Search

Abstract Manufacturing of metallic components using additive manufacturing technique is of great interest for the industrial applications. Here, the mechanical and microstructural responses of a 316 L stainless steel (316LSS) built by selective laser melting (SLM) with XOY and XOZ directions were revealed by performing in situ neutron diffraction tensile tests. The tensile strength of the XOY-printed samples reaches 700 MPa, while the tensile strength of the XOZ-printed samples is less than 600 MPa. The as-printed 316LSS exhibits anisotropy in tensile property due to the formation of different fractions of nano-sized dimples, twin boundaries, diffraction peak and lattice constants during tensile tests at room temperature. Therefore, choosing right printing direction plays a vital role in forming of metal parts using SLM for further application.

Abstract The DNA damage checkpoint is a highly conserved signaling pathway induced by genotoxin exposure or endogenous genome stress. It alters many cellular processes such as arresting the cell cycle progression and increasing DNA repair capacities. However, cells can downregulate the checkpoint after prolonged stress exposure to allow continued growth and alternative repair. Strategies that can dampen the DNA damage checkpoint are not well understood. Here, we report that budding yeast employs a pathway composed of the scaffold protein Rtt107, its binding partner Mms22, and an Mms22-associated ubiquitin ligase complex to downregulate the DNA damage checkpoint. Mechanistically, this pathway promotes the proteasomal degradation of a key checkpoint factor, Rad9. Furthermore, Rtt107 binding to Mms22 helps to enrich the ubiquitin ligase complex on chromatin for targeting the chromatin-bound form of Rad9. Finally, we provide evidence that the Rtt107-Mms22 axis operates in parallel with the Rtt107-Slx4 axis, which displaces Rad9 from chromatin. We thus propose that Rtt107 enables a bifurcated “anti-Rad9” strategy to optimally downregulate the DNA damage checkpoint.

The dimensional compensation technology can achieve high dense metal parts with precise dimensions for binder jet 3D printing (BJ3DP). In this study, two models (cuboid and gear) of BJ3DP 316L stainless steel (BJ3DP316LSS) parts were established. Numerical simulation and experimental volume shrinkage of the BJ3DP316LSS sintered parts via dimensional compensations technology were investigated. When the dimensional compensation coefficient was set as 1.25, the BJ3DP316LSS cuboids and gears exhibited high densification as 99.6% and 99.4%, respectively. The experimental dimension deviation rates of cuboid and gear parts after dimensional compensations ranged from −3.56% to −0.15% and from 0.89% to 3.42%, respectively. Due to twinning-induced plasticity mechanism, the BJ3DP316LSS sintered gear part via dimensional compensation technology exhibited high hardness (∼139 HV), high yield strength (∼249 MPa), high ultimate tensile strength (∼546 MPa) and excellent elongation (∼62%), which are higher than those of the reported 316LSS samples.

Wire arc additive manufacturing (WAAM) has high potential in fabricating large-scale structural components, offering advantages such as high forming efficiency, mold-free production, and superior energy utilization. Al–Cu alloys undergo rapid solidification and thermal cycling during WAAM, leading to anisotropy in their mechanical properties, which can compromise the performance of the alloys. To address this issue, this study proposes a homogenization treatment strategy. Employing electron microscopy, mechanical testing machines and other testing methods, a systematic analysis of the microstructure and mechanical properties of as-deposited Al–Cu alloys before and after homogenization is conducted. The investigation reveals that the as-deposited WAAM Al–Cu alloys exhibits a heterogeneous structure of fine equiaxed grains and coarse columnar grains, which significantly differentiates the mechanical properties along the scanning direction and the deposition direction. Notably, the elongation along the deposition direction falls below 8%, unsatisfactory for practical applications. An optimized homogenization treatment of 510 °C for 24 h is established. After homogenization, the coarse columnar grains transform into equiaxed grains, while the fine equiaxed grains grow, enhancing microstructural uniformity. Additionally, the homogenization treatment mitigates geometrically necessary dislocations and reduces solute segregation at grain boundaries. Consequently, the anisotropy in mechanical properties of WAAM Al–Cu alloys is eliminated after homogenization, and the elongation is elevated to over 10.2%. Moreover, we also found that homogenization facilitates the dissolution of coarse θ′ phases and promotes the precipitation of θ″ phases during artificial aging, resulting in higher strength and ductility in T6 treated Al–Cu alloy.

