Most patients with triple negative breast cancer (TNBC) do not respond to anti-PD1/PDL1 immunotherapy, indicating the necessity to explore immune checkpoint targets. B7H3 is a highly glycosylated ...protein. However, the mechanisms of B7H3 glycosylation regulation and whether the sugar moiety contributes to immunosuppression are unclear. Here, we identify aberrant B7H3 glycosylation and show that N-glycosylation of B7H3 at NXT motif sites is responsible for its protein stability and immunosuppression in TNBC tumors. The fucosyltransferase FUT8 catalyzes B7H3 core fucosylation at N-glycans to maintain its high expression. Knockdown of FUT8 rescues glycosylated B7H3-mediated immunosuppressive function in TNBC cells. Abnormal B7H3 glycosylation mediated by FUT8 overexpression can be physiologically important and clinically relevant in patients with TNBC. Notably, the combination of core fucosylation inhibitor 2F-Fuc and anti-PDL1 results in enhanced therapeutic efficacy in B7H3-positive TNBC tumors. These findings suggest that targeting the FUT8-B7H3 axis might be a promising strategy for improving anti-tumor immune responses in patients with TNBC.
Silicon can improve drought tolerance of plants, but the mechanism still remains unclear. Previous studies have mainly concentrated on silicon-accumulating plants, whereas less work has been ...conducted in silicon-excluding plants, such as tomato (Solanum lycopersicum L.). In this study, we investigated the effects of exogenous silicon (2.5 mmol L–1) on the chlorophyll fluorescence and expression of photosynthesis-related genes in tomato seedlings (Zhongza 9) under water stress induced by 10％ (w/v) polyethylene glycol (PEG-6000). The results showed that under water stress, the growth of shoot and root was inhibited, and the chlorophyll and carotenoid concentrations were decreased, while silicon addition improved the plant growth and increased the concentrations of chlorophyll and carotenoid. Under water sterss, chlorophyll fluorescence parameters such as PSll maximum photochemical efficiency (Fv/Fm), effective quantum efficiency, actual photochemical quantum efficiency (ФPSII), photosynthetic electron transport rate (ETR), and photochemical quenching coefficient (qP) were decreased; while these changes were reversed in the presence of added silicon. The expressions of some photosynthesis-related genes including PetE, PetF, PsbP, PsbQ, PsbW, and Psb28 were down-regulated under water stress, and exogenous Si could partially up-regulate their expressions. These results suggest that silicon plays a role in the alleviation of water stress by modulating some photosynthesis-related genes and regulating the photochemical process, and thus promoting photosynthesis.
The purpose of this study was to investigate the early risk factors for the exacerbation of coronavirus disease 2019 (COVID‐19) pneumonia. Restrospective analysis of clinical data of 85 patients ...infected with severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2), including gender, age, comorbidities, symptoms, blood routine, clotting profile, biochemical examination, albumin, myocardial enzyme profile, inflammatory markers, and chest computed tomography (CT). All laboratory examinations were measured within first 24 hours after admission, and chest CT was performed before admission. A total of 56 (65.9%) patients had a history of exposure to the Huanan seafood market in Wuhan. Fever and dry cough accounted for the highest percentage of all symptoms. Male COVID‐2019 patients were more likely to develop severe pneumonia. Patients with severe and critical conditions are older and have higher rates of hypertension (P = .003) and coronary heart disease (P = .017). All severe and critical patients infected with SARS‐CoV‐2 showed bilateral lung involvement and have more multiple lobes involvement than common patients (P < .001). Severe and critical patients showed higher white blood cell count (P = .006), neutrophil (NEU) count (P = .001), NEU% (P = .002), procalcitonin (P = .011), C‐reactive protein (P = .003), prothrombin time (P = .035), D‐dimer (P = .025), aspartate aminotransferase (P = .006), and lower lymphocyte (LYM) count (P = .019), LYM% (P = .001), albumin (P < .001). Logistic regression analysis showed that NEU count is an independent risk factor for deterioration, with the threshold of 6.5 × 109·L−1. We concluded that the laboratory independent risk factor for the progression of COVID‐19 pneumonia is NEU count. In addition, COVID‐19 patients with bilateral lung involvement or multiple lobes involvement should be taken seriously and actively treated to prevent deterioration of the disease.
