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Cuproptosis, dependent on Cu overload, presents novel opportunities for cancer therapy. Cu-based nanomaterials have shown excellent advantages for the intracellular delivery of Cu. However, the biological process of Cu nanomaterials transporting Cu ions into cancer cells remains unclear. In this study, we tracked the Cu ion release process of copper nanowires (CuNWs) and copper nanoparticles (CuNPs) at the single-cell level. CuNWs with 5-µm length and CuNPs were found to be completely internalized by cancer cells. Interestingly, CuNWs escaped from the endolysosomal system, whereas CuNPs were mainly trapped in the lysosomes. This specific intracellular distribution of CuNWs led to cytoplasmic Cu ion overload, directly damaging mitochondria and inducing dihydrolipoamide S-acetyltransferase (DLAT) protein aggregation. Through these excessive Cu ions, CuNWs triggered more efficient cuproptosis than CuNPs to further increase cell death. Thus, CuNWs are more effective in delivering Cu ions than CuNPs, providing a novel perspective for designing cuproptosis-based functional nanomaterials for cancer therapy.

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BACKGROUND: Many studies have demonstrated the effectiveness of chimeric antigen receptor-T (CAR-T) cell therapy for relapsed or refractory multiple myeloma (RRMM), but the hematologic toxicity has not been well characterized. METHODS: A total of 111 adults with RRMM who received BCMA CAR-T cells, BCMA + CD19 CAR-T cells or tandem BCMA/CD19 dual-target (BC19) CAR-T cells infusion were enrolled. We characterized cytopenia and hematologic recovery at different time points after CAR-T-cell therapy, analyzed the effect of cytopenia on prognosis and identified the risk factors. RESULTS: Patients had a high probability of cytopenia, with anemia, neutropenia and thrombocytopenia occurring in 92%, 95% and 73%, respectively. There were 60 (54%) patients had prolonged hematologic toxicity (PHT) after D28. The median hemoglobin and platelet count were significantly lower at D28 post-CAR-T cell therapy than at baseline. Hemoglobin increased to above baseline at D90. The median absolute neutrophil count was lower than baseline at D0 and D28, and it recovered to baseline at D180. The baseline level of lactate dehydrogenase was associated with thrombocytopenia. Extramedullary involvement was associated with hemoglobin recovery, while the baseline level of albumin and types of CAR-T were related to platelet recovery. Patients with anemia at baseline and at D0, D180 and D360 had shorter progression-free survival (PFS), while anemia at D0, D60, D180 and D360 was associated with shorter overall survival (OS). Neutropenia at D0 was associated with shorter PFS and patients with neutropenia at D90 or D180 had shorter OS. Patients with thrombocytopenia at any time had shorter PFS and OS. Compared to patients without PHT, patients with PHT had shorter PFS and OS. CONCLUSIONS: The majority of RRMM patients treated with CAR-T cells experienced cytopenia. Cytopenia occurred at specific time points was associated with a poorer prognosis.

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Using GIS technology, this study investigated the spatiotemporal distribution pattern of influenza incidence in Xinjiang from 2014 to 2023 based on influenza surveillance data. The study revealed a noticeable fluctuation trend in influenza incidence rates in Xinjiang, particularly notable spikes observed in 2019 and 2023. The results of the 3-year moving average showed a significant long-term upward trend in influenza incidence rates, confirmed by Theil-Sen method (MAD = 2.202, p < 0.01). Global spatial autocorrelation analysis indicated significant positive spatial autocorrelation in influenza incidence rates from 2016 and from 2018 to 2023 (Moran's I > 0, P < 0.05). Local spatial autocorrelation analysis further revealed clustering patterns in different regions, with high-high clustering and low-high clustering predominating in northern Xinjiang, and low-low clustering predominating in southern Xinjiang. Hotspot analysis indicated a progressive rise in the number of influenza incidence hotspots, primarily concentrated in northern Xinjiang, particularly in Urumqi, Ili Kazakh Autonomous Prefecture, and Hotan Prefecture. Standard deviation ellipse analysis and the trajectory of influenza incidence gravity center migration showed that the transmission range of influenza in Xinjiang has been expanding, with the epidemic center gradually moving northward. The spatiotemporal heterogeneity of influenza incidence in Xinjiang highlights the need for differentiated and precise influenza prevention and control strategies in different regions to address the changing trends in influenza prevalence.

