Genetic variation has an important role in the development of non-small-cell lung cancer (NSCLC). However, genetic factors for lung cancer have not been fully identified, especially in Chinese ...populations, which limits the use of existing polygenic risk scores (PRS) to identify subpopulations at high risk of lung cancer for prevention. We therefore aimed to identify novel loci associated with NSCLC risk, and generate a PRS and evaluate its utility and effectiveness in the prediction of lung cancer risk in Chinese populations.
To systematically identify genetic variants for NSCLC risk, we newly genotyped 19 546 samples from Chinese NSCLC cases and controls from the Nanjing Medical University Global Screening Array Project and did a meta-analysis of genome-wide association studies (GWASs) of 27 120 individuals with NSCLC and 27 355 without NSCLC (13 327 cases and 13 328 controls of Chinese descent as well as 13 793 cases and 14 027 controls of European descent). We then built a PRS for Chinese populations from all reported single-nucleotide polymorphisms that have been reported to be associated with lung cancer risk at genome-wide significance level. We evaluated the utility and effectiveness of the generated PRS in predicting subpopulations at high-risk of lung cancer in an independent prospective cohort of 95 408 individuals from the China Kadoorie Biobank (CKB) with more than 10 years' follow-up.
We identified 19 susceptibility loci to be significantly associated with NSCLC risk at p≤5·0 × 10
, including six novel loci. When applied to the CKB cohort, the PRS of the risk loci successfully predicted lung cancer incident cases in a dose-response manner in participants at a high genetic risk (top 10%) than those at a low genetic risk (bottom 10%; adjusted hazard ratio 1·96, 95% CI 1·53-2·51; p
=2·02 × 10
). Specially, we observed consistently separated curves of lung cancer events in individuals at low, intermediate, and high genetic risk, respectively, and PRS was an independent effective risk stratification indicator beyond age and smoking pack-years.
We have shown for the first time that GWAS-derived PRS can be effectively used in discriminating subpopulations at high risk of lung cancer, who might benefit from a practically feasible PRS-based lung cancer screening programme for precision prevention in Chinese populations.
National Natural Science Foundation of China, the Priority Academic Program for the Development of Jiangsu Higher Education Institutions, National Key R&D Program of China, Science Foundation for Distinguished Young Scholars of Jiangsu, and China's Thousand Talents Program.
Mycoplasma gallisepticum (MG) is the primary pathogen of chronic respiratory diseases (CRDs) in chickens. In poultry production, antibiotics are mostly used to prevent and control MG infection, but ...the drug resistance and residue problems caused by them cannot be ignored. Glycyrrhizic acid (GA) is derived from licorice, a herb traditionally used to treat various respiratory diseases. Our study results showed that GA significantly inhibited the mRNA and protein expression of pMGA1.2 and GapA in vitro and in vivo. Furthermore, the network pharmacology study revealed that GA most probably resisted MG infection through the MAPK signaling pathway. Our results demonstrated that GA inhibited MG-induced expression of MMP2/MMP9 and inflammatory factors through the p38 and JUN signaling pathways, but not the ERK pathway in vitro. Besides, histopathological sections showed that GA treatment obviously attenuated tracheal and lung damage caused by MG invasion. In conclusion, GA can inhibit MG-triggered inflammation and apoptosis by suppressing the expression of MMP2/MMP9 through the JNK and p38 pathways and inhibit the expression of virulence genes to resist MG. Our results suggest that GA might serve as one of the antibiotic alternatives to prevent MG infection.
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•Bioinspired jellyfish-like carbon/manganese nanomotor is developed.•Near-infrared light and H2O2 dual-propulsion is achieved.•Cooperation of dual-propulsion and •OH catalytic ...activity actively enhances tumor chemodynamic therapy.
Chemodynamic therapy (CDT), which catalyzes the production of highly toxic reactive oxygen species (ROS), has been widely used in tumor therapy in the past five years. However, most of the current nanomaterials for CDT are difficult to penetrate into the tumor effectively due to the lack of motility, resulting in an unsatisfactory CDT effect. Herein, bioinspired jellyfish-like carbon/manganese nanomotors (JCMNs) are designed to achieve hydrogen peroxide (H2O2) and NIR light dual-propulsion for the enhanced CDT therapy. Based on the jellyfish-like asymmetric structure, the manganese component can catalyze H2O2 to generate chemical concentration gradient, propelling JCMNs to dynamically generate ROS in cells by self-diffusiophoresis. In addition, the carbon component of JCMNs can absorb near-infrared (NIR) light to produce a temperature gradient, driving JCMNs to enhance tumor penetration by self-thermophoresis. The combination of chemical and NIR light propulsions significantly improves the efficiency of tumor CDT, revealing that it should be a reasonable strategy to promote the development of nanobiomedicine by endowing nanosystems with propulsion capacity.