In this study, a refined hot forming process for age-hardened aluminum alloys that is referred to as the pre-hardened hot forming (PHF) process was investigated. The ductility of the AA7075-T6 alloy ...was significantly improved during this process, which was evaluated through hot tensile tests ranging from 200 °C to 400 °C. Based on these results, hot stamping tests for automotive components were successfully conducted, and mechanical property testing of post-formed parts were carried out. The results indicate that under the forming temperature of 200 °C, the tensile strength of the formed component maintained more than 92% of the original T6 sheet blank tensile strength and more than 93% of the yield strength. Moreover, the post-formed strength did not decrease monotonically with increasing forming temperature. There was an abnormal drop in the strength of the component formed at 300 °C, which is obviously lower than that of the vicinal temperatures (250 °C and 350 °C). Microstructure observations and differential scanning calorimetry (DSC) analysis were conducted to explore the microstructure of the formed components. The results showed that there was no obvious difference among the grain sizes of the formed components under different forming temperatures. The sample formed at 250 °C maintained a large amount of the η′ phase, while the coarse η phase was the dominant precipitate in the microstructure of the sample formed at 300 °C. The contributions of grain boundary strengthening and precipitation strengthening were evaluated based on the Hall-Petch equation and Orowan strengthening theory, respectively. The calculation results showed good agreement with the experimental data. All the results indicated that direct forming of the AA7075-T6 alloy was achieved by the PHF process and that the forming temperature should be limited below 300 °C to obtain satisfactory mechanical properties without a subsequent artificial aging process.
Abstract
Background
Super-enhancers (SEs) play a crucial role in cancer, which is often associate with activated oncogenes. However, little is known about how SEs facilitate tumour suppression. ...Individuals with Down syndrome exhibit a remarkably reduced incidence of breast cancer (BC), moving the search for tumor suppressor genes on human chromosome 21 (HSA21). In this study, we aim to identify and explore potential mechanisms by which SEs are established for tumor suppressor RCAN1.4 on HSA21 in BC.
Methods
In silico analysis and immunohistochemical staining were used to assess the expression and clinical relevance of RCAN1.4 and RUNX3 in BC. Function experiments were performed to evaluate the effects of RCAN1.4 on the malignancy of breast carcinoma in vitro and in vivo. ChIP-seq data analysis, ChIP-qPCR, double-CRISPR genome editing, and luciferase reporter assay were utilized to confirm RUNX3 was involved in regulating RCAN1.4-associated SE in BC. The clinical value of co-expression of RCAN1.4 and RUNX3 was evaluated in BC patients.
Results
Here, we characterized RCAN1.4 as a potential tumour suppressor in BC. RCAN1.4 loss promoted tumour metastasis to bone and brain, and its overexpression inhibited tumour growth by blocking the calcineurin-NFATc1 pathway. Unexpectedly, we found RCAN1.4 expression was driven by a ~ 23 kb-long SE. RCAN1.4-SE
distal
was sensitive to BRD4 inhibition, and its deletion decreased RCAN1.4 expression by over 90% and induced the malignant phenotype of BC cells. We also discovered that the binding sites in the SE region of RCAN1.4 were enriched for consensus sequences of transcription factor RUNX3. Knockdown of RUNX3 repressed the luciferase activity and also decreased H3K27ac enrichment binding at the SE region of RCAN1.4. Furthermore, abnormal SE-driven RCAN1.4 expression mediated by RUNX3 loss could be physiologically significant and clinically relevant in BC patients. Notably, we established a prognostic model based on RCAN1.4 and RUNX3 co-expression that effectively predicted the overall survival in BC patients.
Conclusions
These findings reveal an important role of SEs in facilitating tumour suppression in BC. Considering that the combination of low RCAN1.4 and low RUNX3 expression has worse prognosis, RUNX3-RCAN1.4 axis maybe a novel prognostic biomarker and therapeutic target for BC patients.
•Se- and O-co-inserted MoS2 (Se-MoS2) is achieved simply by adding Se precursor.•Se-MoS2 contains abundant 1T phase and S defects.•Se-MoS2 exhibits outstanding HER activity close to state-of-the-art ...Pt/C.•DFT calculations indicate that Se-MoS2 has higher DOS near Fermi energy than MoS2.•The augment of DOS near Fermi energy conduces to enhance the HER activity of Se-MoS2.