BackgroundPancreatic cancer remains one of the deadliest malignancies, largely due to its late diagnosis and lack of effective therapeutic targets.Materials and methodsUsing traditional machine learning methods, including random-effects meta-analysis and forward-search optimization, we developed a robust signature validated across 14 publicly available datasets, achieving a summary AUC of 0.99 in training datasets and 0.89 in external validation datasets. To further validate its clinical relevance, we analyzed 55 peripheral blood samples from pancreatic cancer patients and healthy controls using qPCR.ResultsThis study identifies and validates a novel five-gene transcriptomic signature (LAMC2, TSPAN1, MYO1E, MYOF, and SULF1) as both diagnostic biomarkers and potential drug targets for pancreatic cancer. The differential expression of these genes was confirmed, demonstrating their utility in distinguishing cancer from normal conditions with an AUC of 0.83. These findings establish the five-gene signature as a promising tool for both early, non-invasive diagnostics and the identification of actionable drug targets.ConclusionA five-gene signature is established robustly and has utility in diagnostics and therapeutic targeting. These findings lay a foundation for developing diagnostic tests and targeted therapies, potentially offering a pathway toward improved outcomes in pancreatic cancer management.

In this study, the pure Al and binary Al–Ni alloys with Ni addition of 1, 3, 6, and 10 wt % were coated via micro arc oxidation (MAO) in a tetraborate and phosphate based electrolyte for 60 min. With increased Ni content, the color of MAO coating became darker due to increased Ni-containing compounds on the surface. The Ni played a negative effect on the coating growth, decreasing both the coating thickness and surface roughness. The coatings on the Al–Ni alloys were mainly composed of γ-Al2O3 and α-Al2O3, and the Ni facilitated the formation of α-Al2O3 in the coating. Nanoparticles of NiO were generated around the edge of discharge channels for Al–6Ni and Al–10Ni alloys after a certain oxidation time. All coatings exhibited a uniform and dense surface structure, with the outer layer being more compact than the inner layer. Many tiny pores were found in the inner layer. Despite the corrosion resistance was decreased, the anti-wear performance of MAO treated samples was improved with the increased Ni content in the matrix. While, the corrosion resistance of the coated samples decreased with the adding of Ni content in the matrix.

Abstract Identifying new targets for overcoming radioresistance is crucial for improving the efficacy of lung cancer radiotherapy, given that tumor cell resistance is a leading cause of treatment failure. Recent research has spotlighted the significance of Musashi2 (MSI2) in cancer biology. In this study, we first demonstrated that MSI2 plays a key function in regulating the radiosensitivity of lung cancer. The expression of MSI2 is negatively correlated with overall survival in cancer patients, and the knockdown of MSI2 inhibits tumorigenesis and increases radiosensitivity of lung cancer cells. Cellular radiosensitivity, which is closely linked to DNA damage, is influenced by MSI2 interaction with ataxia telangiectasia mutated and Rad3‐related kinase (ATR) and checkpoint kinase 1 (CHK1) post‐irradiation; moreover, knockdown of MSI2 inhibits the ATR‐mediated DNA damage response pathway. RNA‐binding motif protein 17 (RBM17), which is implicated in DNA damage repair, exhibits increased interaction with MSI2 post‐irradiation. We found that knockdown of RBM17 disrupted the interaction between MSI2 and ATR post‐irradiation and increased the radiosensitivity of lung cancer cells. Furthermore, we revealed the potential mechanism of MSI2 recruitment into the nucleus with the assistance of RBM17 to activate ATR to promote radioresistance. This study provides novel insights into the potential application of MSI2 as a new target in lung cancer radiotherapy.