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Taking into account the fluctuation of the growth rate on the left and right sides of the classic QGLF, a quadratic exponential quality gain-loss function (QGLF) is created based on the asymmetric QGLF. The two scenarios of non-normal distribution (triangular distribution) and truncated normal distribution of quality characteristic values are optimized using the quadratic exponential quality gain-loss process mean. Through the case study approaches, the empirical validity and applicability of the quadratic exponential QGLF model are thoroughly assessed, confirming its effectiveness in improving quality management practices.

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The complex anatomy and biology of craniofacial bones pose difficulties in their effective and precise reconstruction. Injectable hydrogels (IHs) with water-swollen networks are emerging as a shape-adaptive alternative for noninvasively rebuilding craniofacial bones. The advent of versatile nanomaterials (NMs) customizes IHs with strengthened mechanical properties and therapeutically favorable performance, presenting excellent contenders over traditional substitutes. Structurally, NM-reinforced IHs are energy dissipative and covalently crosslinked, providing the mechanics necessary to support craniofacial structures and physiological functions. Biofunctionally, incorporating unique NMs into IH expands a plethora of biological activities, including immunomodulatory, osteogenic, angiogenic, and antibacterial effects, further favoring controllable dynamic tissue regeneration. Mechanistically, NM-engineered IHs optimize the physical traits to direct cell responses, regulate intracellular signaling pathways, and control the release of biomolecules, collectively bestowing structure-induced features and multifunctionality. By encompassing state-of-the-art advances in NM-integrated IHs, this review offers a foundation for future clinical translation of craniofacial bone reconstruction.

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Viruses are the most abundant yet understudied members that may influence microbial metabolism in activated sludge treating antibiotic production wastewater. This study comprehensively investigated virome community characteristics under the selection pressure of nine types and different concentrations of antibiotics using a metagenomics approach. Of the 15,514 total viral operational taxonomic units (tOTUs) recovered, only 37.5 % were annotated. Antibiotics altered the original viral community structure in activated sludge. The proportion of some pathogenic viral families, including Herpesviridae_like, increased significantly in reactors treating erythromycin production wastewater. In total, 16.5 % of the tOTUs were associated with two or more hosts. tOTUs rarely carried antibiotic resistance genes (ARGs), and the ARG types in the tOTUs did not match the ARGs carried by the bacterial hosts. This suggests that transduction contributes little to the horizontal ARG transfer. Auxiliary metabolic genes (AMGs) were prevalent in tOTUs, and those involved in folate biosynthesis were particularly abundant, indicating their potential to mitigate antibiotic-induced host damage. This study provides comprehensive insights into the virome community in activated sludge treating antibiotic production wastewater and sheds light on the potential role of viral AMGs in mitigating antibiotic-induced stress.

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Inflammatory bowel disease (IBD) encompasses a group of non-specific chronic intestinal inflammatory conditions of unclear etiology. The current treatment and long-term management primarily involve biologics. Nevertheless, some patients experience treatment failure or intolerance to biologics [1], making these patients a primary focus of IBD research. The Janus kinase (JAK)-Signal Transducers and Activator of Transcription (STAT) signal transduction pathway is crucial to the regulation of immune and inflammatory responses [2], and plays an important role in the pathogenesis of IBD. JAK inhibitors alleviate IBD by suppressing the transmission of JAK-STAT signaling pathway. As the first small-molecule oral inhibitor for IBD, JAK inhibitors greatly improved the treatment of IBD and have demonstrated significant efficacy, with tofacitinib and upadacitinib being approved for the treatment of ulcerative colitis (UC) [3]. JAK inhibitors can effectively alleviate intestinal inflammation in IBD patients who have failed to receive biologics, which may bring new treatment opportunities for refractory IBD patients. This review aims to elucidate the crucial roles of JAK-STAT signal transduction pathway in IBD pathogenesis, examine its role in various cell types within IBD, and explore the research progress of JAK inhibitors as therapeutic agents, paving the road for new IBD treatment strategies.

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We designed two series of NIR-II PTAs with D-A or D-A-D structures, in which the introduction of thiophene promotes a bathochromic shift of emission into the NIR-II region, helps to improve the cellular uptake of the PTAs and facilitates NIR-II imaging-guided PDT/PTT cancer phototherapy.

