Explore the vast range of titles available.

Breast cancer is the most frequent malignancy in women worldwide, and triple-negative breast cancer (TNBC) patients have the worst prognosis and highest risk of recurrence. The therapeutic strategies for TNBC are limited. It is urgent to develop new methods to enhance the efficacy of TNBC treatment. Previous studies demonstrated that D-mannose, a hexose, can enhance chemotherapy in cancer and suppress the immunopathology of autoimmune diseases. Here, we show that D-mannose can significantly facilitate TNBC treatment via degradation of PD-L1. Specifically, D-mannose can activate AMP-activated protein kinase (AMPK) to phosphorylate PD-L1 at S195, which leads to abnormal glycosylation and proteasomal degradation of PD-L1. D-mannose–mediated PD-L1 degradation promotes T cell activation and T cell killing of tumor cells. The combination of D-mannose and PD-1 blockade therapy dramatically inhibits TNBC growth and extends the lifespan of tumor-bearing mice. Moreover, D-mannose–induced PD-L1 degradation also results in messenger RNA destabilization of DNA damage repair–related genes, thereby sensitizing breast cancer cells to ionizing radiation (IR) treatment and facilitating radiotherapy of TNBC in mice. Of note, the effective level of D-mannose can be easily achieved by oral administration in mice. Our study unveils a mechanism by which D-mannose targets PD-L1 for degradation and provides methods to facilitate immunotherapy and radiotherapy in TNBC. This function of D-mannose may be useful for clinical treatment of TNBC.

The acute liver injury (ALI) and hepatic fibrosis caused by the co-treatment of lipopolysaccharide (LPS)/ d -galactosamine (D-GalN) have been extensively studied. However, whether LPS/D-GalN are genotoxic has been left unknown. In this study, male mice were divided into eight groups with eight animals in each group. For acute challenge of LPS/D-GalN, the mice in each group received a combination of LPS/D-GalN via intraperitoneal injection at the dose of 25 μg/kg/250 mg/kg, 25 μg/kg/500 mg/kg, or 50 μg/kg/500 mg/kg body weight. An additional group for chronic administration of test compounds was conducted by i.p. injection of LPS/D-GalN (10 μg/kg/100 mg/kg) every other day for 8 weeks. Saline solution (0.9%) and cyclophosphamide (CTX) (50 mg/kg body weight) given by i.p. injection was used as the negative and positive control, respectively. The results of single cell gel electrophoresis (SCGE) assay indicated that acute exposure of the mice to LPS/D-GalN caused severe DNA damage in hepatic cells, but not in the brain, sperm or bone marrow cells, which evidenced the genotoxicity of LPS/D-GalN administrated in combination. Interestingly, the chronic administration of LPS/D-GalN triggered significant genotoxic effects not only in hepatic but also in brain cells, with negative results in sperm and bone marrow cells. Histopathological examination in the liver and brain tissues revealed changes consistent with the SCGE results. The present study indicates genotoxic potential of LPS/D-GalN co-administered in mice, which may serve as an in vivo experimental model for relevant genotoxic study.

How cancer cells evade the therapeutic effects of immune checkpoint blockade is largely unknown. Here, we report that fibrinogen-like protein 1 (FGL1), a newly identified immune checkpoint ligand, was modified by acetylation at Lys 98 in hepatocellular carcinoma (HCC), which targeted it for proteasomal degradation. Sirtuin 2 (SIRT2) deacetylated and stabilized FGL1, thus promoting immune evasion. Notably, the SIRT2 inhibitor 2-Cyano-3-[5-(2,5-dichlorophenyl)-2-furanyl]-N-5-quinolinyl-2-propenamide (AGK2) enhanced acetylation of FGL1 and reduced FGL1 protein levels in vitro. The combination of AGK2 and programmed death ligand 1 (PD-L1) blockade effectively suppressed tumor growth and improved overall survival of mice. Furthermore, aspirin, an old drug, could directly acetylate FGL1 at Lys 98 and promote its degradation in vitro. Aspirin enhanced the immunotherapeutic efficacy, induced tumor regression, and extended the lifespan of tumor-bearing mice. Furthermore, the SIRT2/FGL1 axis was expressed in HCC specimens. Collectively, these findings unveil an acetylation-mediated regulation of FGL1, identify a potential target for HCC immunotherapy, and provide therapeutic strategies for the clinical treatment of HCC.

