USP11 promotes glycolysis by regulating HIF-1α stability in hepatocellular carcinoma.

Understanding the mechanisms underlying metastasis in hepatocellular carcinoma (HCC) is crucial for developing new therapies against this fatal disease. Deubiquitinase ubiquitin-specific protease 11 (USP11) belongs to the deubiquitinating family and has previously been reported to play a critical role in cancer pathogenesis. Although it has been established that USP11 can facilitate the metastasis and proliferation ability of HCC, the underlying regulatory mechanisms are poorly understood. The primary objective of this research was to reveal hitherto undocumented functions of USP11 during HCC progression, especially those related to metabolism. Under hypoxic conditions, USP11 was found to significantly impact the glycolysis of HCC cells, as demonstrated through various techniques, including RNA-Seq, migration and colony formation assays, EdU and co-immunoprecipitation. Interestingly, we found that USP11 interacted with the HIF-1α complex and maintained HIF-1α protein stability by removing ubiquitin. Moreover, USP11/HIF-1α could promote glycolysis through the PDK1 and LDHA pathways. In general, our results demonstrate that USP11 promotes HCC proliferation and metastasis through HIF-1α/LDHA-induced glycolysis, providing new insights and the experimental basis for developing new treatments for this patient population.

AURKB promotes bladder cancer progression by deregulating the p53 DNA damage response pathway via MAD2L2.

BACKGROUND: Bladder cancer (BC) is the most common urinary tract malignancy. Aurora kinase B (AURKB), a component of the chromosomal passenger protein complex, affects chromosomal segregation during cell division. Mitotic arrest-deficient 2-like protein 2 (MAD2L2) interacts with various proteins and contributes to genomic integrity. Both AURKB and MAD2L2 are overexpressed in various human cancers and have synergistic oncogenic effects; therefore, they are regarded as emerging therapeutic targets for cancer. However, the relationship between these factors and the mechanisms underlying their oncogenic activity in BC remains largely unknown. The present study aimed to explore the interactions between AURKB and MAD2L2 and how they affect BC progression via the DNA damage response (DDR) pathway. METHODS: Bioinformatics was used to analyze the expression, prognostic value, and pro-tumoral function of AURKB in patients with BC. CCK-8 assay, colony-forming assay, flow cytometry, SA-ß-gal staining, wound healing assay, and transwell chamber experiments were performed to test the viability, cell cycle progression, senescence, and migration and invasion abilities of BC cells in vitro. A nude mouse xenograft assay was performed to test the tumorigenesis ability of BC cells in vivo. The expression and interaction of proteins and the occurrence of the senescence-associated secretory phenotype were detected using western blot analysis, co-immunoprecipitation assay, and RT-qPCR. RESULTS: AURKB was highly expressed and associated with prognosis in patients with BC. AURKB expression was positively correlated with MAD2L2 expression. We confirmed that AURKB interacts with, and modulates the expression of, MAD2L2 in BC cells. AURKB knockdown suppressed the proliferation, migration, and invasion abilities of, and cell cycle progression in, BC cells, inducing senescence in these cells. The effects of AURKB knockdown were rescued by MAD2L2 overexpression in vitro and in vivo. The effects of MAD2L2 knockdown were similar to those of AURKB knockdown. Furthermore, p53 ablation rescued the MAD2L2 knockdown-induced suppression of BC cell proliferation and cell cycle arrest and senescence in BC cells. CONCLUSIONS: AURKB activates MAD2L2 expression to downregulate the p53 DDR pathway, thereby promoting BC progression. Thus, AURKB may serve as a potential molecular marker and a novel anticancer therapeutic target for BC.

Genotype selection identified elite lines through quantitative trait loci mapping of agronomically important traits in wheat.

