optimization strategy for reducing defects and achieving high strength in BMGs.

Rapid growth in industrial sectors such as automotive and shipbuilding has highlighted the significance of strip casting technology to produce lightweight alloys, particularly aluminum alloys widely used in both industrial production and daily life. Twin-roll casting (TRC), as an economically and environmentally friendly method for slab/strip production and processing, has attracted significant interest from researchers. However, the development of TRC aluminum alloys faces many challenges due to limited understanding of microstructural characteristics and control mechanisms. To further enhance comprehension of TRC aluminum alloys, this article reviews the influencing parameters, control methods, and existing issues related to TRC sub-rapid solidification (SRS) microstructure. It firstly summarizes TRC equipment types and their solidification characteristics, followed by a detailed analysis on key parameters affecting the evolution of TRC microstructure including rolling speed, roll separation force (RSF), and heat transfer coefficient (HTC). Finally, solutions to TRC defects are summarized and evaluated alongside their underlying mechanisms. This article provides a comprehensive review of the characteristics and control mechanisms of TRC microstructure while offering valuable insights for the future production of high-quality TRC aluminum strips.

An in-depth understanding of the bimodal scale particle reinforced composites, including the particle content and size, phase constitution and distribution, and their effects on mechanical properties and deformation mechanisms, is essential to advance the study of high performance high entropy alloys (HEAs). In this study, the bimodal-sized (nano + micron)(N + M)-Al2O3P/CoCrFeMnNi reinforced composites and monomadal-sized micron(M)-Al2O3P/CoCrFeMnNi reinforced composites were successfully fabricated using a two-step ball milling process in conjunction with spark plasma sintering (SPS) technology. Results showed that the Al2O3P/CoCrFeMnNi composites primarily consisted of fcc structure, with Al2O3 and MnAl2O4 as secondary phases. The M-Al2O3P reinforced composites contained obvious heterogeneous structure while (N + M)-Al2O3P reinforced composites exhibited a multi-scale grain structure comprising of double-sized reinforcement and multiple-sized matrix grains. The yield strength (YS) of bimodal-size particle reinforced composites was higher than that of monomadal particle reinforced composites. For example, the YS of (N-5)/(M − 5) and (N-5)/(M − 10) composites was 117% and 133% higher than that of HEA, respectively. Intriguingly, (N + M)-Al2O3P reinforced composites effectively addressed the issue of reduced material strength caused by a high concentration of particles with a monomadal size. Moreover, the composites of (N-5)/(M − 5) and (N-5)/(M − 10) with a high content of lightweight Al2O3P effectively contributed to the reduction in density of HEA, exhibiting a decrease by 11% and 17% compared to pure HEA, respectively.

Background: Diabetic bone healing remains a great challenge due to its pathological features including biochemical disturbance, excessive inflammation, and reduced blood vessel formation. In previous studies, small intestine submucosa (SIS) has been demonstrated for its immunomodulatory and angiogenic properties, which are necessary to diabetic bone healing. However, the noticeable drawbacks of SIS such as fast degradation rate, slow gelling time, and weak mechanical property seriously impede the 3D printing of SIS for bone repair. Method: In this study, we developed a novel kind of 3D-printed scaffold composed of alginate, nano-hydroxyapatite, and SIS. The morphological characterization, biocompatibility, and in vitro biological effects of the scaffolds were evaluated, and an established diabetic rat model was used for testing the in vivo biological effect of the scaffold after implantation. Results: The in vitro and in vivo results show that the addition of SIS can tune the immunomodulatory properties and angiogenic and osteogenic performances of 3D-printed scaffold, where the macrophages polarization of M2 phenotype, migration and tube formation of HUVECs, as well as osteogenic expression of ALP, are all improved, which bode well with the functional requirements for treating diabetic bone nonunion. Furthermore, the incorporation of alginate substantially improves the printability of composites with tunable degradation properties, thereby broadening the application prospect of SIS-based materials in the field of tissue engineering. Conclusion: The fabricated 3D-printed Alg/HA/SIS scaffold provides desirable immunomodulatory effect, as well as good osteogenic and angiogenic performances in vitro and in vivo, which properties are well-suited with the requirement for treating diabetic bone defects. Translational potential of this article: The incorporation of SIS and alginate acid not only provides good printability of the newly fabricated 3D-printed Alg/HA/SIS scaffold, but also improves its immunoregulatory and angiogenic properties, which suits well with the requirement for treating diabetic bone disease and opens up new horizons for the development of implants associating diabetic bone healings.