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BACKGROUND: Left ventricular diastolic dysfunction (LVDD) is a manifestation of heart failure, with both its incidence and prevalence increasing annually. Currently, no pharmacological treatments are available for LVDD, highlighting the urgent need for new therapeutic discoveries. Ginsenosides are commonly used in cardiovascular therapy. Previous research has synthesized the ginsenoside precursor molecule, 20S-O-Glc-DM (C20DM), through biosynthesis. C20DM shows greater bioavailability, eco-friendliness, and cost-effectiveness compared to traditional ginsenosides, positioning it as a promising option for treating LVDD. PURPOSE: This study firstly documents the therapeutic activity of C20DM against LVDD and unveils its potential mechanisms of action. It provides a pharmacological basis for C20DM as a new cardiovascular therapeutic agent. METHODS: In this study, models of LVDD in mice and ISO-induced H9C2 cell damage were developed. Cell viability, ROS and Ca2+ levels, mitochondrial membrane potential, and proteins associated with mitochondrial biogenesis and autophagy were evaluated in the in vitro experiments. Animal experiments involved administering medication for 3 weeks to validate the therapeutic effects of C20DM and its impact on mitochondria and autophagy. RESULTS: Research has shown that C20DM is more effective than Metoprolol in treating LVDD, significantly lowering the E/A ratio, e'/a' ratio, and IVRT, and ameliorating myocardial inflammation and fibrosis. C20DM influences the activity of PGC-1α, downregulates PINK1 and Parkin, thereby enhancing mitochondrial quality control, and restoring mitochondrial oxidative respiration and membrane potential. Furthermore, C20DM reduces excessive autophagy in cardiomyocytes via the AMPK-mTOR-ULK1 pathway, diminishing cardiomyocyte hypertrophy and damage. CONCLUSIONS: Overall, our research indicates that C20DM has the potential to enhance LVDD through the regulation of mitochondrial quality control and cellular autophagy, making it a promising option for heart failure therapy.

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A Pd-catalyzed decarbonylative Michaelis-Arbuzov reaction of carboxylic acids and triaryl phosphites for preparing aryl phosphonates under anhydride-free conditions has been reported. In this context, triaryl phosphites serve as both reagents for activating the carboxylic acids and substrates for the reaction. There have been no reports to date of efficient and direct methods for the in situ activation of carboxylic acids using triaryl phosphites. In comparison to known methods, this reaction avoids the use of organohalides and has an excellent functional group tolerance for the synthesis of various aryl phosphonates from triaryl phosphites and carboxylic acids. This reaction is scalable and applicable to the synthesis of aryl phosphonates featuring bioactive fragments.

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OBJECTIVE: The purpose of this meta-analysis was to examine the clinicopathological and prognostic significance of tertiary lymphocytic infiltrates in lung cancer. METHOD: A systematic search was performed in many databases, including PubMed, Web of Science, Cochrane Library, Embase, CNKI, Wangfangdate, and CBM, up until January 2024. We calculated the hazard ratio (HR), odds ratios (OR), and confidence interval (CI), and accomplished this meta-analysis with Stata 15 software. RESULT: 14 studies, including 3101 patients, were subjected to analysis. High TLS detection was associated with a longer OS (HR = 0.545, 95% CI: 0.359-0.827, p = 0.004), DFS (HR = 0.431, 95% CI: 0.350-0.531, p < 0.001), and RFS (HR = 0.430, 95% CI: 0.325-0.569, p < 0.001). Meanwhile, it was observed that a higher detection of TLS was significantly correlated with the administration of adjuvant chemotherapy (OR = 1.505, 95% CI: 1.017-2.225, p = 0.041). Not only that, but there was a higher occurrence of significantly elevated TLS detection in the early N stages (N = 0) compared to the advanced N stages (N = 1, 2, and 3) (OR = 1.604, 95% CI: 1.021-2.521, p = 0.04). CONCLUSION: Elevated detection of TLS has been observed to be correlated with extended OS, DFS, and RFS in cases of lung cancer. This finding suggests that TLS could potentially serve as a valuable prognostic biomarker for lung cancer.

