Disulfidptosis-related genes serve as potential prognostic biomarkers and indicate tumor microenvironment characteristics and immunotherapy response in prostate cancer.

Disulfidptosis, a newly identified programmed cell death pathway in prostate cancer (PCa), is closely associated with intracellular disulfide stress and glycolysis. This study aims to elucidate the roles of disulfidptosis-related genes (DRGs) in the pathogenesis and progression of PCa, with the goal of improving diagnostic and therapeutic approaches. We analyzed PCa datasets and normal tissue transcriptome data from TCGA, GEO, and MSKCC. Using consensus clustering analysis and LASSO regression, we developed a risk scoring model, which was validated in an independent cohort. The model's predictive accuracy was confirmed through Kaplan-Meier curves, receiver operating characteristic (ROC) curves, and nomograms. Additionally, we explored the relationship between the risk score and immune cell infiltration, and examined the tumor microenvironment and somatic mutations across different risk groups. We also investigated responses to immunotherapy and drug sensitivity. Our analysis identified two disulfidosis subtypes with significant differences in survival, immune environments, and treatment responses. According to our risk score, the high-risk group exhibited poorer progression-free survival (PFS) and higher tumor mutational burden (TMB), associated with increased immune suppression. Functional enrichment analysis linked high-risk features to key cancer pathways, including the IL-17 signaling pathway. Moreover, drug sensitivity analysis revealed varied responses to chemotherapy, suggesting the potential for disulfidosis-based personalized treatment strategies. Notably, we identified PROK1 as a crucial prognostic marker in PCa, with its reduced expression correlating with disease progression. In summary, our study comprehensively assessed the clinical implications of DRGs in PCa progression and prognosis, offering vital insights for tailored precision medicine approaches.

Genetic Analysis of Egg Production Traits in Luhua Chickens: Insights from a Multi-Trait Animal Model and a Genome-Wide Association Study.

Egg production plays a pivotal role in the economic viability of hens. To analyze the genetic rules of egg production, a total of 3151 Luhua chickens were selected, the egg production traits including egg weight at first laying (Start-EW), egg weight at 43 weeks (EW-43), egg number at 43 weeks (EN-43), and total egg number (EN-All) were recorded. Then, the effects of related factors on egg production traits were explored, using a multi-trait animal model for genetic parameter estimation and a genome-wide association study (GWAS). The results showed that body weight at first egg (BWFE), body weight at 43 weeks (BW-43), age at first egg (AFE), and seasons had significant effects on the egg production traits. Start-EW and EW-43 had moderate heritability of 0.30 and 0.21, while EN-43 and EN-All had low heritability of 0.13 and 0.16, respectively. Start-EW exhibited a robust positive correlation with EW-43, while Start-EW was negatively correlated with EN-43 and EN-All. Furthermore, gene ontology (GO) results indicated that Annexin A2 (ANXA2) and Frizzled family receptor 7 (FZD7) related to EW-43, Cyclin D1 (CCND1) and A2B adenosine receptor (ADORA2B) related to EN-All, and have been found to be mainly involved in metabolism and growth processes, and deserve more attention and further study. This study contributes to accelerating genetic progress in improving low heritability egg production traits in layers, especially in Luhua chickens.

Efficacy and Safety of Bufei Jiedu Granules in Treating Multidrug-Resistant Pulmonary Tuberculosis: A Multi-center, Double-Blinded and Randomized Controlled Trial.