Wheat is one of the most important staple foods in the world. Genetic characterization of wheat agronomically important traits is crucial for yield improvement through molecular breeding. In this study, a recombinant inbred line (RIL) population was developed by crossing a local adapted high yield variety Jimai 22 (JM22) with an external variety Cunmai no.1 (CM1). A high-density genetic map containing 7,359 single nucleotide polymorphism (SNP) markers was constructed. Quantitative trait loci (QTL) mapping identified 61 QTL for eight yield-related traits under six environments (years). Among them, 17 QTL affecting spike number per plant, grain number per spike and thousand grain weight showed high predictability for theoretical yield per plant (TYP), of which, 12 QTL alleles positively contributed to TYP. Nine promising candidate genes for seven of the 12 QTL were identified including three known wheat genes and six rice orthologs. Four elite lines with TYP increased by 5.6%-15.2% were identified through genotype selection which carried 7-9 favorable alleles from JM22 and 2-3 favorable alleles from CM1 of the 12 QTL. Moreover, the linked SNPs of the 12 QTL were converted to high-throughput kompetitive allele-specific PCR (KASP) markers and validated in the population. The mapped QTL, identified promising candidate genes, developed elite lines and KASP markers are highly valuable in future genotype selection to improve wheat yield. Supplementary Information: The online version contains supplementary material available at 10.1007/s11032-024-01496-3.

Correlation between the development of phage resistance and the original antibiotic resistance of host bacteria under the co-exposure of antibiotic and bacteriophage.

Bacteriophages (phages) are viruses capable of regulating the proliferation of antibiotic resistant bacteria (ARB). However, phages that directly cause host lethality may quickly select for phage resistant bacteria, and the co-evolutionary trade-offs under varying environmental conditions, including the presence of antibiotics, remains unclear as to their impact on phage and antibiotic resistance. Here, we report the emergence of phage resistance in three distinct E. coli strains with varying resistance to ß-lactam antibiotics, treated with different ampicillin (AMP) concentrations. Hosts exhibiting stronger antibiotic resistance demonstrated a higher propensity to develop and maintain stable phage resistance. When exposed to polyvalent phage KNT-1, the growth of AMP-sensitive E. coli K12 was nearly suppressed within 18 h, while the exponential growth of AMP-resistant E. coli TEM and super-resistant E. coli NDM-1 was delayed by 12 h and 8 h, respectively. The mutation frequency and mutated colony count of E. coli NDM-1 were almost unaffected by co-existing AMP, whereas for E. coli TEM and K12, these metrics significantly decreased with increasing AMP concentration from 8 to 50 µg/mL, becoming unquantifiable at 100 µg/mL. Furthermore, the fitness costs of phage resistance mutation and its impact on initial antibiotic resistance in bacteria were further examined, through analyzing AMP susceptibility, biofilm formation and EPS secretion of the isolated phage resistant mutants. The results indicated that acquiring phage resistance could decrease antibiotic resistance, particularly for hosts lacking strong antibiotic resistance. The ability of mutants to form biofilm contributes to antibiotic resistance, but the correlation is not entirely positive, while the secretion of extracellular polymeric substance (EPS), especially the protein content, plays a crucial role in protecting the bacteria from both antibiotic and phage exposure. This study explores phage resistance development in hosts with different antibiotic resistance and helps to understand the limitations and possible solutions of phage-based technologies.

Response Properties of Electrorheological Composite Hydrophilic Elastomers Based on Different Morphologies of Magnesium-Doped Strontium Titanate.

As smart materials, electrorheological elastomers (EREs) formed by pre-treating active electrorheological particles are attracting more and more attention. In this work, four Mg-doped strontium titanate (Mg-STO) particles with spherical, dendritic, flake-like, and pinecone-like morphologies were obtained via hydrothermal and low-temperature co-precipitation. XRD, SEM, Raman, and FT-IR were used to characterize these products. The results showed that Mg-STOs are about 1.5-2.0 µm in size, and their phase structures are dominated by cubic crystals. These Mg-STOs were dispersed in a hydrogel composite elastic medium. Then, Mg-STO/glycerol/gelatin electrorheological composite hydrophilic elastomers were obtained with or without an electric field. The electric field response properties of Mg-doped strontium titanate composite elastomers were investigated. We concluded that dendritic Mg-STO composite elastomers are high-performance EREs, and the maximum value of their energy storage was 8.70 MPa. The significant electrorheological performance of these products is helpful for their applications in vibration control, force transducers, smart structures, dampers, and other fields.