In this paper, 2024 Al matrix composites reinforced by nanocrystalline high-entropy alloy particles (NC-HEAp), SiC particles, and coarse-grained high-entropy alloy particles (CG-HEAp) were fabricated via powder metallurgy, and a comparative study of different reinforcements was deeply conducted. The results showed that reinforcement types significantly influenced the morphology of composite powders, and the grain size and interfacial condition of composites. After ball milling, irregular granular NC-HEA-Al and SiC–Al composite powders were produced while the CG-HEA-Al composite powders exhibited flake shapes, and particle size of NC-HEAp sharply decreased and was significantly smaller than the other two reinforcements. The Cu-rich diffusion layer, a high dislocation density, and a thin oxide layer were formed in the interfaces of NC-HEA-Al, SiC–Al, and CG-HEA-Al composites, respectively. The NC-HEA-Al composite possessed the highest strength due to the best effect of grain refinement, while the SiC–Al composite displayed better ductility attributed to higher work hardening rate after the yield stage than that of the NC-HEA-Al composite. The CG-HEA-Al composites showed the least attractive mechanical properties, related to a poor interface bonding and pre-existing cracks in CG-HEAp. Furthermore, the differences in strengthening mechanisms of the three composites were also discussed. This work provides guidelines for designing metal matrix composites fabricated by powder metallurgy.

The interaction problem of waves with a body floating near the marginal ice zone is studied, where the marginal ice zone is modeled as an array of multiple uniformly sized floating ice sheets. The linear velocity potential theory is applied for fluid flow, and the thin elastic plate mode is utilized to describe the ice sheet deflection. A hybrid method is used to solve the disturbed velocity potential; i.e., around the floating body, a boundary integral equation is established, while in the domain covered by ice sheets, the velocity potential is expanded into an eigenfunction series, and in the far-field with a free surface, a similar eigenfunction expansion is used to satisfy the radiation condition. The boundary integral equation and the coefficients of the eigenfunction expansions are solved together based on the continuous conditions of pressure and velocity on the interface between the sub-domains. Extensive results for the equivalent Young’s modulus of the ice sheet array and hydrodynamic force on the body are provided, and the effect of individual ice sheet length as well as wave parameters are investigated in detail.

Grain refinement with a facile process without additional alloying is quite desired for strengthening the Al alloys. Using the melt spinning process, we obtained the ultra-fine grained foils of Al–Mg–Si–Cu alloy (AA6061), then the foils followed by hot extrusion to produce the rods for industrial applications. The yield strength of the extruded melt-spun rod is 102% higher than that of the extruded rods of the alloy by a conventional direct chill casting. The electron backscatter diffraction results reveal that the average grain diameter in the extruded melt-spun sample is only 1.35 μm, indicating that the sample is an ultra-fine grained alloy. Through the Hall–Petch relationship, the finer grains contribute to a 66.9% increase in yield strength of the extruded rod. Moreover, the fiber texture occupied 68% of the volume fraction after hot extrusion, contributing to 30.5% improvement of the yield strength in the extruded melt-spun sample. This study shows that the ultra-fine grained Al–Mg–Si–Cu alloy rods have excellent mechanical properties, which provides a strong potential for industrial application.

In this paper, the optimum fluoride component in the multifunctional refining flux used for recycling aluminum scrap was determined. Theoretical analysis of solid fluxing shows that strong stripping ability of oxide layer on aluminum surface for the flux and appropriate interfacial tensions between Al melt / inclusion (σM-I), flux / inclusion (σF-I), and flux / Al melt (σF-M) are indispensable for making the flux achieve the properties of covering, drossing, and cleaning simultaneously. In term of four preliminarily selected fluoride salts, i.e., KF, AlF3, K3AlF6 and KAlF4, the results of interfacial tension measurements indicates that, combined addition of A-type fluoride (KF) and B-type fluoride (AlF3, K3AlF6 and KAlF4) to equimolar NaCl-KCl can just offset the shortage of single addition of KF which means worsening the separating effect of flux from melt surface and weakening the wettability of flux on the inclusions due to the lower σF-M and the higher σF-I respectively. Additionally, coalescence behaviors of aluminum droplets in molten fluxes reveals that, KF, K3AlF6 or KAlF4 possesses stronger stripping ability of oxide layer, while the stripping ability of oxide layer for AlF3 is weaker. Ultimately, the combination of KF with K3AlF6 or/and KAlF4 is ascertained to be an optimum selection for fluoride component in the multifunctional refining flux.