OBJECTIVE: To assess the efficacy and safety of Bufei Jiedu (BFJD) ranules as adjuvant therapy for patients with multidrug-resistant pulmonary tuberculosis (MDR-PTB). METHODS: A large-scale, multi-center, double-blinded, and randomized controlled trial was conducted in 18 sentinel hospitals in China from December 2012 to December 2016. A total of 312 MDR-PTB patients were randomly assigned to BFJD Granules or placebo groups (1:1) using a stratified randomization method, which both received the long-course chemotherapy regimen for 18 months (6 Am-Lfx-P-Z-Pto, 12 Lfx-P-Z-Pto). Meanwhile, patients in both groups also received BFJD Granules or placebo twice a day for a total of 18 months, respectively. The primary outcome was cure rate. The secondary outcomes included time to sputum-culture conversion, changes in lung cavities and quality of life (QoL) of patients. Adverse reactions were monitored during and after the trial. RESULTS: A total of 216 cases completed the trial, 111 in the BFJD Granules group and 105 in the placebo group. BFJD Granules, as an adjuvant treatment, increased the cure rate by 13.6% at the end of treatment, compared with the placebo (58.4% vs. 44.8%, P=0.02), and accelerated the median time to sputum-culture conversion (5 months vs. 11 months). The cavity closure rate of the BFJD Granules group (50.6%, 43/85) was higher than that of the placebo group (32.1%, 26/81; P=0.02) in patients who completed the treatment. At the end of the intensive treatment, according to the 36-item Short Form, the BFJD Granules significantly improved physical functioning, general health, and vitality of patients relative to the placebo group (all P<0.01). Overall, the death rates in the two groups were not significantly different; 5.1% (8/156) in the BFJD Granules group and 2.6% (4/156) in the placebo group. CONCLUSIONS: Supplementing BFJD Granules with the long-course chemotherapy regimen significantly increased the cure rate and cavity closure rates, and rapidly improved QoL of patients with MDR-PTB (Registration No. ChiCTR-TRC-12002850).

Explainable and visualizable machine learning models to predict biochemical recurrence of prostate cancer.

PURPOSE: Machine learning (ML) models presented an excellent performance in the prognosis prediction. However, the black box characteristic of ML models limited the clinical applications. Here, we aimed to establish explainable and visualizable ML models to predict biochemical recurrence (BCR) of prostate cancer (PCa). MATERIALS AND METHODS: A total of 647 PCa patients were retrospectively evaluated. Clinical parameters were identified using LASSO regression. Then, cohort was split into training and validation datasets with a ratio of 0.75:0.25 and BCR-related features were included in Cox regression and five ML algorithm to construct BCR prediction models. The clinical utility of each model was evaluated by concordance index (C-index) values and decision curve analyses (DCA). Besides, Shapley Additive Explanation (SHAP) values were used to explain the features in the models. RESULTS: We identified 11 BCR-related features using LASSO regression, then establishing five ML-based models, including random survival forest (RSF), survival support vector machine (SSVM), survival Tree (sTree), gradient boosting decision tree (GBDT), extreme gradient boosting (XGBoost), and a Cox regression model, C-index were 0.846 (95%CI 0.796-0.894), 0.774 (95%CI 0.712-0.834), 0.757 (95%CI 0.694-0.818), 0.820 (95%CI 0.765-0.869), 0.793 (95%CI 0.735-0.852), and 0.807 (95%CI 0.753-0.858), respectively. The DCA showed that RSF model had significant advantages over all models. In interpretability of ML models, the SHAP value demonstrated the tangible contribution of each feature in RSF model. CONCLUSIONS: Our score system provide reference for the identification for BCR, and the crafting of a framework for making therapeutic decisions for PCa on a personalized basis.

Sixty Years of Frequency-Domain Monaural Speech Enhancement: From Traditional to Deep Learning Methods.

Frequency-domain monaural speech enhancement has been extensively studied for over 60 years, and a great number of methods have been proposed and applied to many devices. In the last decade, monaural speech enhancement has made tremendous progress with the advent and development of deep learning, and performance using such methods has been greatly improved relative to traditional methods. This survey paper first provides a comprehensive overview of traditional and deep-learning methods for monaural speech enhancement in the frequency domain. The fundamental assumptions of each approach are then summarized and analyzed to clarify their limitations and advantages. A comprehensive evaluation of some typical methods was conducted using the WSJ + Deep Noise Suppression (DNS) challenge and Voice Bank + DEMAND datasets to give an intuitive and unified comparison. The benefits of monaural speech enhancement methods using objective metrics relevant for normal-hearing and hearing-impaired listeners were evaluated. The objective test results showed that compression of the input features was important for simulated normal-hearing listeners but not for simulated hearing-impaired listeners. Potential future research and development topics in monaural speech enhancement are suggested.