MTHFD2 promotes PD-L1 expression via activation of the JAK/STAT signalling pathway in bladder cancer.

Although combination chemotherapy is widely used for bladder cancer (BC) treatment, the recurrence and progression rates remain high. Therefore, novel therapeutic targets are required. Methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) contributes to tumourigenesis and immune evasion in several cancers; however, its biological function in BC remains unknown. This study aimed to investigate the expression, prognostic value and protumoural function of MTHFD2 in BC and elucidate the mechanism of programmed death-ligand 1 (PD-L1) upregulation by MTHFD2. An analysis using publicly available databases revealed that a high MTHFD2 expression was correlated with clinical features and a poor prognosis in BC. Furthermore, MTHFD2 promoted the growth, migration, invasion and tumourigenicity and decreased the apoptosis of BC cells in vivo and in vitro. The results obtained from databases showed that MTHFD2 expression was correlated with immune infiltration levels, PD-L1 expression, and the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway. The expression of MTHFD2, PD-L1 and JAK/STAT signalling pathway-related proteins increased after interferon gamma treatment and decreased after MTHFD2 knockdown. Moreover, addition of a JAK/STAT pathway activator partially reduced the effect of MTHFD2 knockdown on BC cells. Collectively, our findings suggest that MTHFD2 promotes the expression of PD-L1 through the JAK/STAT signalling pathway in BC.

Characterization and identification of the powdery mildew resistance gene in wheat breeding line ShiCG15-009.

Powdery mildew, caused by Blumeria graminis f. sp. tritici (Bgt), is a serious fungal disease that critically threatens the yield and quality of wheat. Utilization of host resistance is the most effective and economical method to control this disease. In our study, a wheat breeding line ShiCG15-009, released from Hebei Province, was highly resistant to powdery mildew at all stages. To dissect its genetic basis, ShiCG15-009 was crossed with the susceptible cultivar Yannong 21 to produce F1, F2 and F2:3 progenies. After genetic analysis, a single dominant gene, tentatively designated PmCG15-009, was proved to confer resistance to Bgt isolate E09. Further molecular markers analysis showed that PmCG15-009 was located on chromosome 2BL and flanked by markers XCINAU130 and XCINAU143 with the genetic distances 0.2 and 0.4 cM, respectively, corresponding to a physic interval of 705.14-723.48 Mb referred to the Chinese Spring reference genome sequence v2.1. PmCG15-009 was most likely a new gene differed from the documented Pm genes on chromosome 2BL since its different origin, genetic diversity, and physical position. To analyze and identify the candidate genes, six genes associated with disease resistance in the candidate interval were confirmed to be associated with PmCG15-009 via qRT-PCR analysis using the parents ShiCG15-009 and Yannong 21 and time-course analysis post-inoculation with Bgt isolate E09. To accelerate the transfer of PmCG15-009 using marker-assisted selection (MAS), 18 closely or co-segregated markers were evaluated and confirmed to be suitable for tracing PmCG15-009, when it was transferred into different wheat cultivars.

SQLE Knockdown inhibits bladder cancer progression by regulating the PTEN/AKT/GSK3ß signaling pathway through P53.

Bladder cancer (BCa) is one of the most common malignancies worldwide. However, the lack of accurate and effective targeted drugs has become a major problem in current clinical treatment of BCa. Studies have demonstrated that squalene epoxidase (SQLE), as a key rate-limiting enzyme in cholesterol biosynthesis, is involved in cancer development. In this study, our analysis of The Cancer Genome Atlas, The Genotype-Tissue Expression, and Gene Expression Omnibus databases showed that SQLE expression was significantly higher in cancer tissues than it was in adjacent normal tissues, and BCa tissues with a high SQLE expression displayed a poor prognosis. We then confirmed this result in qRT-PCR and immunohistochemical staining experiments, and our vitro studies demonstrated that SQLE knockdown inhibited tumor cell proliferation and metastasis through the PTEN/AKT/GSK3ß signaling pathway. By means of rescue experiments, we proved that that P53 is a key molecule in SQLE-mediated regulation of the PTEN/AKT/GSK3ß signaling pathway. Simultaneously, we verified the above findings through a tumorigenesis experiment in nude mice. In conclusion, our study shows that SQLE promotes BCa growth through the P53/PTEN/AKT/GSK3ß axis, which may serve as a therapeutic biological target for BCa.