Nonlinear interaction of two or three synchronized coplanar filaments was demonstrated to generate plasma gratings with high electron density capable of effectively exciting samples. This excitation ...was further enhanced by multi-photoionization and electron collision. Consequently, an increase in laser pulse energy led to a decrease in the full width at half maxima (FWHM) of spectral lines, primarily observed in breakdown spectroscopic lines due to electron signal enhancement. Moreover, by measuring the emission line intensity as a function of time delay and excitation laser pulse energy, the radiative lifetime and self-absorption correlation coefficient of neutral atomic and ionic lines were determined to exhibit longed plasma lifetimes in the presence of filament interaction. The enhancement was particularly notable when using three coplanar coupled filaments for excitation, as it resulted in a plasma lifetime increase of approximately 50-60 ns compared to that when using two filaments for atomic lines. These findings indicate that high-electron density in plasma gratings could improve the application of filament-induced breakdown spectroscopy by enhancing spectral resolution, radiative lifetime, and spectral reproducibility.
The interaction of two or three filaments generates a plasma grating, with a focus lens collecting the plasma emission into a spectrometer from the side direction after plasma grating ablating the sample.
Nitrogen (N) limits plant productivity, and its uptake and assimilation may be regulated by N sources, N assimilating enzymes, and N assimilation genes. Mastering the regulatory mechanisms of N ...uptake and assimilation is a key way to improve plant nitrogen use efficiency (NUE). However, it is poorly known how these factors interact to influence the growth process of pecans. In this study, the growth, nutrient uptake and N assimilation characteristics of pecan were analyzed by aeroponic cultivation at varying
NH
4
+
/
NO
3
−
ratios (0/0, 0/100,25/75, 50/50, 75/25,100/0 as CK, T1, T2, T3, T4, and T5). The results showed that T4 and T5 treatments optimally promoted the growth, nutrient uptake and N assimilating enzyme activities of pecan, which significantly increased aboveground biomass, average relative growth rate (RGR), root area, root activity, free amino acid (FAA) and total organic carbon (TOC) concentrations, nitrate reductase (NR), nitrite reductase (NiR), glutamine synthetase (GS), glutamate synthase (Fd-GOGAT and NADH-GOGAT), and glutamate dehydrogenase (GDH) activities. According to the qRT-PCR results, most of the N assimilation genes were expressed at higher levels in leaves and were mainly significantly up-regulated under T1 and T4 treatments. Correlation analysis showed that a correlation between N assimilating enzymes and N assimilating genes did not necessarily exist. The results of partial least squares path model (PLS-PM) analysis indicated that N assimilation genes could affect the growth of pecan by regulating N assimilation enzymes and nutrients. In summary, we suggested that the
NH
4
+
/
NO
3
−
ratio of 75:25 was more beneficial to improve the growth and NUE of pecan. Meanwhile, we believe that the determination of plant N assimilation capacity should be the result of a comprehensive analysis of N concentration, N assimilation enzymes and related genes.
Accumulating evidence indicates the absence of paternally derived miRNAs, piwiRNAs, and proteins may be one important factor contributing to developmental failure in somatic cell cloned embryos. In ...the present study, we found microRNA-449b (miR-449b) was highly expressed in sperm. Target gene predictions and experimental verification indicate that several embryonic development-related genes, including CDK6, c-MYC, HDAC1 and BCL-2, are targets of miR-449b. We therefore investigated the role of miR-449b using somatic cell nuclear transfer (SCNT) embryo model. Bovine fetal fibroblasts, expressing miR-449b through a doxycycline (dox) induced expression system were used as nuclear donor cells for SCNT. The results showed that miR-449b expression in SCNT embryos significantly enhanced the cleavage rate at 48 h after activation and the levels of H3K9 acetylation at the 2-cell to 8-cell stages, meanwhile, significantly decreased the apoptosis index of blastocysts. In addition, we verified miR-449b could regulate the expression levels of CDK6, c-MYC, HDAC1 and BCL-2. In conclusion, the present study shows that miR-449b expression improves the first cleavage division, epigenetic reprogramming and apoptotic status of bovine preimplantation cloned embryos.
