Elevated serum levels of human epididymis protein 4 in adult patients with proliferative lupus nephritis.

Background: This study aimed to access whether serum human epididymis protein 4 (HE4) level could identify lupus nephritis (LN) pathological classes in adults and children. Methods: The serum HE4 levels of 190 healthy subjects and 182 patients with systemic lupus erythematosus (SLE) (61 adult-onset LN [aLN], 39 childhood-onset LN [cLN], and 82 SLE without LN) were determined using Architect HE4 kits and an Abbott ARCHITECT i2000SR Immunoassay Analyzer. Results: Serum HE4 level was significantly higher in the aLN patients (median, 85.5 pmol/L) than in the patients with cLN (44 pmol/L, P < 0.001) or SLE without LN (37 pmol/L, P < 0.001), or the healthy controls (30 pmol/L, P < 0.001). Multivariate analysis showed that serum HE4 level was independently associated with aLN. Stratified by LN class, serum HE4 level was significantly higher in the patients with proliferative LN (PLN) than in those with non-PLN, and this difference was found only in aLN (median, 98.3 versus 49.3 pmol/L, P = 0.021) but not in cLN. Stratified by activity (A) and chronicity (C) indices, the aLN patients with class IV (A/C) possessed significantly higher serum HE4 levels than those with class IV (A) (median, 195.5 versus 60.8 pmol/L, P = 0.006), and this difference was not seen in the class III aLN or cLN patients. Conclusion: Serum HE4 level is elevated in patients with class IV (A/C) aLN. The role of HE4 in the pathogenesis of chronic lesions of class IV aLN needs further investigation.

Impacts of corn intercropping with soybean, peanut and millet through different planting patterns on population dynamics and community diversity of insects under fertilizer reduction.

Corn is one of the key grain crops in China and the excessive use of chemical fertilizers and pesticides seriously damages the ecological environment in fields. To explore a more scientific and reasonable way to plant corn and simultaneously reduce the overuse of chemical fertilizers and pesticides, the impact of corn intercropping with soybean, peanut, and millet, respectively, through five planting patterns, including three intercropping patterns (2 corn rows to 2, 3 and 4 rows of soybean/peanut or 2, 4 and 6 millet rows, respectively) and two monoculture patterns of corn and soybean, peanut or millet under normal (600 kg/ha) and reduced (375 kg/ha) levels of NPK (N:P2O5:K2O = 15:15:15) fertilization on the population abundance and community diversity of insects, leaf nutrients, and induced plant hormones jasmonic acid (JA) and salicylic acid (SA) was studied in 2018 and 2019. The results showed that the insect community indexes of the species number (S), the diversity index (H), and the uniformity index (E) generally increased under intercropping and were significantly higher than those under corn monoculture. The prevalence of Asian corn borer (Ostrinia furnacalis) on the intercropping corn plants decreased by based on the average of seven surveys per year for each treatment 2.9 to 17 heads per 30 plants compared with that on the monoculture corn plants. The number of natural enemy insect species on corn plants under intercropping was significantly higher than that under corn monoculture. That is, intercropping may decrease the population of Asian corn borers by increasing S, H, E, and natural enemy insect species (NEI). Moreover, intercropping type and fertilizer level significantly affected corn leaf nutrient contents. Compared with the normal fertilizer level, fertilizer reduction significantly reduced the foliar contents of amino acids, soluble protein, and soluble sugar in corn plants. In addition, corn-soybean and corn-peanut intercropping significantly increased the three nutrient contents in corn leaves compared with corn monoculture. In terms of corn nutrients, intercropping could compensate for the effects of fertilizer reduction. The foliar content of JA in corn-soybean intercropping was significantly higher than in corn monoculture. Under corn-soybean and corn-peanut intercropping, SA was significantly lower than under corn monoculture. Overall, intercropping, not fertilizer reduction, can significantly increase insect community diversity while reducing the population abundances of the key insect pest species on corn plants. Intercropping reduced the SA content, increased amino acids and thus reduced the susceptibility of corn to the pest insects.

Elevated CO2 Altered Rice VOCs Aggravate Population Occurrence of Brown Planthoppers by Improving Host Selection Ability.