Objective Circulating microRNAs (miRNAs) have promising potential as diagnostic or prognostic biomarkers for hepatocellular carcinoma (HCC). This study aimed to analyze the clinical significance of serum exosomal miR-320a expression in patients with HCC. Methods A total of 104 patients with HCC, 55 patients with chronic liver disease (CLD), and 50 healthy volunteers were enrolled. Serum exosomal miR-320a levels were measured by quantitative reverse-transcriptase polymerase chain reaction and compared among the groups. The relationships between exosomal miR-320a levels and clinicopathological factors in patients with HCC were also analyzed. Results Serum exosomal miR-320a levels were significantly lower in patients with HCC compared with patients with CLD and healthy controls. Receiver-operating characteristic curve analysis showed that serum exosomal miR-320a had good diagnostic value for distinguishing between HCC subjects and normal controls. Serum exosomal miR-320a levels were significantly elevated 1 month after surgery in patients with HCC. Moreover, serum exosomal miR-320a downregulation was strongly associated with positive lymph node metastasis, positive vein invasion, advanced TNM stage, and shorter survival. Serum exosomal miR-320a was confirmed as an independent prognostic marker for HCC. Conclusions Collectively, these results indicate that serum exosomal miR-320a might be a potential biomarker for the detection and prognosis of HCC.

The integrated platform provides a safe operating environment for high-rise residential construction and enables the simultaneous advancement of main structural works and facade operations. However, the construction workflow based on an integrated platform is highly complex, with tightly interlinked processes, making construction duration optimization an urgent issue. Focusing on the construction characteristics of the integrated platform for facade operations and the coordinated execution of structural and facade works, this study investigates the problem of construction duration optimization. With the objective of minimizing the overall construction period, the logical relationships among various processes are systematically sorted out, and a mathematical optimization model is established that considers precedence constraints, overlapping relationships, and labor resource conditions. By introducing a genetic algorithm, the optimal construction scheme under the shortest possible duration is obtained. An empirical analysis based on an actual engineering project demonstrates that the construction cycle of a standard floor was shortened from the original 6 days to 5 days, effectively reducing technical interruptions on site and lowering labor resource demand by 10–15%. This improvement enhances lean construction performance at the project level. The research results provide theoretical support and methodological reference for construction duration optimization using integrated construction equipment and hold significant engineering value and practical significance for promoting the digitalization, systematization, and efficiency of building construction.

The production of broadband frequency spectra from narrowband wave forcing in geophysical flows remains an open problem. Here we consider a related theoretical problem that points to the role of time-dependent vortical flow in producing this effect. Specifically, we apply multi-scale analysis to the transport equation of wave action density in a homogeneous stationary random background flow under the Wentzel–Kramers–Brillouin approximation. We find that, when some time dependence in the mean flow is retained, wave action density diffuses both along and across surfaces of constant frequency in wavenumber–frequency space; this stands in contrast to previous results showing that diffusion occurs only along constant-frequency surfaces when the mean flow is steady. A self-similar random background velocity field is used to show that the magnitude of this frequency diffusion depends non-monotonically on the time scale of variation of the velocity field. Numerical solutions of the ray-tracing equations for rotating shallow water illustrate and confirm our theoretical predictions. Notably, the mean intrinsic wave frequency increases in time, which by wave action conservation implies a concomitant increase of wave energy at the expense of the energy of the background flow.

Widespread deployment of NH 3 -adsorbing MOF materials remains challenging due to the significant energy-penalty of regeneration. In this work, we address this limitation by integrating photothermal technologies into a bipyridinium-functionalized MOF matrix, enabling effective NH 3 desorption in a more eco-friendly and sustainable manner. This MOF adsorbent exhibits selective NH 3 capture via specific hydrogen bonding interactions, rendering it suitable for purifying effluent gases in industrial NH 3 synthesis. The NH 3 adsorption process is accompanied by an obvious color change due to the formation of bipyridinium radicals through an electron transfer reaction between NH 3 molecules and bipyridinium ligands. This distinctive property endows the MOF with favorable NH 3 detection capabilities. Furthermore, the colored MOF matrix functions as an exceptional photothermal medium under 808 nm laser irradiation, effectively facilitating the release of captured NH 3 molecules through light-triggered localized heating. Importantly, the synthesis of this MOF material can be scaled up to gram-level with minimal complexity using a straightforward one-pot reflux method, significantly enhancing its practical applicability. An eco-friendly and sustainable NH 3 desorption process has been successfully realized in a bipyridinium-bearing MOF adsorbent via free radical-dominated photothermal conversion for localized heating.