Timely removal of DNA recombination intermediates is critical for genome stability. The DNA helicase-topoisomerase complex, Sgs1-Top3-Rmi1 (STR), is the major pathway for processing these intermediates to generate conservative products. However, the mechanisms that promote STR-mediated functions remain to be defined. Here we show that Sgs1 binds to poly-SUMO chains and associates with the Smc5/6 SUMO E3 complex in yeast. Moreover, these interactions contribute to the sumoylation of Sgs1, Top3, and Rmi1 upon the generation of recombination structures. We show that reduced STR sumoylation leads to accumulation of recombination structures, and impaired growth in conditions when these structures arise frequently, highlighting the importance of STR sumoylation. Mechanistically, sumoylation promotes STR inter-subunit interactions and accumulation at DNA repair centers. These findings expand the roles of sumoylation and Smc5/6 in genome maintenance by demonstrating that they foster STR functions in the removal of recombination intermediates.

SLX4 interacts with several endonucleases to resolve structural barriers in DNA metabolism. SLX4 also interacts with telomeric protein TRF2 in human cells. The molecular mechanism of these interactions at telomeres remains unknown. Here, we report the crystal structure of the TRF2-binding motif of SLX4 (SLX4TBM) in complex with the TRFH domain of TRF2 (TRF2TRFH) and map the interactions of SLX4 with endonucleases SLX1, XPF, and MUS81. TRF2 recognizes a unique HxLxP motif on SLX4 via the peptide-binding site in its TRFH domain. Telomeric localization of SLX4 and associated nucleases depend on the SLX4-endonuclease and SLX4-TRF2 interactions and the protein levels of SLX4 and TRF2. SLX4 assembles an endonuclease toolkit that negatively regulates telomere length via SLX1-catalyzed nucleolytic resolution of telomere DNA structures. We propose that the SLX4-TRF2 complex serves as a double-layer scaffold bridging multiple endonucleases with telomeres for recombination-based telomere maintenance.

The WDR5 subunit of the MLL complex enforces active chromatin and can bind RNA; the relationship between these two activities is unclear. Here we identify a RNA binding pocket on WDR5, and discover a WDR5 mutant (F266A) that selectively abrogates RNA binding without affecting MLL complex assembly or catalytic activity. Complementation in ESCs shows that WDR5 F266A mutant is unable to accumulate on chromatin, and is defective in gene activation, maintenance of histone H3 lysine 4 trimethylation, and ESC self renewal. We identify a family of ESC messenger and lncRNAs that interact with wild type WDR5 but not F266A mutant, including several lncRNAs known to be important for ESC gene expression. These results suggest that specific RNAs are integral inputs into the WDR5-MLL complex for maintenance of the active chromatin state and embryonic stem cell fates.

In this paper, a finite element model is developed to investigate residual stress and microstructural changes in 18CrNiMo7-6 alloy steel during pre-mixed jet strengthening. The model employs a dislocation density-based constitutive relationship, with parameters optimized via a genetic algorithm. A fully coupled stress integration algorithm ensures the numerical stability. The model is validated by experiments, with a maximum error of 2.6% in predicting residual stress. It is shown that the dislocation cell sizes measured from experiments are consistent with that obtained by simulations. As the peening intensity increases, the maximum residual stress, the depth of a residual stress layer, and the thickness of a compressive residual stress layer gradually increase. The rise in residual stress is accompanied by formation of dislocation proliferation and refined microstructural layers. Additionally, the depth of a refined layer increases with a higher pre-mixed jet intensity. While the coverage increase has a minimal impact on the smallest average dislocation cell size, larger shot diameters lead to smaller dislocation cell sizes.