It is predicted that plant volatile organic compounds (VOCs) are affected by the atmospheric CO2 levels rising globally, which further affects the interaction between plants and herbivorous insects, especially the host selection behavior of herbivorous insects. In this study, the effects of elevated CO2 on the host-selection behavior of the brown planthopper (BPH) Nilaparvata lugens, and the emission of VOCs from the healthy and BPH-damaged rice plants were studied simultaneously to make clear the population occurrence of BPH under global climate change. Compared with ambient CO2, elevated CO2 significantly increased the host selection percent of BPH for the healthy (CK) and BPH-damaged rice plants, and the host selection percent of BPH for the BPH-damaged rice plants was significantly higher than that for the healthy rice plants under elevated CO2, which might be regulated by the transcription levels of OBP1, OBP2 and CSP8 in BPH due to the upregulated transcriptional levels of these three genes of BPH under elevated CO2. In addition, we analyzed and quantified the emission of VOCs in rice plants grown under ambient CO2 and elevated CO2 by GS-MS. A total of 36 VOCs from rice plants were identified into eight categories, including alkanes, alkenes, alcohols, aldehydes, ketones, esters, phenols and aromatic hydrocarbons. Elevated CO2 significantly decreased the contents of heptadecane, linalool and limonene from rice plants compared with ambient CO2. Besides, the contents of linalool, phytol, decanal, 1-methyldecalin and 2,6-diphenylphenol from BPH-damaged rice plants under ambient CO2, and undecane, hexadecane, nonanal and 2,6-diphenylphenol from BPH-damaged rice plants under elevated CO2 were all significantly higher than those from healthy rice plants. The percentage composition of phenols was positively correlated with the host selection rate of BPH. Our study indicates that elevated CO2 is beneficial to promote the host selection ability of BPH for rice plants damaged by BPHs due to the changed plant VOCs.

Machine learning and deep learning enabled fuel sooting tendency prediction from molecular structure.

Soot formation models become increasingly important in advanced renewable fuels formulation for soot reduction benefit. This work evaluates performance of machine learning (ML) and deep learning (DL) to predict yield sooting index (YSI) from chemical structure and proposes a tailor-made convolution neural network (CNN)-SDSeries38 for regression problem. In ML, a novel quantitative structure-property relationship (QSPR) is developed for feature extraction and the relationship between molecular structure and YSI is built by ML algorithm. In DL, SDSeries38 contains 9 feature learning modules, 1 regression module for automated feature learning and regression. It adopts standard series network architecture and modular structure, each feature learning module is a stack of convolution, batch normalization, activation, pooling layers. ML-QSPR model outperforms SDSeries38 in accuracy (RMSE = 7.563 vs 19.58), computational speed and the former applies to fuel mixtures. In DL, SDSeries38 network exceeds 10 classical CNN and provides a generic architecture enabling transfer application to other regression problem. DL application to regression is still in its infancy and there is no complete guide on how to develop specific CNN architectures for regression. Some gaps need to be filled: (1) Specially developed CNN architectures for regression are required; (2) The performances of direct transfer learning the classical CNN architectures from classification to regression are modest. A modular structure with typical function modules may provide an ideal solution; (3) Going deeper into the sequence of convolution layers improves predictive accuracy, but bears in mind to keep the number of layers below the threshold to avoid vanishing gradient.

Mutant p53 cooperates with ETS2 to promote etoposide resistance.

Mutant p53 (mtp53) promotes chemotherapy resistance through multiple mechanisms, including disabling proapoptotic proteins and regulating gene expression. Comparison of genome wide analysis of mtp53 binding revealed that the ETS-binding site motif (EBS) is prevalent within predicted mtp53-binding sites. We demonstrate that mtp53 regulates gene expression through EBS in promoters and that ETS2 mediates the interaction with this motif. Importantly, we identified TDP2, a 5'-tyrosyl DNA phosphodiesterase involved in the repair of DNA damage caused by etoposide, as a transcriptional target of mtp53. We demonstrate that suppression of TDP2 sensitizes mtp53-expressing cells to etoposide and that mtp53 and TDP2 are frequently overexpressed in human lung cancer; thus, our analysis identifies a potentially "druggable" component of mtp53's gain-of-function activity.

Pleiotropic functions of EAPII/TTRAP/TDP2: cancer development, chemoresistance and beyond.