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Hepatic ischemia/reperfusion (I/R) injury is an important cause of liver function impairment following liver surgery. The ubiquitin-proteasome system (UPS) plays a crucial role in protein quality control and has substantial impact on the hepatic I/R process. Although OTU deubiquitinase 1 (OTUD1) is involved in diverse biological processes, its specific functional implications in hepatic I/R are not yet fully understood. This study demonstrates that OTUD1 alleviates oxidative stress, apoptosis, and inflammation induced by hepatic I/R injury. Mechanistically, OTUD1 deubiquitinates and activates nuclear factor erythroid 2-related factor 2 (NRF2) through its catalytic site cysteine 320 residue and ETGE motif, thereby attenuating hepatic I/R injury. Additionally, administration of a short peptide containing the ETGE motif significantly mitigates hepatic I/R injury in mice. Overall, our study elucidates the mechanism and role of OTUD1 in ameliorating hepatic I/R injury, providing a theoretical basis for potential treatment using ETGE-peptide.

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Molecular phosphorescence in the second near-infrared window (NIR-II, 1000-1700 nm) holds promise for deep-tissue optical imaging with high contrast by overcoming background fluorescence interference. However, achieving bright and stable NIR-II molecular phosphorescence suitable for biological applications remains a formidable challenge. Herein, we report a new series of symmetric isocyanorhodium(I) complexes that could form oligomers and exhibit bright, long-lived (7-8 µs) phosphorescence in aqueous solution via metallophilic interaction. Ligand substituents with enhanced dispersion attraction and electron-donating properties were explored to extend excitation/emission wavelengths and enhanced stability. Further binding the oligomers with fetal bovine serum (FBS) resulted in NIR-II molecular phosphorescence with high quantum yields (up to 3.93 %) and long-term stability in biological environments, enabling in vivo tracking of single-macrophage dynamics and high-contrast time-resolved imaging. These results pave the way for the development of highly-efficient NIR-II molecular phosphorescence for biomedical applications.

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Catalytic oxidation at mild conditions is crucial for mitigating the high pressure and high temperature challenges associated with current catalytic wet air oxidation (CWAO) technologies in wastewater treatment. Among potential materials for catalytic oxidation reactions, polycrystalline MnO2 existed in natural minerals holds considerable promise. However, the relationships between different crystal phases of MnO2 and their catalytic activity sources in aqueous phase remain uncertain and subject to debate. In this research, we synthesized various MnO2 crystal phases, comprising α-, ß-, δ-, γ-, ε-, and λ-MnO2, and assessed their catalytic oxidation efficiency during low-temperature heating for treatment of organic pollutants. Our findings demonstrate that λ-MnO2 exhibits the highest catalytic activity, followed by δ-MnO2, γ-MnO2, α-MnO2, ε-MnO2, and ß-MnO2. The variations in catalytic activity among different MnO2 are attributed to variances in their oxygen vacancy abundance and redox activity. Furthermore, we identified the primary active species, which include Mn3+ and superoxide radicals (•O2-) generated by surface lattice oxygen of MnO2. This research highlights the critical role of crystal phases in influencing oxygen vacancy content, redox activity, and overall catalytic performance, providing valuable insights for the rational design of MnO2 catalysts tailored for effective organic pollutant degradation in CWAO applications.