Abstract Background The therapeutic efficacy and prognosis of various tumors can be assessed using the systemic immune-inflammatory index (SII) and prognostic nutritional index (PNI). Despite their potential, no studies have investigated the prognostic value of the combined SII-PNI score for outcomes in patients with extensive small cell lung cancer (ES-SCLC) treated with chemotherapy and immune checkpoint inhibitors (ICIs). Materials and methods Our study retrospectively examined 213 ES-SCLC patients treated with chemotherapy and ICIs across two institutions. The patients were divided into three groups based on their SII-PNI scores. Cox regression analysis was employed to identify independent prognostic factors. A nomogram was constructed based on these independent factors. With 1000 repeated samples, the bootstrap method was used to validate the nomogram model internally. The model’s performance was assessed using calibration curves, receiver operating characteristic (ROC) curves, and decision curve analysis (DCA). Result Before and after chemotherapy with immune checkpoint inhibitors (ICIs), SII was significantly higher in the PD group compared with the PR group (both p

Summary: We experimentally investigated the carrier-envelope phase (CEP) effect on above-threshold ionization (ATI) process of argon in frustrated tunneling ionization regime. For the first time, we found the asymmetrical fast oscillation of the ionization probability with a period around π/6 in ATI spectrum, to the best of our knowledge. Simulation results agreed well with the experimental data. Two kinds of electron trajectories were resolved to interpret the experimental observations. One was the tunneling ionization directly from the ground state, which was responsible for the asymmetry in spectrum, while the other one was tunneling ionization from the excited states, which contributed to the π/6 oscillation. Our results served as evidence that the bound states population was controlled by the CEP.

Statistical data indicate that Xinjiang is having the second-highest particulate matter emissions in China over the past two years, yet relevant research data are scarce. PM10 includes a variety of toxic organic substances, including nitro-PAHs (NPAHs) and oxy-PAHs (OPAHs). The objective of this study was to characterize and ascertain the sources of PM10-bound NPAHs and OPAHs in the core area of the Ili River Valley. To analyze 18 NPAHs and 5 OPAHs, gas chromatography-mass spectrometry (GC-MS) was employed, revealing median concentrations of 449.09 pg/m3 for Σ18NPAHs and 9.38 ng/m3 for Σ5OPAHs. The levels of NPAHs and OPAHs were higher in the heating season (Σ18NPAHs: 641.97 pg/m3; Σ5OPAHs: 16.41 ng/m3) than in the non-heating season (Σ18NPAHs: 268.68 pg/m3; Σ5OPAHs: 2.61 ng/m3) in the core area of the Ili River Valley. During the heating season, concentrations were higher in urban areas than in rural areas, with the reverse trend noted in the non-heating season. Source apportionment, conducted through the characteristic ratio method and positive matrix factorization (PMF), identified coal/biomass combustion as the primary source of NPAHs and OPAHs. Moreover, the increase in inhalation and dermal contact lifetime cancer risk (ILCR) values for all sampling sites, seasons, and age categories within the core area of the Ili River Valley ranged from 2.05E-11–5.02E-08, 7.59E-13–1.26E-09, respectively. These values were all below 10–6, suggesting the absence of carcinogenic risk from exposure to these contaminants.

BackgroundPropranolol for infantile hemangiomas (IHs) is effective and relatively safe. However, propranolol has different formulations and there is no consensus on the optimal formulation for IHs. The propranolol oral solution was not used in China until 2022.ObjectiveTo evaluate the efficacy and safety of propranolol tablets and an oral solution in infants with high-risk IH.MethodsA retrospective cohort study was conducted involving 234 consecutive patients with a clinical diagnosis of high-risk IH who were treated with propranolol between August 2018 and February 2023 (propranolol tablets, 168 patients; propranolol oral solution, 66 patients). All patients were assessed in the hospital at the initiation of treatment and in the outpatient setting during treatment. The Hemangioma Activity and Severity Index was used to monitor the clinical activity of the hemangioma after propranolol treatment.ResultsBased on the Hemangioma Activity and Severity Index, 66.52% and 69.15% improvement occurred in the propranolol tablet and oral solution groups, respectively. 23.21% of patients in the propranolol tablet group and 42.42% in the oral solution group achieved >75% score improvement (X2 = 8.557; P = 0.003). Adverse reactions occurred in 34 (20.24%) and 11 patients (16.67%) in the propranolol tablet and oral solution groups, respectively. The most common adverse reaction in the propranolol tablet group was liver function abnormalities due to mild elevation of liver enzymes (X2 = 4.09; P = 0.045).ConclusionBoth propranolol tablets and oral solution had positive efficacy in patients with high-risk IHs, but more patients in the propranolol oral solution group achieve >75% score improvement compared to the propranolol tablet group. No life-threatening adverse reactions occurred in either group but liver function abnormalities were more likely to occur in patients treated with propranolol tablets.