EAPII (also called TTRAP, TDP2), a protein identified a decade ago, has recently been shown to function as an oncogenic factor. This protein was also proven to be the first 5'- tyrosyl-DNA phosphodiesterase. EAPII has been demonstrated to have promiscuous protein associations, broad responsiveness to various extracellular signals, and pleiotropic functions in the development of human diseases including cancer and neurodegenerative disease. Emerging data suggest that EAPII is a multi-functional protein: EAPII repairs enzyme (topoisomerase)-mediated DNA damage by removing phosphotyrosine from DNA adducts; EAPII is involved in multiple signal transduction pathways such as TNF-TNFR, TGFß and MAPK, and EAPII is responsive to immune defense, inflammatory response, virus infection and DNA toxins (chemo or radiation therapy). This review focuses on the current understanding of EAPII biology and its potential relations to many aspects of cancer development, including chromosome instability, tumorigenesis, tumor metastasis and chemoresistance, suggesting it as a potential target for intervention in cancer and other human diseases.

Thymomegaly, microsplenia, and defective homeostatic proliferation of peripheral lymphocytes in p51-Ets1 isoform-specific null mice.

Ets1 is a member of the Ets transcription factor family. Alternative splicing of exon VII results in two naturally occurring protein isoforms: full-length Ets1 (p51-Ets1) and Ets1(DeltaVII) (p42-Ets1). These isoforms bear key distinctions regarding protein-protein interactions, DNA binding kinetics, and transcriptional target specificity. Disruption of both Ets1 isoforms in mice results in the loss of detectable NK and NKT cell activity and defects in B and T lymphocytes. We generated mice that express only the Ets1(DeltaVII) isoform. Ets1(DeltaVII) homozygous mice express no p51-Ets1 and elevated levels of the p42-Ets1 protein relative to the wild type and display increased perinatal lethality, thymomegaly, and peripheral lymphopenia. Proliferation was increased in both the thymus and the spleen, while apoptosis was decreased in the thymus and increased in the spleen of homozygotes. Significant elevations of CD8(+) and CD8(+)CD4(+) thymocytes were observed. Lymphoid cell (CD19(+), CD4(+), and CD8(+)) reductions were predominantly responsible for diminished spleen cellularity, with fewer memory cells and a failure of homeostatic proliferation to maintain peripheral lymphocytes. Collectively, the Ets1(DeltaVII) mutants demonstrate lymphocyte maturation defects associated with misregulation of p16(Ink4a), p27(Kip1), and CD44. Thus, a balance in the differential regulation of Ets1 isoforms represents a potential mechanism in the control of lymphoid maturation and homeostasis.

RNA-dependent integrin alpha3 protein localization regulated by the Muscleblind-like protein MLP1.

We show that localized expression of the integrin alpha3 protein is regulated at the level of RNA localization by the human homologue of Drosophila Muscleblind, MLP1/MBLL/MBNL2, a unique Cys3His zinc-finger protein. This is supported by the following observations: MLP1 knockdown abolishes localization of integrin alpha3 to the adhesion complexes; MLP1 is localized in adhesion plaques that contain phospho-focal adhesion kinase; this localization is microtubule-dependent; integrin alpha3 transcripts colocalize with MLP1 in distinct cytoplasmic loci; integrin alpha3 transcripts are physically associated with MLP1 in cells and MLP1 binds to a specific ACACCC motif in the integrin alpha3 3' untranslated region (UTR) in vitro; and a green fluorescent protein (GFP) open reading frame-integrin alpha3 3' UTR chimeric gene directs GFP protein localization to distinct cytoplasmic loci near the cell periphery, which is dependent on MLP1 and is mediated by the ACACCC motif but is independent of the integrin alpha3 signal peptide.

Caspase-1 is a direct target gene of ETS1 and plays a role in ETS1-induced apoptosis.

ETS1, the founding member of Ets transcriptional factor family, plays an important role in cell proliferation, differentiation, lymphoid cell development, transformation, angiogenesis, and apoptosis. Previous work has shown that ETS1 represses tumorigenicity of colon carcinoma cells in vivo, and that the p42-ETS1 protein bypasses a defect in apoptosis in colon carcinoma cells through the up-regulation of caspase-1 expression. In this report, we show that expression of p42-ETS1 inhibits tumorigenicity of colon cancer DLD-1 cells through induction of apoptosis in vivo. In support of the hypothesis that caspase-1 might be a target involved in the sensitization of DLD-1 cells to Fas-induced apoptosis by ETS1, overexpression of caspase-1 bypasses Fas-induced apoptosis in these cells as well. Furthermore, ETS1-mediated apoptosis was observed in MOP8 cells, a transformed mouse NIH3T3 cell line. To determine whether ETS1 activates the transcription of caspase-1, luciferase reporters driven by the wild-type and mutant caspase-1 promoters were generated. Both p51-ETS1 and p42-ETS1 transactivated the caspase-1 transcription and a functional Ets binding site is identified in the caspase-1 promoter. Wild-type caspase-1 promoter (pGL3-ICE) was strongly transactivated by ETS1 and this transactivation was dramatically diminished by the mutation of the potential Ets binding site (-525 bp). In addition, electrophoretic mobility shift assay and chromatin immunoprecipitation assay showed complex formation between this binding site and ETS1 proteins. Taken together, ETS1 transcriptionally induces the expression of caspase-1; as such, the regulatory control of caspase-1 expression by ETS1 may underlie the apoptotic susceptibility modulated by ETS1 in specific tumor cells.

