Genetic Dissection of Phosphorus Use Efficiency and Genotype-by-Environment Interaction in Maize

Genotype-by-environment interaction (G-by-E) is a common but potentially problematic phenomenon in plant breeding. In this study, we investigated the genotypic performance and two measures of plasticity on a phenotypic and genetic level by assessing 234 maize doubled haploid lines from six populations for 15 traits in seven macro-environments with a focus on varying soil phosphorus levels. It was found intergenic regions contributed the most to the variation of phenotypic linear plasticity. For 15 traits, 124 and 31 quantitative trait loci (QTL) were identified for genotypic performance and phenotypic plasticity, respectively. Further, some genes associated with phosphorus use efficiency, such as Zm00001eb117170, Zm00001eb258520, and Zm00001eb265410, encode small ubiquitin-like modifier E3 ligase were identified. By significantly testing the main effect and G-by-E effect, 38 main QTL and 17 interaction QTL were identified, respectively, in which MQTL38 contained the gene Zm00001eb374120, and its effect was related to phosphorus concentration in the soil, the lower the concentration, the greater the effect. Differences in the size and sign of the QTL effect in multiple environments could account for G-by-E. At last, the superiority of G-by-E in genomic selection was observed. In summary, our findings will provide theoretical guidance for breeding P-efficient and broadly adaptable varieties.     

Fascaplysin Induces Apoptosis and Ferroptosis,and Enhances Anti-PD-1 Immunotherapy in Non-Small Cell Lung Cancer (NSCLC) by Promoting PD-L1 Expression

Fascaplysin is a natural product isolated from sponges with a wide range of anticancer activities. However, the mechanism of fascaplysin against NSCLC has not been clearly studied. In this study, fascaplysin was found to inhibit migration by regulating the wnt/β-catenin signaling pathway and reversing the epithelial–mesenchymal transition phenotype. Further research showed that the anti-NSCLC effect of fascaplysin was mainly through the induction of ferroptosis and apoptosis. Fascaplysin-induced ferroptosis in lung cancer cells, evidenced by increased levels of ROS and Fe²⁺ and downregulation of ferroptosis-associated protein and endoplasmic reticulum stress, was involved in fascaplysin-induced ferroptosis. In addition, ROS was found to mediate fascaplysin-induced apoptosis. Fascaplysin significantly upregulated the expression of PD-L1 in lung cancer cells, and enhanced anti-PD-1 antitumor efficacy in a syngeneic mouse model. Therefore, these results suggest that fascaplysin exerts anticancer effects by inducing apoptosis and ferroptosis in vitro, and improving the sensitivity of anti-PD-1 immunotherapy in vivo. Fascaplysin is a promising compound for the treatment of NSCLC.     

Conservation Study of Imprinted Genes in Maize Triparental Heterozygotic Kernels

Genomic imprinting is a classic epigenetic phenomenon related to the uniparental expression of genes. Imprinting variability exists in seeds and can contribute to observed parent-of-origin effects on seed development. Here, we conducted allelic expression of the embryo and endosperm from four crosses at 11 days after pollination (DAP). First, the F1 progeny of B73(♀) × Mo17(♂) and the inducer line CAU5 were used as parents to obtain reciprocal crosses of BM-C/C-BM. Additionally, the F1 progeny of Mo17(♀) × B73(♂) and CAU5 were used as parents to obtain reciprocal crosses of MB-C/C-MB. In total, 192 and 181 imprinted genes were identified in the BM-C/C-BM and MB-C/C-MB crosses, respectively. Then, by comparing the allelic expression of these imprinted genes in the reciprocal crosses of B73 and CAU5 (BC/CB), fifty-one Mo17-added non-conserved genes were identified as exhibiting imprinting variability. Fifty-one B73-added non-conserved genes were also identified by comparing the allelic expression of imprinted genes identified in BM-C/C-BM, MB-C/C-MB and MC/CM crosses. Specific Gene Ontology (GO) terms were not enriched in B73-added/Mo17-added non-conserved genes. Interestingly, the imprinting status of these genes was less conserved across other species. The cis-element distribution, tissue expression and subcellular location were similar between the B73-added/Mo17-added conserved and B73-added/Mo17-added non-conserved imprinted genes. Finally, genotypic and phenotypic analysis of one non-conserved gene showed that the mutation and overexpression of this gene may affect embryo and kernel size, which indicates that these non-conserved genes may also play an important role in kernel development. The findings of this study will be helpful for elucidating the imprinting mechanism of genes involved in maize kernel development.     