Application of three-dimensional printing individualized titanium mesh in alveolar bone defects with different Terheyden classifications: A retrospective case series study.

OBJECTIVE: To present the results of guided bone regeneration (GBR) with three-dimensional printing individualized titanium mesh (3D-PITM) applied to alveolar bone defects with different Terheyden classifications and the factors affecting the osteogenic outcome. MATERIALS AND METHODS: Fifty-nine patients, presenting with 61 defect sites, were enrolled between 2018 and 2021. GBR+3D-PITM was obtained with simultaneous or second stage implant placement. The complication rate, the success rate of the bone grafting procedure and the survival rate of the implant were documented. Bone gain, thickness of pseudo-periosteum and peri-implant marginal bone loss (MBL) were measured through digital methods by imaging data (CBCT and X-ray). RESULTS: Out of 61 sites, 20 were exposed (exposure rate: 32.8%). The width, height, and volume bone gain at P3 (mesh removal) were 5.22 ± 3.19 mm, 5.01 ± 2.83 mm, and 588.91 ± 361.23 mm3 , respectively. From P2 (3D-PITM+GBR) to P3 , changes in bone gain were not statistically different in the different Terheyden classifications, the occurrence of exposure (p < .001 for all dimensions) and the different type of pseudo-periosteum (p = .030 for width and p = .002 for height) were significantly correlated with the reduction of bone gain. Terheyden classification of the defect sites was significantly associated with the occurrence of exposure (p = .014) and types of the pseudo-periosteum (p = .015). CONCLUSION: The 3D-PITM can be used in alveolar bone defects with different Terheyden classification, but cases with severe vertical bone defects have a greater chance of the 3D-PITM exposure and the exposure can affect the outcome of bone augmentation.

Genetic Analysis and Molecular Identification of the Powdery Mildew Resistance in 116 Elite Wheat Cultivars/Lines.

Powdery mildew, caused by Blumeria graminis f. sp. tritici (Bgt), is a destructive disease worldwide. Host resistance is the preferred method for limiting the disease epidemic, protecting the environment, and minimizing economic losses. In the present study, the reactions to powdery mildew for a collection of 600 wheat cultivars and breeding lines from different wheat-growing regions were tested using the Bgt isolate E09. Next, 116 resistant genotypes were identified and then crossed with susceptible wheat cultivars/lines to produce segregating populations for genetic analysis. Among them, 87, 19, and 10 genotypes displayed single, dual, and multiple genic inheritance, respectively. To identify the Pm gene(s) in those resistant genotypes, 16 molecular markers for 13 documented Pm genes were used to test the resistant and susceptible parents and their segregating populations. Of the 87 wheat genotypes that fitted the monogenic inheritance, 75 carried the Pm2a allele. Three, two, one, and two genotypes carried Pm21, Pm6, Pm4, and the recessive genes pm6 and pm42, respectively. Four genotypes did not carry any of the tested genes, suggesting that they might have other uncharacterized or new genes. The other 29 wheat cultivars/lines carried two or more of the tested Pm genes and/or other untested genes, including Pm2, Pm5, Pm6, and/or pm42. It was obvious that Pm2 was widely used in wheat production, whereas Pm1, Pm24, Pm33, Pm34, Pm35, Pm45, and Pm47 were not detected in any of these resistant wheat genotypes. This study clarified the genetic basis of the powdery mildew resistance of these wheat cultivars/lines to provide information for their rational utilization in different wheat-growing regions. Moreover, some wheat genotypes which may have novel Pm gene(s) were mined to enrich the diversity of resistance source.