Objectives: Clostridioides difficile ranks among the primary sources of healthcare-related infections and diarrhoea in numerous nations. We evaluated the drug susceptibility and resistance mechanisms of C. difficile isolates from a hospital in Chongqing, China, and identified resistance rates and resistance mechanisms that differed from previous findings. Methods: The toxin genes and drug resistance genes of clinical strains were detected using Polymerase Chain Reaction (PCR), and these strains were subjected to Multilocus Sequence Typing (MLST). The agar dilution technique was employed for assessing susceptibility of antibiotics. Clinical data collection was completed through a review of electronic medical records. Results: A total of 67 strains of toxin-producing C. difficile were detected. All C. difficile isolates demonstrated susceptibility to both metronidazole and vancomycin. However, resistance was observed in 8.95%, 16.42%, 56.72%, 56.72%, 31.34% and 5.97% of the isolates for tigecycline, tetracycline, clindamycin, erythromycin, moxifloxacin and rifampin, respectively. Among the strains with toxin genotypes A + B + CDT - and belonging to the ST3, six strains exhibited reduced susceptibility to tigecycline (MIC=0.5mg/L) and tetracycline (MIC=8mg/L). The tetA(P) and tetB(P) genes were present in these six strains, but were absent in tetracycline-resistant strains. Resistance genes (ermB, tetM, tetA(P) and tetB(P)) and mutations (in gyrA, gyrB, and rpoB) were identified in resistant strains. Conclusions: In contrast to prior studies, we found higher proportions of ST3 isolates with decreased tigecycline sensitivity, sharing similar resistance patterns and resistance genes. In the resistance process of tigecycline and tetracycline, the tetA(P) and tetB(P) genes may play a weak role.

To ensure optimal penetration in direct current (DC) argon tungsten arc welding, a method was proposed to recognize the molten pool penetration during molten pool oscillation under alternating cusp-shaped magnetic field (ACSMF). An arc discharge model is established to analyze the oscillation mechanism of the molten pool under ACSMF. The periodic variation of arc shape induces the periodic oscillation to establish a mapping relationship with the fluctuation of arc voltage waveform. At the excitation current of 3 A and frequency of 10 Hz, the arc voltage waveform undergoes abrupt changes at 1.26 V and 1.37 V, corresponding to the critical and the full penetration states, respectively. The errors in identifying moving penetration are 0.8 % and 0.7 %, with a full penetration weld, demonstrating a penetration rate of 100 %, indicating effective penetration recognition. Arc sensing technology for tungsten inert gas (TIG) welding under ACSMF is poised for gradual application in single-side welding and double-side forming of medium and thick plates. It is anticipated to evolve towards real-time identification technology for molten pool penetration monitoring.

In unconsolidated sandstone reservoirs, presence of numerous movable grains and a complex grain size composition necessitates a clear understanding of the physical clogging process for effective groundwater recharge in groundwater-source heat pump systems. To investigate this, a series of seepage experiments was conducted under in situ stress conditions using unconsolidated sandstone samples with varying grain compositions. The clogging phenomenon arises from the combined effects of grain migration and compaction, wherein the migration of both original and secondary crushed fine-grain particles blocks the seepage channels. Notably, grain composition influences the migration and transport properties of the grains. For samples composed of smaller grains, the apparent permeability demonstrates a transition from stability to decrease. In contrast, samples with larger grains experience a skip at the stability stage and directly enter the decrease stage, with a minor exception of a slight increase observed. Furthermore, a unique failure mode characterized by diameter shrinkage in the upper part of the sample is observed due to the combined effects of grain migration and in situ stress-induced compaction. These testing results contribute to a better understanding of the clogging mechanism caused by the coupled effects of grain migration and compaction during groundwater recharge in unconsolidated sandstone reservoirs used in groundwater-source heat pump systems.

Background: Real-world vaccine effectiveness following the third dose of vaccination against SARS-CoV-2 remains less investigated among people with HIV (PWH). Methods: PWH receiving the third dose of BNT162b2 and mRNA-1273 (either 50- or 100-μg) were enrolled. Participants were followed for 180 days until the fourth dose of COVID-19 vaccination, SARS-CoV-2 infection, seroconversion of anti-nucleocapsid IgG, death, or loss to follow-up. Anti-spike IgG was determined every 1–3 months. Results: Of 1427 participants undergoing the third-dose COVID-19 vaccination, 632 (44.3%) received 100-μg mRNA-1273, 467 (32.8%) 50-μg mRNA-1273, and 328 (23.0%) BNT162b2 vaccine and the respective rate of SARS-CoV-2 infection or seroconversion of anti-nucleocapsid IgG was 246.1, 280.8 and 245.2 per 1000 person-months of follow-up (log-rank test, p = 0.28). Factors associated with achieving anti-S IgG titers >1047 BAU/mL included CD4 count 200 copies/mL (aOR, 0.27; 95% CI, 0.09–0.80), having achieved anti-spike IgG >141 BAU/mL within 3 months after primary vaccination (aOR, 3.69; 95% CI, 2.68–5.07), receiving BNT162b2 vaccine as the third dose (aOR, 0.20; 95% CI, 0.10–0.41; reference, 100-μg mRNA-1273), and having previously received two doses of mRNA vaccine in primary vaccination (aOR, 2.46; 95% CI, 1,75-3.45; reference, no exposure to mRNA vaccine). Conclusions: PWH receiving different types of the third dose of COVID-19 vaccine showed similar vaccine effectiveness against SARS-CoV-2 infection. An additional dose with 100-μg mRNA-1273 could generate a higher antibody response than with 50-μg mRNA-1273 and BNT162b2 vaccine.