A Novel L-Phenylalanine Dipeptide Inhibits the Growth and Metastasis of Prostate Cancer Cells via Targeting DUSP1 and TNFSF9

Prostate cancer (PCa) is a common malignant cancer of the urinary system. Drug therapy, chemotherapy, and radical prostatectomy are the primary treatment methods, but drug resistance and postoperative recurrence often occur. Therefore, seeking novel anti-tumor compounds with high efficiency and low toxicity from natural products can produce a new tumor treatment method. Matijin-Su [N-(N-benzoyl-L-phenylalanyl)-O-acetyl-L-phenylalanol, MTS] is a phenylalanine dipeptide monomer compound that is isolated from the Chinese ethnic medicine Matijin (Dichondra repens Forst.). Its derivatives exhibit various pharmacological activities, especially anti-tumor. Among them, the novel MTS derivative HXL131 has a significant inhibitory effect against prostate tumor growth and metastasis. This study is designed to investigate the effects of HXL131 on the growth and metastasis of human PCa cell lines PC3 and its molecular mechanism through in vitro experiments combined with proteomics, molecular docking, and gene silencing. The in vitro results showed that HXL131 concentration dependently inhibited PC3 cell proliferation, induced apoptosis, arrested cell cycle at the G2/M phase, and inhibited cell migration capacity. A proteomic analysis and a Western blot showed that HXL131 up-regulated the expression of proliferation, apoptosis, cell cycle, and migration-related proteins CYR61, TIMP1, SOD2, IL6, SERPINE2, DUSP1, TNFSF9, OSMR, TNFRSF10D, and TNFRSF12A. Molecular docking, a cellular thermal shift assay (CETSA), and gene silencing showed that HXL131 had a strong binding affinity with DUSP1 and TNFSF9, which are important target genes for inhibiting the growth and metastasis of PC3 cells. This study demonstrates that HXL131 exhibited excellent anti-prostate cancer activity and inhibited the growth and metastasis of prostate cancer cells by regulating the expression of DUSP1 and TNFSF9.     

Discovery of Flavonoids as Novel Inhibitors of ATP Citrate Lyase: Structure–Activity Relationship and Inhibition Profiles

ATP citrate lyase (ACLY) is a key enzyme in glucolipid metabolism and its aberrantly high expression is closely associated with various cancers, hyperlipemia and atherosclerotic cardiovascular diseases. Prospects of ACLY inhibitors as treatments of these diseases are excellent. To date, flavonoids have not been extensively reported as ACLY inhibitors. In our study, 138 flavonoids were screened and 21 of them were subjected to concentration–response curves. A remarkable structure–activity relationship (SAR) trend was found: ortho-dihydroxyphenyl and a conjugated system maintained by a pyrone ring were critical for inhibitory activity. Among these flavonoids, herbacetin had a typical structure and showed a non–aggregated state in solution and a high inhibition potency (IC₅₀ = 0.50 ± 0.08 μM), and therefore was selected as a representative for the ligand–protein interaction study. In thermal shift assays, herbacetin improved the thermal stability of ACLY, suggesting a direct interaction with ACLY. Kinetic studies determined that herbacetin was a noncompetitive inhibitor of ACLY, as illustrated by molecular docking and dynamics simulation. Together, this work demonstrated flavonoids as novel and potent ACLY inhibitors with a remarkable SAR trend, which may help design high–potency ACLY inhibitors. In–depth studies of herbacetin deepened our understanding of the interactions between flavonoids and ACLY.     

Microbe-Derived Antioxidants Reduce Lipopolysaccharide-Induced Inflammatory Responses by Activating the Nrf2 Pathway to Inhibit the ROS/NLRP3/IL-1β Signaling Pathway