SP100 inhibits ETS1 activity in primary endothelial cells.

SP100 was first identified as a nuclear autoimmune antigen and is a constituent of the nuclear body. SP100 interacts with the ETS1 transcription factor, and we have previously shown that SP100 reduces ETS1-DNA binding and inhibits ETS1 transcriptional activity on the MMP1 and uPA promoters. We now demonstrate that SP100 expression is upregulated by interferons, which have been shown to be antiangiogenic, in primary endothelial cells. As ETS1 is functionally important in promoting angiogenesis, we tested the hypothesis that ETS1 activity is negatively modulated by SP100 in endothelial cells. SP100 directly antagonizes ETS1-mediated morphological changes in human umbilical vein endothelial cell (HUVEC) network formation and reduces HUVEC migration and invasion. To further understand the functional relationship between ETS1 and SP100, cDNA microarray analysis was utilized to assess reprogramming of gene expression by ETS1 and SP100. A subset of the differentially regulated genes, including heat-shock proteins (HSPs) H11, HSPA1L, HSPA6, HSPA8, HSPE1 and AXIN1, BRCA1, CD14, CTGF (connective tissue growth factor), GABRE (gamma-aminobutyric acid A receptor epsilon), ICAM1, SNAI1, SRD5A1 (steroid-5-alpha-reductase 1) and THY1, were validated by real-time PCR and a majority showed reciprocal expression in response to ETS1 and SP100. Interestingly, genes that are negatively regulated by ETS1 and upregulated by SP100 have antimigratory or antiangiogenic properties. Collectively, these data indicate that SP100 negatively modulates ETS1-dependent downstream biological processes.

SP100 expression modulates ETS1 transcriptional activity and inhibits cell invasion.

The ETS1 transcription factor is a member of the Ets family of conserved sequence-specific DNA-binding proteins. ETS1 has been shown to play important roles in various cellular processes such as proliferation, differentiation, lymphoid development, motility, invasion and angiogenesis. These diverse roles of ETS1 are likely to be dependent on specific protein interactions. To identify proteins that interact with ETS1, a yeast two-hybrid screen was conducted. Here, we describe the functional interaction between SP100 and ETS1. SP100 protein interacts with ETS1 both in vitro and in vivo. SP100 is localized to nuclear bodies and ETS1 expression alters the nuclear body morphology in living cells. SP100 negatively modulates ETS1 transcriptional activation of the MMP1 and uPA promoters in a dose-dependent manner, decreases the expression of these endogenous genes, and reduces ETS1 DNA binding. Expression of SP100 inhibits the invasion of breast cancer cells and is induced by Interferon-alpha, which has been shown to inhibit the invasion of cancer cells. These data demonstrate that SP100 modulates ETS1-dependent biological processes.

EAPII interacts with ETS1 and modulates its transcriptional function.

Ets proteins constitute a family of conserved sequence-specific DNA-binding proteins and function as transcription factors. ETS1 plays important roles in differentiation, lymphoid cell development, invasiveness and angiogenesis. Such diverse roles of ETS1 are likely to be dependent on its associated proteins. A yeast two-hybrid screen was conducted and here we describe a novel ETS1 interacting protein designated as ETS1-associated protein II (EAPII). EAPII protein interacts with ETS1 and other Ets proteins (ETS2 and FLI1) both in vitro and in vivo. Indirect immunofluorescence demonstrated that EAPII is predominately localized to the nucleus of mammalian cells. EAPII negatively modulates ETS1 transcriptional activity and attenuates synergistic transactivation by ETS1 and AP-1. Significantly, re-expression of EAPII inhibits the migration of epithelial cancer cells, but does not affect cell viability. Therefore, EAPII is a novel ETS1 modulator that regulates specific aspects of the ETS1 functions.