Inefficient drug penetration hurdled by the stroma in the tumor tissue leads to a diminished therapeutic effect for drugs and a reduced infiltration level of immune cells. Herein, we constructed a PEGylated dendritic epirubicin (Epi) prodrug (Epi-P4D) to regulate the metabolism of cancer-associated fibroblasts (CAFs), thus enhancing Epi penetration into both multicellular tumor spheroids (MTSs) and tumor tissues in mouse colon cancer (CT26), mouse breast cancer (4T1) and human breast cancer (MDA-MB-231) models. Enhanced cytotoxicity against CT26 MTSs and remarkable antitumor efficacy of Epi-P4D were ascribed to reduced fibronectin, α-SMA, and collagen secretion. Besides, thinning of the tumor tissue stroma and efficient eradication of tumor cells promoted the immunogenic cell death effect for dendritic cell (DC) maturation and subsequent immune activation, including elevating the CD4+ T cell population, reducing CD4+ and CD8+ T cell hyperactivation and exhaustion, and amplifying the natural killer (NK) cell proportion and effectively activating them. As a result, this dendritic nanomedicine thinned the stroma of tumor tissues to enhance drug penetration and facilitate immune cell infiltration for elevated antitumor efficacy.

Bile acids (BAs) are synthesized by the host liver from cholesterol and are delivered to the intestine, where they undergo further metabolism by gut microbes and circulate between the liver and intestines through various transporters. They serve to emulsify dietary lipids and act as signaling molecules, regulating the host's metabolism and immune homeostasis through specific receptors. Therefore, disruptions in BA metabolism, transport, and signaling are closely associated with cholestasis, metabolic disorders, autoimmune diseases, and others. Botanical triterpenoids and steroids share structural similarities with BAs, and they have been found to modulate BA metabolism, transport, and signaling, potentially exerting pharmacological or toxicological effects. Here, we have updated the research progress on BA, with a particular emphasis on new-found microbial BAs. Additionally, the latest advancements in targeting BA metabolism and signaling for disease treatment are highlighted. Subsequently, the roles of botanical triterpenoids in BA metabolism, transport, and signaling are examined, analyzing their potential pharmacological, toxicological, or drug interaction effects through these mechanisms. Finally, a research paradigm is proposed that utilizes the gut microbiota as a link to interpret the role of these important natural products in BA signaling.

Background: Lorlatinib is a brain-penetrant, third-generation anaplastic lymphoma kinase (ALK) inhibitor indicated for ALK-positive metastatic non-small cell lung cancer (NSCLC). In a global phase II study, patients who experience disease progression despite prior treatment with ALK tyrosine kinase inhibitors (TKIs) was assessed. Herein, we report real-world clinical outcomes of lorlatinib-treated patients with ALK-positive advanced NSCLC who were heavily pretreated and progressed on first- and second-generation ALK-TKIs, in a Taiwanese population under the lorlatinib expanded access program (EAP). Methods: This multicenter observational study examined the effectiveness and safety of ALK-positive advanced NSCLC patients that progressed from previous second-generation ALK-TKI therapy and received lorlatinib treatment subsequently. Patients who received lorlatinib treatment under EAP between Jul 2017 and Sep 2019 were eligible. Patients were followed for at least one year from the first lorlatinib treatment until study completion. Results: Sixty-three patients were eligible for safety analysis (male: 46.0 %; median age: 52.8 [27.5–78.3] years; brain metastases: 81.0 %). Fifty-four patients with more than one-month lorlatinib treatment were included in the effectiveness analysis. Prior to lorlatinib treatment, 10 patients (18.5 %) received one ALK-TKI, 27 (50.0 %) received two ALK-TKIs, and 17 (31.5 %) received three or more ALK-TKIs. The overall median rwPFS was 9.2 months (95 % confidence interval: 5.3–21.1). The best overall response rate (n = 51) was 13.7 %, with a disease control rate of 80.4 %. Conclusion: Lorlatinib exhibits substantial activity and tolerability when used clinically in a later-line setting in a Taiwanese population with ALK-positive advanced NSCLC.

Introduction: Peanut is susceptible to infection of Aspergillus fungi and conducive to aflatoxin contamination, hence developing aflatoxin-resistant variety is highly meaningful. Identifying functional genes or loci conferring aflatoxin resistance and molecular diagnostic marker are crucial for peanut breeding. Objectives: This work aims to (1) identify candidate gene for aflatoxin production resistance, (2) reveal the related resistance mechanism, and (3) develop diagnostic marker for resistance breeding program. Methods: Resistance to aflatoxin production in a recombined inbred line (RIL) population derived from a high-yielding variety Xuhua13 crossed with an aflatoxin-resistant genotype Zhonghua 6 was evaluated under artificial inoculation for three consecutive years. Both genetic linkage analysis and QTL-seq were conducted for QTL mapping. The candidate gene was further fine-mapped using a secondary segregation mapping population and validated by transgenic experiments. RNA-Seq analysis among resistant and susceptible RILs was used to reveal the resistance pathway for the candidate genes. Results: The major effect QTL qAFTRA07.1 for aflatoxin production resistance was mapped to a 1.98 Mbp interval. A gene, AhAftr1 (Arachis hypogaea Aflatoxin resistance 1), was detected structure variation (SV) in leucine rich repeat (LRR) domain of its production, and involved in disease resistance response through the effector-triggered immunity (ETI) pathway. Transgenic plants with overexpression of AhAftr1(ZH6) exhibited 57.3% aflatoxin reduction compared to that of AhAftr1(XH13). A molecular diagnostic marker AFTR.Del.A07 was developed based on the SV. Thirty-six lines, with aflatoxin content decrease by over 77.67% compared to the susceptible control Zhonghua12 (ZH12), were identified from a panel of peanut germplasm accessions and breeding lines through using AFTR.Del.A07. Conclusion: Our findings would provide insights of aflatoxin production resistance mechanisms and laid meaningful foundation for further breeding programs.