Inflammation plays an important role in the innate immune response, yet overproduction of inflammation can lead to a variety of chronic diseases associated with the innate immune system; therefore, modulation of the excessive inflammatory response has been considered a major strategy in the treatment of inflammatory diseases. Activation of the ROS/NLRP3/IL-1β signaling axis has been suggested to be a key initiating phase of inflammation. Our previous study found that microbe-derived antioxidants (MA) are shown to have excellent antioxidant and anti-inflammatory properties; however, the mechanism of action of MA remains unclear. The current study aims to investigate whether MA could protect cells from LPS-induced oxidative stress and inflammatory responses by modulating the Nrf2-ROS-NLRP3-IL-1β signaling pathway. In this study, we find that MA treatment significantly alleviates LPS-induced oxidative stress and inflammatory responses in RAW264.7 cells. MA significantly reduce the accumulation of ROS in RAW264.7 cells, down-regulate the levels of pro-inflammatory factors (TNF-α and IL-6), inhibit NLRP3, ASC, caspase-1 mRNA, and protein levels, and reduce the mRNA, protein levels, and content of inflammatory factors (IL-1β and IL-18). The protective effect of MA is significantly reduced after the siRNA knockdown of the NLRP3 gene, presumably related to the ability of MA to inhibit the ROS-NLRP3-IL-1β signaling pathway. MA is able to reduce the accumulation of ROS and alleviate oxidative stress by increasing the content of antioxidant enzymes, such as SOD, GSH-Px, and CAT. The protective effect of MA may be due to its ability of MA to induce Nrf2 to enter the nucleus and initiate the expression of antioxidant enzymes. The antioxidant properties of MA are further enhanced in the presence of the Nrf2 activator SFN. After the siRNA knockdown of the Nrf2 gene, the antioxidant and anti-inflammatory properties of MA are significantly affected. These findings suggest that MA may inhibit the LPS-stimulated ROS/NLRP3/IL-1β signaling axis by activating Nrf2-antioxidant signaling in RAW264.7 cells. As a result of this study, MA has been found to alleviate inflammatory responses and holds promise as a therapeutic agent for inflammation-related diseases.     

Aquaporin Gating: A New Twist to Unravel Permeation through Water Channels

Aquaporins (AQPs) are small transmembrane tetrameric proteins that facilitate water, solute and gas exchange. Their presence has been extensively reported in the biological membranes of almost all living organisms. Although their discovery is much more recent than ion transport systems, different biophysical approaches have contributed to confirm that permeation through each monomer is consistent with closed and open states, introducing the term gating mechanism into the field. The study of AQPs in their native membrane or overexpressed in heterologous systems have experimentally demonstrated that water membrane permeability can be reversibly modified in response to specific modulators. For some regulation mechanisms, such as pH changes, evidence for gating is also supported by high-resolution structures of the water channel in different configurations as well as molecular dynamics simulation. Both experimental and simulation approaches sustain that the rearrangement of conserved residues contributes to occlude the cavity of the channel restricting water permeation. Interestingly, specific charged and conserved residues are present in the environment of the pore and, thus, the tetrameric structure can be subjected to alter the positions of these charges to sustain gating. Thus, is it possible to explore whether the displacement of these charges (gating current) leads to conformational changes? To our knowledge, this question has not yet been addressed at all. In this review, we intend to analyze the suitability of this proposal for the first time.     

PD-BertEDL: An Ensemble Deep Learning Method Using BERT and Multivariate Representation to Predict Peptide Detectability

Peptide detectability is defined as the probability of identifying a peptide from a mixture of standard samples, which is a key step in protein identification and analysis. Exploring effective methods for predicting peptide detectability is helpful for disease treatment and clinical research. However, most existing computational methods for predicting peptide detectability rely on a single information. With the increasing complexity of feature representation, it is necessary to explore the influence of multivariate information on peptide detectability. Thus, we propose an ensemble deep learning method, PD-BertEDL. Bidirectional encoder representations from transformers (BERT) is introduced to capture the context information of peptides. Context information, sequence information, and physicochemical information of peptides were combined to construct the multivariate feature space of peptides. We use different deep learning methods to capture the high-quality features of different categories of peptides information and use the average fusion strategy to integrate three model prediction results to solve the heterogeneity problem and to enhance the robustness and adaptability of the model. The experimental results show that PD-BertEDL is superior to the existing prediction methods, which can effectively predict peptide detectability and provide strong support for protein identification and quantitative analysis, as well as disease treatment.     

Towards an In Vitro 3D Model for Photosynthetic Cancer Treatment: A Study of Microalgae and Tumor Cell Interactions

As hypoxic tumors show resistance to several clinical treatments, photosynthetic microorganisms have been recently suggested as a promising safe alternative for oxygenating the tumor microenvironment. The relationship between organisms and the effect microalgae have on tumors is still largely unknown, evidencing the need for a simple yet representative model for studying photosynthetic tumor oxygenation in a reproducible manner. Here, we present a 3D photosynthetic tumor model composed of human melanoma cells and the microalgae Chlamydomonas reinhardtii, both seeded into a collagen scaffold, which allows for the simultaneous study of both cell types. This work focuses on the biocompatibility and cellular interactions of the two cell types, as well as the study of photosynthetic oxygenation of the tumor cells. It is shown that both cell types are biocompatible with one another at cell culture conditions and that a 10:1 ratio of microalgae to cells meets the metabolic requirement of the tumor cells, producing over twice the required amount of oxygen. This 3D tumor model provides an easy-to-use in vitro resource for analyzing the effects of photosynthetically produced oxygen on a tumor microenvironment, thus opening various potential research avenues.