A disruption in the expression of gga-miR-365-3p was confirmed in the Mycoplasma gallisepticum (MG)-infected Chicken primary alveolar type II epithelial (CP-II) cells based on previous sequencing ...results, but the role it plays in the infection was unclear. In the present study, we demonstrate that MG evaded cellular host immunity via a gga-miR-365-3p/SOCS5-JAK/STATs negative feedback loop. Specifically, we found that at the initial stage of MG infection in cells, gga-miR-365-3p was rapidly increased and activated the JAK/STAT signaling pathway by inhibiting SOCS5, which induced the secretion of inflammatory factors and triggered immune response against MG infection. Over time, though, the infection progressed, MG gradually destroyed the immune defences of CP-II cells. In late stages of infection, MG escaped host immunity by reducing intracellular gga-miR-365-3p and inhibiting the JAK/STAT pathway to suppress the secretion of inflammatory factors and promote MG adhesion or invasion. These results revealed the game between MG and host cell interactions, providing a new perspective to gain insight into the pathogenic mechanisms of MG or other pathogens. Meanwhile, they also contributed to novel thoughts on the prevention and control of MG and other pathogenic infections, shedding light on the immune modulating response triggered by pathogen invasion and their molecular targeting.
As crucial enzymes in the lipid metabolic network, long-chain acyl-CoA synthases (LACSs) are members of the acyl-activated enzyme superfamily and play a crucial role in epidermal wax synthesis, plant ...lipid anabolic metabolism, and stress tolerance. In this study, 11 pecan
genes were identified and categorized into five groups and located on nine chromosomes. The significant degree of conservation in the AtLACS and CiLACS protein sequences was demonstrated by multiple sequence alignment and conserved motif analysis. Cis-acting element analysis identified numerous stress-responsive and hormone-inducible elements in the promoter regions of
genes. The expression levels of
and
were considerably up-regulated under salt and drought stress, according to the qRT-RCR study. Treatment with ABA also led to increased expression levels of
,
,
, and
. Notably,
,
,
, and
exhibited peak expression levels at 135 days after anthesis and are likely to have been crucial in the accumulation of seed kernel oil. Moreover, the
gene was shown to be located in the cytoplasm. These findings offer a theoretical framework for clarifying the roles of
genes in the processes of pecan kernel oil synthesis and response to abiotic stressors.
•Zn-LDH@GOX degraded mutp53 across multiple mutant categories.•Zn2+ recovered wtp53 conformation and induced the mutp53 degradation through autophagy.•GOX disrupts the HSP90/mutp53 complex, leading ...to mutp53 degradation via ubiquitination-mediated proteasomal pathway.•Zn-LDH and GOX displayed the mutually synergistic degradation of mutp53 and inhibition of tumor growth in vivo.
Tumor protein 53 (Tp53), a key regulator of suppressor genes, is commonly mutated in numerous malignant diseases. Consequently, elimination mutant protein 53 (mutp53) represents an appealing strategy for treating mutp53-related tumors. However, the treatment of these mutations remained challenging due to its formidable limitations. In this study, by loading glucose oxidase (GOX) into Zn-based layered double hydroxides (Zn-LDH) interlayer, a pH-responsive ultrathin nanotherapeutic platform (Zn-LDH@GOX) was created to suppress tumors growth by degrading mutp53. Upon exposure to the acidic environment of lysosomes, the lattice structure of Zn-LDH@GOX was partially disrupted, leading to the release of Zn2+ ions and GOX into the cytoplasm. The increased intracellular concentration of Zn2+ facilitated the restoration of wild-type protein 53 (wtp53) conformation, which in turn degraded mutp53 through activated autophagic pathways. Meanwhile, GOX-induced Heat Shock Protein 90 (HSP90) disruption resulted in the liberation of mutp53 from the HSP90/mutp53 complex and reactivated its degradation via the ubiquitination-mediated proteasomal pathway. In vitro and in vivo experiments confirmed the significant suppression of mutp53 expression and inhibition of tumor growth by Zn-LDH@GOX. Our work offers a novel pH-responsive nanotherapeutic platform with immense potential for mutp53 tumor-specific therapy.
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