Introduction: Herbicide application is a highly efficiency method of weed control that boots agricultural output and assures food security. The development of novel herbicides focuses on improved bioactivity and new modes of action. The amino acid biosynthesis was validated as a promising novel mode of action for herbicidal compounds. However, the amino acid biosynthesis enzyme remains largely unexplored for herbicidal targets. Objectives: Serine hydroxymethyl transferase (SHMT) is an essential enzyme in the photorespiratory cycle. The study aims to explore Conyza canadensis SHMT1 (CcSHMT1) as a promising target for herbicide discovery. Methods: Structure determination of CcSHMT1 was resolved by X-ray crystallography. Virtual screening docking experiments were performed with Glide version 5.5. Novel derivatives of dimethyl 2-acetamido terephthalate were further designed, synthesized, and bioassay. The druggability of the inhibitor was evidenced by ultrastructural changes in mitochondria, in vivo and vitro enzyme activity assays, and genetics analysis. Results: CcSHMT1 has a typical PLP-dependent enzyme 3D structure. The dimethyl 2-acetamido terephthalate-containing compounds had herbicidal activity. Dimethyl 2-(2-(4-(2-(4-bromo-2-chlorophenoxy) acetyl)piperazin-1-yl)acetamido) terephthalate (Compound 9ay, EC50 = 193.8 g a.i./ ha) exhibited the highest herbicidal activity on tested weed among the synthesized compounds. Compound 9ay had no obvious adverse effect on the growth of maize and honeybees. Compound 9ay was verified to target CcSHMT1 as an herbicide candidate. Conclusion: A first-in-class CcSHMT1 inhibitor that could be developed as a potent herbicide with a new mode of action and provide an avenue for discovering novel inhibitors of pyridoxal-5-phosphate-dependent enzymes.

Ventricular meningiomas are neoplastic cells originating from the ependymal lining of the central canal of the spinal cord and the ventricles of the brain. These tumorigenic cells predominantly manifest in the fourth ventricle, followed by the spinal cord. Most intraparenchymal ventricular meningiomas are located within the brain tissue, exhibiting a higher degree of malignancy compared to their intracerebroventricular counterparts. While intracranial dissemination and metastasis to the spinal cord can occur, extra-neurologic metastasis is an exceedingly rare phenomenon that lacks a clear elucidation regarding its underlying mechanism. The authors presented a case of supratentorial brain parenchymal type ventricular meningioma surgical treatment in a young female patient, occurring two years after the development of multiple metastases in both lungs, pleura, and mediastinum. This may be attributed to the high malignancy degree and strong invasiveness of this lesion, as well as its proximity to the dura mater and venous sinus. The craniotomy provided an opportunity for tumor cells to invade the adjacent venous sinus, leading to dissemination through the blood system. Additionally, postoperative radiation and chemotherapy were administered to inhibit tumor angiogenesis; however, these treatments also increased the likelihood of tumor cell invasion into neighboring brain tissues and distant metastasis.

Bear bile has been a valuable and effective medicinal material in traditional Chinese medicine (TCM) for over 13 centuries. However, the current practice of obtaining it through bear farming is under scrutiny for its adverse impact on bear welfare. Here, we present a new approach for creating artificial bear bile (ABB) as a high-quality and sustainable alternative to natural bear bile. This study addresses the scientific challenges of creating bear bile alternatives through interdisciplinary collaborations across various fields, including resources, chemistry, biology, medicine, pharmacology, and TCM. A comprehensive efficacy assessment system that bridges the gap between TCM and modern medical terminology has been established, allowing for the systematic screening of therapeutic constituents. Through the utilization of chemical synthesis and enzyme engineering technologies, our research has achieved the environmentally friendly, large-scale production of bear bile therapeutic compounds, as well as the optimization and recomposition of ABB formulations. The resulting ABB not only closely resembles natural bear bile in its composition but also offers advantages such as consistent product quality, availability of raw materials, and independence from threatened or wild resources. Comprehensive preclinical efficacy evaluations have demonstrated the equivalence of the therapeutic effects from ABB and those from commercially available drained bear bile (DBB). Furthermore, preclinical toxicological assessment and phase I clinical trials show that the safety of ABB is on par with that of the currently used DBB. This innovative strategy can serve as a new research paradigm for developing alternatives for other endangered TCMs, thereby strengthening the integrity and sustainability of TCM.