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Importance: The sustainable effectiveness and safety of a nonphysician community health care practitioner-led intensive blood pressure intervention on cardiovascular disease have not, to the authors' knowledge, been studied, especially in the older adult population. Objective: To evaluate such a multifaceted model with a more stringent blood pressure treatment goal (<130/80 mm Hg) among patients aged 60 years and older with hypertension. Design, Setting, and Participants: This was a 48-month follow-up study of the China Rural Hypertension Control Project (CRHCP), an open-cluster randomized clinical trial, conducted from 2018 to 2023. Participants 60 years and older and younger than 60 years with a diagnosis of hypertension from the CRHCP trial were included for analysis. Individuals were recruited from 326 villages in rural China. Interventions: The well-trained, nonphysician, community health care practitioner implemented a multifaceted intervention program (eg, initiation or titration of antihypertensive medications) to achieve a blood pressure level of less than 130/80 mm Hg, supervised by primary care physicians. Main Outcomes and Measures: Cardiovascular disease (a composite of myocardial infarction, stroke, heart failure requiring hospitalization, and cardiovascular disease death). Results: A total of 22 386 individuals 60 years and older with hypertension and 11 609 individuals younger than 60 years with hypertension were included in the analysis. The mean (SD) age of the participants was 63.0 (9.0) years and included 20 825 females (61.3%). Among the older individuals with hypertension, a total of 11 289 patients were randomly assigned to the intervention group and 11 097 to the usual-care group. During a median (IQR) of 4.0 (4.0-4.1) years, there was a significantly lower rate of total cardiovascular disease (1133 [2.7%] vs 1433 [3.5%] per year; hazard ratio [HR], 0.75; 95% CI, 0.69-0.81; P < .001) and all-cause mortality (1111 [2.5%] vs 1210 [2.8%] per year; HR, 0.90; 95% CI, 0.83-0.98; P = .01) in the intervention group than in the usual-care group. For patients younger than 60 years, the risk reductions were also significant for total cardiovascular disease (HR, 0.64; 95% CI, 0.56-0.75; P < .001), stroke (HR, 0.64; 95% CI, 0.55-0.76; P < .001), heart failure (HR, 0.39; 95% CI, 0.18-0.87; P = .02), and cardiovascular death (HR, 0.54; 95% CI, 0.37-0.77; P < .001), with all interaction P values for age groups greater than .05. In both age categories, the incidences of injurious falls, symptomatic hypotension, syncope, and the results for kidney outcomes did not differ significantly between groups. Conclusions and Relevance: In both the aging and younger general population with hypertension, the nonphysician health care practitioner-led, multifaceted, intensive blood pressure intervention model could effectively and safely reduce the risk of cardiovascular disease and all-cause death. Trial Registration: ClinicalTrials.gov Identifier: NCT03527719.

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With the emergence of combined surgical treatments, complemented by radiotherapy and chemotherapy, survival rates for esophageal cancer patients have improved, but the overall 5-year survival rate remains low. Therefore, there is an urgent need for further research into the pathogenesis of esophageal cancer and the development of effective prevention, diagnosis, and treatment methods. We initially utilized the GeneCards and DisGeNET databases to identify the esophageal cancer-associated gene WWOX (WW domain containing oxidoreductase). Subsequently, we employed RT-qPCR (Reverse transcription-quantitative PCR) and WB (western blot) to investigate the differential expression of WWOX in HEEC (human esophageal endotheliocytes) and various ESCC (esophageal squamous cell carcinoma) cell lines. We further evaluated alterations in cell proliferation, migration and apoptosis via CCK8 (cell counting kit-8) and clonal formation, Transwell assays and flow cytometry. Additionally, we investigated changes in protein expressions related to the Hippo signaling pathway (YAP/TEAD) through RT-qPCR and WB. Lastly, to further elucidate the regulatory mechanism of WWOX in ESCC, we performed exogenous YAP rescue experiments in ESCC cells with WWOX overexpression to investigate the alterations in apoptosis and proliferation. Results indicated that the expression of WWOX in ESCC was significantly downregulated. Subsequently, upon overexpression of WWOX, ESCC cell proliferation and migration decreased, while apoptosis increased. Additionally, the expression of YAP and TEAD were reduced. However, the sustained overexpression of YAP attenuated the inhibitory effects of WWOX on ESCC cell malignancy. In conclusion, WWOX exerts inhibitory effects on the proliferation and migration of ESCC and promotes apoptosis by suppressing the Hippo signaling pathway. These findings highlight the potential of WWOX as a novel target for the diagnosis and treatment of esophageal cancer.