IntroductionUlcerative colitis (UC), a form of inflammatory irritable bowel disease, is characterized by a recurrent and persistent nonspecific inflammatory response. Polydatin (PD), a natural stilbenoid polyphenol with potent properties, exhibits unexpected beneficial effects beyond its well-documented anti-inflammatory and antioxidant activities. In this study, we presented evidence that PD confers protection against dextran sodium sulfate (DSS)-induced ulcerative colitis.MethodsThe protective effect of PD on colitis was examined in cultured caco-2 cells and DSS-induced colitis mouse model. Bulk RNA sequencing and differential gene expression analysis were used to investigate the protective mechanism of PD on DSS-induced colitis. Ferroptosis was determined by MDA levels, SOD levels, mitochondrial iron accumulation and ROS production. Ferroptosis-related proteins Slc7a11, Nrf2 and Gpx4 levels were measured by western blot, immunohistochemical and immunofluorescence staining.ResultsPD mitigated the DSS-induced increases in pro-inflammatory cytokines (IL-6, TNF-α, and IL-1β), alleviated colon length shortening, reduced morphological damage to the intestinal mucosa, and preserved tight junction proteins (TJ) occludin and Zonula occludens-1 (ZO-1) in both caco-2 cells and murine models of colitis. Mechanistically, PD reversed the reduction of Nrf2, Slc7a11 and Gpx4, the degree of nuclear translocation of Nrf2 induced by DSS in vitro and in vivo significantly. Moreover, the protective effect of PD is attenuated by erastin and resembled that of Fer-1 in caco-2 cells model.DiscussionOur study suggested that PD protects against DSS-induced ulcerative colitis via Nrf2/Slc7a11/Gpx4-dependent inhibition of ferroptosis signalling activation. Further investigation into the precise mechanisms underlying this phenomenon is warranted. The findings presented herein indicated that PD may serve as a potential therapeutic agent for patients with UC.

Abstract Background Community-acquired pneumonia (CAP) patients with chronic obstructive pulmonary disease (COPD) have higher disease severity and mortality compared to those without COPD. However, deep investigation into microbiome distribution of lower respiratory tract of CAP with or without COPD was unknown. Methods So we used metagenomic next generation sequencing (mNGS) to explore the microbiome differences between the two groups. Results Thirty-six CAP without COPD and 11 CAP with COPD cases were retrieved. Bronchoalveolar lavage fluid (BALF) was collected and analyzed using untargeted mNGS and bioinformatic analysis. mNGS revealed that CAP with COPD group was abundant with Streptococcus, Prevotella, Bordetella at genus level and Cutibacterium acnes, Rothia mucilaginosa, Bordetella genomosp. 6 at species level. While CAP without COPD group was abundant with Ralstonia, Prevotella, Streptococcus at genus level and Ralstonia pickettii, Rothia mucilaginosa, Prevotella melaninogenica at species level. Meanwhile, both alpha and beta microbiome diversity was similar between groups. Linear discriminant analysis found that pa-raburkholderia, corynebacterium tuberculostearicum and staphylococcus hominis were more enriched in CAP without COPD group while the abundance of streptococcus intermedius, streptococcus constellatus, streptococcus milleri, fusarium was higher in CAP with COPD group. Conclusions These findings revealed that concomitant COPD have an mild impact on lower airway microbiome of CAP patients.