Metalenses with achromatic performance offer a new opportunity for high-quality imaging with an ultra-compact configuration; however, they suffer from complex fabrication processes and low focusing efficiency. In this study, we propose an efficient design method for achromatic microlenses on a wavelength scale using materials with low dispersion, an adequately designed convex surface, and a thickness profile distribution. By taking into account the absolute chromatic aberration, relative focal length shift (FLS), and numerical aperture (NA), microlens with a certain focal length can be realized through our realized map of geometric features. Accordingly, the designed achromatic microlenses with low-dispersion fused silica were fabricated using a focused ion beam, and precise surface profiles were obtained. The fabricated microlenses exhibited a high average focusing efficiency of 65% at visible wavelengths of 410–680 nm and excellent achromatic capability via white light imaging. Moreover, the design exhibited the advantages of being polarization-insensitive and near-diffraction-limited. These results demonstrate the effectiveness of our proposed achromatic microlens design approach, which expands the prospects of miniaturized optics such as virtual and augmented reality, ultracompact microscopes, and biological endoscopy.

Background: Our previous study synthesized the analgesic effects of repetitive Transcranial Magnetic Stimulation (rTMS) over the dorsolateral prefrontal cortex (DLPFC) trials up to 2019. There has been a significant increase in pain trials in the past few years, along with methodological variabilities such as sample size, stimulation intensity, and rTMS paradigms. Objectives/Methods: This study therefore updated the effects of DLPFC-rTMS on chronic pain and quantified the impact of methodological differences across studies. Results: A total of 36 studies were included. Among them, 26 studies were clinical trials (update = 9, 307/711 patients), and 10 (update = 1, 34/249 participants) were provoked pain studies. The updated meta-analysis does not support an effect on neuropathic pain after including the additional trials (pshort-term = 0.20, pmid-term = 0.50). However, there is medium-to-large analgesic effect in migraine trials extending up to six weeks follow-up (SMDmid-term = −0.80, SMDlong-term = −0.51), that was not previously reported. Methodological differences wthine the studies were considered. DLPFC-rTMS also induces potential improvement in the emotional aspects of pain (SMDshort-term = −0.28). Conclusions: The updated systematic meta-analysis continues to support analgesic effects for chronic pain overall. However, the updated results no longer support DLPFC-rTMS for pain relief in neuropathic pain, and do supports DLPFC-rTMS in the management of migraine. There is also evidence for DLPFC-rTMS to improve emotional aspects of pain.

In the global pursuit of energy conservation, reduction in consumption and emissions, as well as lightweighting, 5xxx-series aluminum alloys have emerged as a promising lightweight and high-strength material with a wide range of applications in aerospace, transportation, building structures, medical devices, and more. However, it is worth noting that 5XXX-series aluminum alloys belong to a category of non-heat-treatable reinforced aluminum alloys with limited means of enhancing their properties through heat treatment. Consequently, the development of high-performance 5XXX-series aluminum alloys poses a significant challenge. This paper provides an overview of the research progress on 5xxx-series aluminum alloys while discussing the current state of research regarding the influence of microalloying elements on their microstructure and properties. Furthermore, it elucidates the emerging trends in synergistic regulation between deformation processes and heat treatment processes for enhancing organizational refinement and improving alloy properties. Additionally, this study analyzes the reinforcement mechanism responsible for the exceptional properties exhibited by 5xxx-series aluminum alloys. Lastly, it discusses the exceptional properties exhibited by 5xxx-series alloys along with their primary areas of application. The findings presented herein can serve as a valuable reference for future advancements in advanced high-performance 5xxx-series aluminum alloys.

To explore the variances between single-reinforced and hybrid-reinforced Al–Mg–Si alloys with TiC and B4C, 10 wt.%-(TiC + B4C)/6061Al, 10 wt.%-B4C/6061Al, 10 wt.%-TiC/6061Al and 6061Al were prepared via wet mixing for 8 h followed by vacuum hot-press sintering at 580 °C and 30 MPa for 2 h. Microstructure evolution, mechanical properties, and wear behavior were investigated in this study. The results show that unlike single reinforcement of TiC, single reinforcement of B4C and hybrid reinforcement of TiC and B4C altered the distribution of Si and facilitated the in-situ formation of SiC. Both single reinforcement and hybrid reinforcement resulted in mixed fracture characteristics of ductile fracture and cleavage fracture, while hybrid reinforcement of TiC and B4C demonstrated superior strength and plasticity matching. At equivalent particle mass fractions, single reinforcement of TiC was more conducive to inducing recrystallization during sintering, followed by single reinforcement of B4C, and hybrid reinforcement of TiC and B4C had the least effect. At equivalent particle mass fractions, single reinforcement of B4C had the most significant effect on improving the wear resistance, followed by hybrid reinforcement of TiC and B4C, and single reinforcement of TiC had the least effect. All particle addition methods demonstrated a mixed wear mechanism involving abrasive wear, adhesive wear, and spalling wear. This study provides valuable insights into the development of aluminum matrix composites.

Low carbon medium manganese steel with chromium and molybdenum addition (4MnCM), alongside a control group without these additions (4Mn), was developed. The quenching (860 °C) and tempering (620 °C) heat treatment process was applied to both steel groups. The influence of Cr and Mo on the microstructure evolution and mechanical properties was examined. The findings revealed that, the low−temperature impact energy values (KV2) of 4MnCM at −60 and −84 °C were enhanced by 104 and 107 J, in comparison to 4Mn. The yield and tensile strength saw an increase of 100 MPa. The higher low-temperature toughness of 4MnCM is attributed, on one hand, to the addition of Cr and Mo, which inhibiting deformation twinning through enhances the stacking fault energy (SFE) of reversed austenite. On the other hand, it is due to the absence of coarse ε−martensite (ε−m) along the crack propagation path. Additionally, the phase transformation of reversed austenite occurs at the crack nucleation stage during the impact process of both steels, which helps alleviate stress concentration and increases the energy required for crack formation. The primary reason for the higher strength of 4MnCM lies in the significant enhancement of precipitation strengthening effects through the precipitation of M6C, M23C6 and Nb/TiC co-precipitation with M6C.