MoS2 is identified as a potential electrocatalyst for H2 evolution reaction (HER) due to its low cost and robust durability. However, the limited active site and low electrical conductivity severely hinder the practical application of MoS2. To address these issues, we herein propose a Se-insertion engineering strategy to fabricate Se- and O-co-inserted MoS2 (Se-MoS2) microspheres composed of intertwined nanosheets. Se and O co-insertion create abundant S defects on the basal plane of MoS2 and thus increase the number of active sites. Additionally, Se and O co-insertion are apt to induce the transition of MoS2 from 2H to 1T phase (~60% 1T MoS2), thereby exhibiting more excellent electric conductivity (~2 orders larger than that of MoS2). Furthermore, optimized Se-MoS2 not only shows electrocatalytic HER activity (an overpotential of 108 mV at 10 mA cm−2 and a Tafel slope of 47 mV dec–1), also inherits the outstanding electrocatalytic durability of pristine MoS2. Density function theory (DFT) calculations reveal that the excellent HER performance of optimized Se-MoS2 can be explained with Volmer-Heyrovsky mechanism, which is intrinsically attributed to the emergence of new band structures near the Fermi energy level of MoS2, increasing the electrical conductivity and reducing the Gibbs free energy of hydrogen adsorption.
Neural stem/progenitor cells (NSPCs) are a promising candidate for the cell‐replacement therapy after central nervous system (CNS) injury. However, the short of sufficient NSPCs migration and ...integration into the lesions is an essential challenge for cell‐based therapy after CNS injury due to the disturbance of local environmental homeostasis. Chondroitin sulfate proteoglycan (CSPG) is obviously accumulated at the lesions and destroyed local homeostasis after CNS injury. The previous study has demonstrated that the CSPG is a dominating ingredient inhibiting axonal regrowth of newly born neurons after CNS injury. NSPCs, a strain of special neural subtypes, hold the capacity of leading processes formation to regulate NSPCs migration, which has the same mechanism as axonal regrowth. Hence, it is worth investigating the effect of CSPG on NSPCs migration and its underlying mechanism. Here, different concentration of CSPG was used to evaluate its effect on NSPCs migration. The results showed that the CSPG suppressed NSPCs migration in a dose‐dependent manner from 10 to 80 µg/mL with phase‐contrast microscopy after 24 hours. Meanwhile, transwell assays were performed to certify the above results. Our data indicated that the 40 µg/mL CSPG obviously suppressed NSPCs migration via decreasing filopodia formation using immunofluorescence staining. Furthermore, data indicated that the 40 µg/mL CSPG upregulated protein tyrosine phosphatase receptor σ (PTPσ) expression and decreased α‐actinin4 (ACTN4) expression through immunofluorescence, reverse transcription polymerase chain reaction, and Western blot assays. While the inhibitory effect was attenuated using PTPσ‐specific small interfering RNA. In addition, data demonstrated that the 40 µg/mL CSPG facilitated NSPCs differentiation into glial fibrillary acidic protein‐positive cells and inhibited NSPCs directing into MAP2‐ and MBP‐positive cells. Collectively, these data demonstrated that the CSPG suppressed NSPCs migration through PTPσ/ACTN4 signaling pathway. Meanwhile, CSPG facilitated NSPCs differentiation into astrocytes and inhibited NSPCs directing into neurons and oligodendrocytes.
The present study indicates that the CSPG hampers NSPCs migration through suppressing filopodia formation.The PTPσ/ACTN4 signaling pathway plays a pivotal role in this process and they act in a negative correlation manner.
Four mononuclear terpyridine complexes Cu(H-L
a
)Cl
2
·CH
3
OH (
1
), Cu(H-L
a
)ClClO
4
(
2
), Cu(H-L
b
)Cl
2
·CH
3
OH (
3
), and Cu(H-L
b
)(CH
3
OH)(DMSO)(ClO
4
)
2
(
4
) were prepared and fully ...characterized. Complexes
1-4
exhibited higher cytotoxic activity against several tested cancer cell lines especially BEL-7402 cells compared to cisplatin, and they showed low toxicity towards normal human liver cells. ICP-MS detection indicated that the copper complexes were accumulated in mitochondria. Mechanistic studies demonstrated that the copper complexes induced G0/G1 arrest and altered the expression of the related proteins of the cell cycle. All copper complexes reduced the mitochondrial membrane potential while increasing the intracellular ROS levels and the release of Ca
2+
. They also up-regulated Bax and down-regulated Bcl-2 expression levels, caused cytochrome
c
release and the activation of the caspase cascade, and induced mitochondrion-mediated apoptosis. Animal studies demonstrated that complex
1
suppressed tumor growth in a mouse xenograft model bearing BEL-7402 tumor cells.