Micro-RNAs play critical roles in initiation and progression of hepatocellular carcinoma. However, the biological role of microRNA-145-5p in hepatocellular carcinoma and how it works are still not clearly understood. Expression levels of microRNA-145-5p in hepatocellular carcinoma cell lines were examined by reverse transcription quantitative polymerase chain reaction. Cell counting kit-8, wound-healing assay, and flow cytometry assay were conducted to investigate the role of microRNA-145-5p von proliferation, migration, and apoptosis. Luciferase reporter assay and Western blot were performed to investigate the correlation between microRNA-145-5p and RAB18. We found microRNA-145-5p was downregulated in hepatocellular carcinoma cell lines compared to the normal cell line. Overexpression of microRNA-145-5p inhibited the proliferation and migration but promoted apoptosis of hepatocellular carcinoma cells in vitro. RAB18 was validated a target of microRNA-145-5p and ectopic expression of RAB18 can promote the proliferation and migration but inhibit apoptosis of hepatocellular carcinoma cells. These findings indicate that microRNA-145-5p functions as a novel tumor suppressor through targeting RAB18, suggesting that microRNA-145-5p might be a potential new therapeutic molecule for the treatment of hepatocellular carcinoma.

El Niño fundamentally elevates the southern South China Sea (SSCS) winter sea surface temperature (SST), and this relationship exhibits significant interdecadal modulation by the Pacific Decadal Oscillation (PDO). Correlation analyses reveal a negative linkage between El Niño-SSCS SST relationship and PDO index (r = −0.5, p < 0.05). Mechanistically, negative PDO phase reconfigures the multi-anticyclone system: a weaker and northeastward-shifted Philippine Sea anticyclone (PSAC, 25° poleward), dissipating northern Indian Ocean anticyclone (NIOAC) and persistent southeastern Indian Ocean anticyclone (SEIOAC) through a reduction in Aleutian low and El Niño intensity. In the negative-minus-positive PDO phase composite, this drives anomalous southerlies/southwesterlies over the SSCS, establishing a zonal SST dipole (west-cooling/east-warming; −0.1 °C/+0.2 °C east/west of 108° E). Ekman dynamics (positive/negative wind stress curl west/east of 108° E), horizontal heat advection and latent heat flux (driven by southwesterly wind) dominate the SST dipole formation. From December to February, Aleutian low suppression and El Niño decay progressively modify the multi-anticyclone system configuration and replace southerly anomalies with northerlies, reducing regional warm SST in the N-P composite. The multi-anticyclone system thus mediates SSCS SST interannual variability, with critical implications for marine predictability under climate oscillations.

With the rapid development of high-speed railways, the quality of service in the waiting halls of high-speed railway stations has become a subject of great concern. In order to clarify the impact of various service elements on the overall satisfaction associated with high-speed railway passenger stations, this study offers an in-depth exploration of the service quality of the waiting halls of high-speed railway stations by considering the physical environment (such as thermal environment, acoustic environment, light environment, and air quality), environmental design (including architectural design, route design, and hygiene situations), and service facilities (such as rest facilities, information facilities, safety features, commercial facilities, and ticketing facilities). The study uses a combination of an online questionnaire and an on-site questionnaire to collect data, and we ensured the reliability and validity of the research results through reliability and validity analyses. The Kano model was used to accurately identify the demand attributes of passengers for various service elements in the departure hall. Linear regression analysis was used to conduct a detailed study of the quantitative relationship between the influencing factors and overall satisfaction, and the satisfaction level of each dimension was systematically calculated to accurately quantify the impact of different factors on the overall satisfaction. Pearson correlation analysis was used to carefully explore the correlations among the factors and reveal the potential relationships. The study clearly depicts the performance of each service element. According to the demand classification of the Kano model, Must-Have Quality (M) elements include air quality, thermal environment, route design, the hygiene situation, and information facilities; Attractive Quality (A) elements include the acoustic environment, light environment, and architectural design; rest facilities, commercial facilities, and ticketing facilities are classified as One-Dimensional Quality (O); and safety facilities are of Indifferent Quality (I). Combined with regression analysis and correlation analysis, these results were used to further determine the focus of service element optimization. By clarifying the attributes of different service elements and their degree of impact on overall satisfaction, the corresponding optimization direction is proposed.