This paper addresses the significant requirements in China's fusion engineering and investigates the preparation technology and performance characterization of high-performance tungsten-based materials used as PFMs. The rolled W–Y2Zr2O7 plate were prepared through sintering and subsequent rolling, and steady-state heat load assessment was conducted under fusion device working conditions. Additionally, the change in mechanical behavior of the rolled plates was investigated across different surfaces. The results also revealed that the rolling plate exhibited a DBTT between RT and 200 °C, with more superior mechanical properties along the RD direction. The flat-plate W–Y2Zr2O7/Cu components demonstrated the ability to withstand 1000 heat load cycles at 10 MW/m2 without cracking, indicating favorable thermo-mechanical performance as PFMs. These findings serve as a valuable reference for the fabrication of tungsten-based materials in fusion engineering.

Three mole percent yttria-stabilized tetragonal zirconia polycrystal (3Y-TZP) ceramics are exemplary materials for dental restoration due to their high mechanical strength, fracture toughness, chemical endurance, and biocompatibility. Nevertheless, 3Y-TZP ceramics are opaque and their CAD/CAM manufacturing process may cause micro-cracks in conventional clinical practice. In this study, 3Y-TZP ceramic samples were prepared using vat photopolymerization, pre-sintering, external staining, and final high-temperature sintering. The microstructures, mechanical properties, optical properties, and cytotoxicity of the 3Y-TZP ceramic samples were investigated. The results indicate that with increasing Fe3+ concentration of staining solution from 0.1 mol/L to 0.3 mol/L and increasing staining time from 5 s to 30 min, the 3Y-TZP ceramic samples showed a tetragonal crystal structure of zirconia with densely packed grains and a slight increase in grain size. The flexural strength, Vickers hardness, and fracture toughness of 3Y-TZP ceramic samples stained in 0.1–0.3 mol/L Fe3+ solution for 5 s to 3 min were all greater than 665 MPa, 11.9 GPa, and 5 MPa m1/2, respectively, meeting the mechanical requirements for clinical application. Colorimetric analysis revealed a decrease in L* (black-white index) from 90.4 to 81.3, an increase in a* (green-red index) from −1.5 to 3.2, and an increase in b* (blue-yellow index) from 11.6 to 20.3, approximating the commercial VITA 3D-Master Shade Guide chromaticity. Furthermore, the 3Y-TZP ceramic samples exhibited a cell viability of 90% or higher toward L929 cells.

Powder Plasma Arc Additive Manufacturing (PPA-AM) technique has tremendous potential for the practical application in medium-entropy alloys (MEAs). In this study, we investigated the effect of heat treatment on microstructural evolution, mechanical properties, and the work hardening behavior in the PPA-AM processed (CoCrNi)90Al5Ti5 MEA. The results show that the As-built specimen is a single-phase FCC structure, displaying strong FCC texture in the deposition direction. The stacking faults (SFs) and dislocations were observed in the alloy, which formed the stacking fault networks and the Lomer-Cottrell locks structure. The plasticity of the alloy increased significantly after the high-temperature heat treatment, which can be attributed to the modifications of the microstructure, such as the weakening of the texture strength and the reduction of the stresses. Low-temperature heat treatment decreases the density of dislocations in the alloy, but promotes the generation of the co-lattice phase. The evolution of the dislocation density, texture strength, and precipitates significantly influenced the strain hardening behavior and mechanical properties. The tensile results showed that the strength and plasticity of the samples were increased after two-step heat treatment. The yield strength, ultimate tensile strength, and elongation to failure were 733 MPa, 1080 MPa, and 22.3%, respectively, which were 16.2%, 20.3%, and 15.5% higher than the As-built samples. This work elucidates the underlying mechanisms of heat treatment on the microstructure and mechanical properties of the alloy.

Different sedimentary zones in coral reefs lead to significant anisotropy in the pore structure of coral reef limestone (CRL), making it difficult to study mechanical behaviors. With X-ray computed tomography (CT), 112 CRL samples were utilized for training the support vector machine (SVM)-, random forest (RF)-, and back propagation neural network (BPNN)-based models, respectively. Simultaneously, the machine learning model was embedded into genetic algorithm (GA) for parameter optimization to effectively predict uniaxial compressive strength (UCS) of CRL. Results indicate that the BPNN model with five hidden layers presents the best training effect in the data set of CRL. The SVM-based model shows a tendency to overfitting in the training set and poor generalization ability in the testing set. The RF-based model is suitable for training CRL samples with large data. Analysis of Pearson correlation coefficient matrix and the percentage increment method of performance metrics shows that the dry density, pore structure, and porosity of CRL are strongly correlated to UCS. However, the P-wave velocity is almost uncorrelated to the UCS, which is significantly distinct from the law for homogenous geomaterials. In addition, the pore tensor proposed in this paper can effectively reflect the pore structure of coral framework limestone (CFL) and coral boulder limestone (CBL), realizing the quantitative characterization of the heterogeneity and anisotropy of pore. The pore tensor provides a feasible idea to establish the relationship between pore structure and mechanical behavior of CRL.