Four terpyridine copper(
ii
) complexes were prepared and they showed excellent cytotoxic activity, which induced mitochondrion-mediated apoptosis and cell cycle arrest in the G0/G1 phase. Complex
1
suppressed cell proliferation
in vivo
.
Key message
Silicon enhances root water uptake in salt-stressed cucumber plants through up-regulating aquaporin gene expression. Osmotic adjustment is a genotype-dependent mechanism for ...silicon-enhanced water uptake in plants.
Silicon can alleviate salt stress in plants. However, the mechanism is still not fully understood, and the possible role of silicon in alleviating salt-induced osmotic stress and the underlying mechanism still remain to be investigated. In this study, the effects of silicon (0.3 mM) on Na accumulation, water uptake, and transport were investigated in two cucumber (
Cucumis sativus
L.) cultivars (‘JinYou 1’ and ‘JinChun 5’) under salt stress (75 mM NaCl). Salt stress inhibited the plant growth and photosynthesis and decreased leaf transpiration and water content, while added silicon ameliorated these negative effects. Silicon addition only slightly decreased the shoot Na levels per dry weight in ‘JinYou 1’ but not in ‘JinChun 5’ after 10 days of stress. Silicon addition reduced stress-induced decreases in root hydraulic conductivity and/or leaf-specific conductivity. Expressions of main plasma membrane aquaporin genes in roots were increased by added silicon, and the involvement of aquaporins in water uptake was supported by application of aquaporin inhibitor and restorative. Besides, silicon application decreased the root xylem osmotic potential and increased root soluble sugar levels in ‘JinYou 1.’ Our results suggest that silicon can improve salt tolerance of cucumber plants through enhancing root water uptake, and silicon-mediated up-regulation of aquaporin gene expression may in part contribute to the increase in water uptake. In addition, osmotic adjustment may be a genotype-dependent mechanism for silicon-enhanced water uptake in plants.
A lot of previous studies have recently reported that the gut microbiota influences the development of colorectal cancer (CRC) in Western countries, but the role of the gut microbiota in Chinese ...population must be investigated fully. The goal of this study was to determine the role of the gut microbiome in the initiation and development of CRC. We collected fecal samples of 206 Chinese individuals: 59 with polyp (group P), 54 with adenoma (group A), 51 with colorectal cancer (group CC), and 42 healthy controls (group HC).16S ribosomal RNA (rRNA) was used to compare the microbiota community structures among healthy controls, patients with polyp, and those with adenoma or colorectal cancer. Our study proved that intestinal flora, as a specific indicator, showed significant differences in its diversity and composition. Sobs, Chao, and Ace indexes of group CC were significantly lower than those of the healthy control group (CC group: Sobs, Chao, and Ace indexes were 217.3 ± 69, 4265.1 ± 80.7, and 268.6 ± 78.1, respectively; HC group: Sobs, Chao, and Ace indexes were 228.8 ± 44.4, 272.9 ± 58.6, and 271.9 ± 57.2, respectively). When compared with the healthy individuals, the species richness and diversity of intestinal flora in patients with colorectal cancer were significantly reduced: PCA and PCoA both revealed that a significant separation in bacterial community composition between the CC group and HC group (with PCA using the first two principal component scores of PC1 14.73% and PC2 10.34% of the explained variance, respectively; PCoA : PC1 = 14%, PC2 = 9%, PC3 = 6%). Wilcox tests was used to analyze differences between the two groups, it reveals that Firmicutes (P=0.000356), Fusobacteria (P=0.000001), Proteobacteria (P=0.000796), Spirochaetes (P=0.013421), Synergistetes (P=0.005642) were phyla with significantly different distributions between cases and controls. The proportion of microorganism composition is varying at different stages of colon cancer development: Bacteroidetes (52.14%) and Firmicutes (35.88%) were enriched in the healthy individuals; on the phylum level, the abundance of Bacteroidetes (52.14%-53.92%-52.46%–47.06%) and Firmicutes (35.88%-29.73%-24.27%–25.36%) is decreasing with the development of health-polyp-adenomas-CRC, and the abundance of Proteobacteria (9.33%-12.31%-16.51%–22.37%) is increasing. PCA and PCOA analysis showed there was no significant (P<0.05) difference in species similarity between precancerous and carcinogenic states. However, the composition of the microflora in patients with precancerous lesions (including patients with adenoma and polyp) was proved to have no significant disparity (P<0.05). Our study provides insights into new angles to dig out potential biomarkers in diagnosis and treatment of colorectal cancer and to provide scientific advice for a healthy lifestyle for the sake of gut microbiota.
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