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BACKGROUND: The 2018/2023 ESC/ESH Guidelines underlined a gap how baseline cardiovascular disease (CVD) risk predicted blood pressure (BP) lowering benefits. Further, 2017 ACC/AHA Guideline and 2021 WHO Guideline recommended implementation studies about intensive BP control. Now, to bridge these guideline gaps, we conducted a post hoc analysis to validate whether the baseline CVD risk influences the effectiveness of the intensive BP control strategy, which was designed by China Rural Hypertension Control Project (CRHCP). METHODS: This is a post hoc analysis of CRHCP, among which participants were enrolled except those having CVD history, over 80 years old, or missing data. Subjects were stratified into quartiles by baseline estimated CVD risk and then grouped into intervention and usual care group according to original assignment in CRHCP. Participants in the intervention group received an integrated, multi-faceted treatment strategy, executed by trained non-physician community health-care providers, aiming to achieve a BP target of < 130/80 mmHg. Cox proportional-hazards models were used to estimate the hazard ratios of outcomes for intervention in each quartile, while interaction effect between intervention and estimated CVD risk quartiles was additionally assessed. The primary outcome comprised myocardial infarction, stroke, hospitalization for heart failure, or CVD deaths. RESULTS: Significant lower rates of primary outcomes for intervention group compared with usual care for each estimated CVD risk quartile were reported. The hazard ratios (95% confidence interval) in the four quartiles (from Q1 to Q4) were 0.59 (0.40, 0.87), 0.54 (0.40, 0.72), 0.72 (0.57, 0.91) and 0.65 (0.53, 0.80), respectively (all Ps < 0.01). There's no significant difference of hazard ratios by intervention across risk quartiles (P for interaction = 0.370). Only the relative risk of hypotension, not symptomatic hypotension, was elevated in the intervention group among upper three quartiles. CONCLUSIONS: Intensive BP lowering strategy designed by CRHCP group was effective and safe in preventing cardiovascular events independent of baseline CVD risk. TRIAL REGISTRATION: The trial is registered with ClinicalTrials.gov, NCT03527719.

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Food adulteration presents a significant challenge due to the evasion of legal oversight and the difficulty of identification. Addressing this issue, there is an urgent need for on-site, rapid, visually based small-scale equipment, along with large-scale screening technology, to enable prompt results without providing opportunities for dishonest traders to react. Colorimetric reactions offer advantages in terms of speed, visualization, and miniaturization. However, there is a scarcity of suitable colorimetric reactions for food adulteration detection, and interference from colored food impurities and easily comparable color results affects accuracy. To overcome limitations, this study introduces a novel approach utilizing polydopamine magnetic nanoparticles to enrich DNA in food samples, effectively eliminating interfering components. By employing gold nanoparticles to generate magnetic-gold nanoparticles, a single magnetic bead achieves simultaneous enrichment, impurity removal, and detection. The use of paper-based biosensors and visualization equipment allows for the visualization and digital analysis of results, achieving a low detection limit of 4.59 nmol mL-1. The method also exhibits high accuracy and repeatability, with a RSD ranging from 1.6 % to 4.0 %. This innovative colorimetric method addresses the need for rapid, miniaturized, and large-scale detection, thus providing a solution for food adulteration challenges.

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To explore a new method to improve the wear resistance of TiNi shape memory alloy (SMA), Ti-50.8Ni alloy was treated by the method of ultrasonic surface shot peening. The microstructure evolution, hardness, and tribological behaviors have been further investigated to evaluate the effect of ultrasonic surface shot peening (USSP). The surface microstructure can be refined to some extent while the basic phase composition has little change. USSP can facilitate the martensitic transformation in the surface layer, which benefits improving the surface hardness. Additionally, the hardness of Ti-50.8Ni alloy increases first and then decreases with the increase of applied load, but the USSP-treated alloy tends to be more sensitive to load. USSP treatment can improve the wear resistance and reduce the coefficient of friction (COF) in case of a low sliding wear speed of 5 mm/s. However, the tribological properties of USSP-treated alloy are reversely worse in the case of 10 mm/s. This is mainly attributed to the combined effect of stress-induced martensite transformation and degeneration resulting from the frictional heating during the dry sliding wear process.

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Type I interferon (IFN) production is crucial in tuberculosis pathogenesis, yet the bacterial factors initiating this process are incompletely understood. CpsA, protein of Mycobacterium marinum and Mycobacterium tuberculosis, plays a key role in maintaining bacterial virulence and inhibiting host cell LC3-associated phagocytosis. By utilizing CpsA full deletion mutant studies, we re-verified its essential role in infection-induced pathology and revealed its new role in type I IFN expression. CpsA deficiency hindered IFN production in infected macrophages in vitro as well as zebrafish and mice in vivo. This effect was linked to the cGAS-TBK1-IRF3 pathway, as evidenced by decreased TBK1 and IRF3 phosphorylation in CpsA-deficient bacterial strain-infected macrophages. Moreover, we further show that CpsA deficiency cause decreased cytosolic DNA levels, correlating with impaired phagosomal membrane rupture. Our findings reveal a new function of mycobacterial CpsA in type I IFN production and offer insight into the molecular mechanisms underlying mycobacterial infection pathology.