Accurate prediction of rockburst proneness is one of challenges for assessing the rockburst risk and selecting effective control measures. This study aims to assess rockburst proneness by considering the energy characteristics and qualitative information during rock failure. Several representative rock types in cylindrical and cuboidal sample shapes were tested under uniaxial compression conditions and the failure progress was detected by a high-speed camera. The far-field ejection mass ratio (FEMR) was determined considering the qualitative failure information of the rock samples. The peak-strength energy impact index and the residual elastic energy index were used to quantitatively evaluate the rockburst proneness of both cylindrical and cuboidal samples. Further, the performance of these two indices was analyzed by comparing their estimates with the FEMR. The results show that the accuracy of the residual elastic energy index is significantly higher than that of the peak-strength energy impact index. The residual elastic energy index and the FEMR are in good agreement for both cylindrical and cuboidal rock materials. This is because these two indices can essentially reflect the common energy release mechanism characterized by the mass, ejection velocity, and ejection distance of rock fragments. It suggests that both the FEMR and the residual elastic energy index can be used to accurately measure the rockburst proneness of cylindrical and cuboidal samples based on uniaxial compression test.

In cold regions, the dynamic compressive strength (DCS) of rock damaged by freeze-thaw weathering significantly influences the stability of rock engineering. Nevertheless, testing the dynamic strength under freeze-thaw weathering conditions is often both time-consuming and expensive. Therefore, this study considers the effect of characteristic impedance on DCS and aims to quickly determine the DCS of frozen-thawed rocks through the application of machine-learning techniques. Initially, a database of DCS for frozen-thawed rocks, comprising 216 rock specimens, was compiled. Three external load parameters (freeze-thaw cycle number, confining pressure, and impact pressure) and two rock parameters (characteristic impedance and porosity) were selected as input variables, with DCS as the predicted target. This research optimized the kernel scale, penalty factor, and insensitive loss coefficient of the support vector regression (SVR) model using five swarm intelligent optimization algorithms, leading to the development of five hybrid models. In addition, a statistical DCS prediction equation using multiple linear regression techniques was developed. The performance of the prediction models was comprehensively evaluated using two error indexes and two trend indexes. A sensitivity analysis based on the cosine amplitude method has also been conducted. The results demonstrate that the proposed hybrid SVR-based models consistently provided accurate DCS predictions. Among these models, the SVR model optimized with the chameleon swarm algorithm exhibited the best performance, with metrics indicating its effectiveness, including root mean square error (RMSE) = 3.9675, mean absolute error (MAE) = 2.9673, coefficient of determination (R2) = 0.98631, and variance accounted for (VAF) = 98.634. This suggests that the chameleon swarm algorithm yielded the most optimal results for enhancing SVR models. Notably, impact pressure and characteristic impedance emerged as the two most influential parameters in DCS prediction. This research is anticipated to serve as a reliable reference for estimating the DCS of rocks subjected to freeze-thaw weathering.

Laser brazing is an esteemed technique for Ti/Al dissimilar alloy welding, yet the emergence of brittle intermetallic compounds (IMCs) restricts its broader application. In-depth knowledge of IMCs formation provides critical insights for process optimization targeting IMCs structural improvement, pivotal to high-performance of Ti/Al joint. Herein, we establish macroscopic heat transfer-fluid flow coupled model for laser brazing welding of Ti/Al dissimilar alloys firstly, followed by a comprehensive characterization of the types, distribution, and crystallographic features of IMCs, thereby elucidating the impact mechanism of laser offset on IMCs growth. Incremented laser offset prompts a conversion from transverse to tangential flow at the Ti/Al interface, attenuates peak temperatures and liquid phase duration, and significantly revises solidification parameters, thereby reducing the IMCs layer to 5 μm, augmenting solid-state transformation characteristic, and diversifying crystallographic orientations of IMCs. Ultimately, enhanced tensile strength in the Ti/Al joint is attributed to the presence of thinner IMCs with finer grains, produced by larger laser offset. This article constitutes a pivotal progression in modeling heat transfer-flow behaviors for Ti/Al laser brazing welding, revealing IMCs genesis with unparalleled granularity guided by crystal selective growth principles. It also lays a theoretical foundation for IMCs micro-structure improvement strategy via temperature-flow regulation.

This study systematically investigates the flow behavior of 7050 aluminum (Al) alloy produced via spray forming and subjected to a proposed pretreatment through thermal compression tests. The experimental findings reveal that the peak stress increased with decreasing deformation temperature or increasing strain rates. The parameters in the Arrhenius constitutive model were determined and verified by experimental results for spray formed (SFed) 7050 Al alloy. Hot deformation activation energy of the SFed 7050 Al alloy (147.38 kJ/mol) is notably lower than that of cast Al–Zn–Mg–Cu–Zr alloys, which is attributed to factors such as fine grains, low segregation, pores, and dispersed Al3Zr induced by pretreatment. Furthermore, processing maps have been constructed at various strains, revealing optimal stable deformation conditions at 300–450 °C/0.001–0.15s−1 and 425–450 °C/0.2–1s−1. Microstructural analysis of deformed samples highlights the critical role of dynamic recrystallization in influencing the stable and unstable areas of the alloy, which may be activated by high temperature and slow strain rate. The hot deformation mechanism of the SFed Al alloy is governed by interactions among η-Mg(Zn,Al,Cu)2 precipitates, dispersed Al3Zr particles, dislocation structures, and (sub-)grain boundaries.

316L stainless steel (316L SS) is easy to be damaged due to poor corrosion and wear resistance, the preparation of composite coating with excellent corrosion and wear resistance properties on the surface can lengthen its service life. In this aspect, Fe-based amorphous CoCrFeNi high entropy alloy (HEA) composite coating was prepared on 316L SS by laser cladding. The microstructure, phase, microhardness, wear and corrosion resistance of the coatings were analyzed by scanning electron microscope (SEM) equipped with energy disperse spectroscopy (EDS), X-ray diffraction (XRD), Vickers hardness tester, electrochemical workstation, and the friction and wear tester. The results show that the phase composition of the coatings was FCC solid solution. The microstructure of the coatings gradually evolved from regular cellular crystals to irregular amorphous structures, while the microhardenss of each coating changed little. The wear and corrosion resistance of the coatings was better than that of the substrate. When the content of Fe-based amorphous is 8%, the properties of the coating are the best.

The drugs extending healthspan in clinic have always been searched. Nitazoxanide is an FDA-approved clinical antiprotozoal drug. Nitazoxanide is rapidly metabolized to tizoxanide after absorption in vivo. Our previous studies find that nitazoxanide and its metabolite tizoxanide induce mild mitochondrial uncoupling and activate cellular AMPK, oral nitazoxanide protects against experimental hyperlipidemia, hepatic steatosis, and atherosclerosis. Here, we demonstrate that both nitazoxanide and tizoxanide extend the lifespan and healthspan of Caenorhabditis elegans through Akt/AMPK/sir 2.1/daf16 pathway. Additionally, both nitazoxanide and tizoxanide improve high glucose-induced shortening of C. elegans lifespan. Nitazoxanide has been a clinical drug with a good safety profile, we suggest that it is a novel anti-aging drug.

Combination immunotherapy has shown promising potential for enhancing the objective response rate compared to immune checkpoint blockade (ICB) monotherapy. However, combination therapy with multi-drugs is limited by the different properties of the agents and inconsistent synergistic targeted delivery. Herein, based on a universal triterpene template and the anticancer active agent ursolic acid (UA), a cytomembrane-coated biomimetic delivery nanoplatform (UR@M) prepared by the self-assembly of a PD-L1 targeted CRISPR/Cas9 system and UA was designed for hepatocellular carcinoma (HCC) treatment. UR@M showed enhanced tumor accumulation in vivo with homologous tumor targeting, and CRISPR in the nanosystem exhibited potent gene-editing efficiency of 76.53% in vitro and 62.42% in vivo with no off-target effects. UA activated the natural immune system through the TLR-2-MyD88-TRAF6 pathway, which synergistically enhanced the proliferation of natural killer cells and dendritic cells and realized excellent immune cytotoxic T cell infiltration by combining with the ICB of PD-L1. The strategy of work along both lines based on innate immune and adaptive immunity displayed a significant effect in tumor regression. Overall, the UA-templated strategy “killed three birds with one stone” by establishing a self-assembly nanosystem, inducing tumor cell death, and promoting synergistic immunostimulation for HCC treatment.

ABSTRACT: Whey protein isolate (WPI)-based nanodelivery systems have recently attracted an increasing amount of attention. Despite this, research focusing on milk protein concentrate (MPC) and micellar casein (MCC) as carriers loaded in hydrophobic compounds is lacking. This study investigated the mediated effect of docosahexaenoic acid (DHA) in 3 different milk proteins for the embedding of astaxanthin (ASTA) after ultrasound-assisted pH-shifting treatment. We then evaluated the application of milk protein carriers in cheese processing by comparing MPC, MCC, and WPI. The particle size, polydispersity index, and zeta potential results of the milk protein–DHA complex suggested that the addition of 0.36 μmol/mL DHA optimized the delivery of milk protein to ASTA. All 3 DHA-mediated milk proteins induced an improvement in encapsulation efficiency and antioxidant properties of ASTA. Furthermore, the DHA-mediated MPC and MCC played a stronger role in improving the bioaccessibility and thermal and storage stability of ASTA than those without DHA. Tests conducted to examine the application in cheese production indicated that MCC carrier had a positive effect on the texture of cheeses. However, the delivery effect was dependent on the milk protein variety, and MCC exhibited the best protection ability of ASTA, followed by MPC and WPI. The simulated digestion and storage stability results of cheese further confirmed that the protein encapsulation mediated by DHA was more conducive to ASTA absorption. These findings suggested that the DHA-mediated milk protein complexes studied here may be suitable hydrophilic delivery carriers for the hydrophobic nutrient ASTA, potentially playing different roles in improving its storage stability and bioaccessibility.