VEGF165b Mutant Promotes the Apoptosis of Murine Breast Cancer Cells Induced by Paclitaxel by Inducing Tumor Vessel Maturation.

INTRODUCTION: The anti-angiogenic agent vascular endothelial growth factor 165b (VEGF165b) mutant (mVEGF165b), which was developed by our laboratory, has superior antitumor activity to that of native VEGF165b; however, its mechanism of action and druggability need further exploration. METHODS: Using the commercial anti-angiogenic drug bevacizumab as a positive control, the mechanism and developability of mVEGF165b were evaluated and explored. The Cell Counting Kit-8 assay was performed to evaluate the effects of mVEGF165b and bevacizumab alone on the proliferation of human umbilical vein endothelial cells (HUVECs). Meanwhile, the inhibitory effects of mVEGF165b and bevacizumab combined with paclitaxel in a mouse model of breast cancer were assessed. Immunohistochemistry was used to detect their effects on tumor vascular maturation, and the terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay was used to detect the apoptosis of tumor cells. RESULTS: In vitro cell experiments confirmed that mVEGF165b inhibited the proliferation of HUVECs with an efficacy equivalent to that of bevacizumab. mVEGF165b and bevacizumab combined with paclitaxel significantly delayed the growth of breast cancer in mice. Immunohistochemistry and the TUNEL assay showed that mVEGF165b and bevacizumab combined with paclitaxel-induced higher vascular maturity and more apoptosis than paclitaxel alone. CONCLUSION: mVEGF165b showed similar efficacy and mechanism of action as bevacizumab, indicating its potential to be developed into a safe and effective anti-angiogenic drug.

Synthesis and Biological Evaluation of Novel 2-Amino-1,4-Naphthoquinone Amide-Oxime Derivatives as Potent IDO1/STAT3 Dual Inhibitors with Prospective Antitumor Effects.

Indoleamine-2,3-dioxygenase 1 (IDO1) and signal transducer and activator of transcription 3 (STAT3) have emerged as significant targets in the tumor microenvironment for cancer therapy. In this study, we synthesized three novel 2-amino-1,4-naphthoquinone amide-oxime derivatives and identified them as dual inhibitors of IDO1 and STAT3. The representative compound NK3 demonstrated effective binding to IDO1 and exhibited good inhibitory activity (hIDO1 IC50 = 0.06 µM), leading to its selection for further investigation. The direct interactions between compound NK3 and IDO1 and STAT3 proteins were confirmed through surface plasmon resonance analysis. A molecular docking study of compound NK3 revealed key interactions between NK3 and IDO1, with the naphthoquinone-oxime moiety coordinating with the heme iron. In the in vitro anticancer assay, compound NK3 displayed potent antitumor activity against selected cancer cell lines and effectively suppressed nuclear translocation of STAT3. Moreover, in vivo assays conducted on CT26 tumor-bearing Balb/c mice and an athymic HepG2 xenograft model revealed that compound NK3 exhibited potent antitumor activity with low toxicity relative to 1-methyl-L-tryptophan (1-MT) and doxorubicin (DOX). Overall, these findings provided evidence that the dual inhibitors of IDO1 and STAT3 may offer a promising avenue for the development of highly effective drug candidates for cancer therapy.

Attenuated Salmonella carrying siRNA-PD-L1 and radiation combinatorial therapy induces tumor regression on HCC through T cell-mediated immuno-enhancement.

Hepatocellular carcinoma (HCC), the most prevalent type of aggressive liver cancer, accounts for the majority of liver cancer diagnoses and fatalities. Despite recent advancements in HCC treatment, it remains one of the deadliest cancers. Radiation therapy (RT) is among the locoregional therapy modalities employed to treat unresectable or medically inoperable HCC. However, radioresistance poses a significant challenge. It has been demonstrated that RT induced the upregulation of programmed death ligand 1 (PD-L1) on tumor cells, which may affect response to PD-1-based immunotherapy, providing a rationale for combining PD-1/PD-L1 inhibitors with radiation. Here, we utilized attenuated Salmonella as a carrier to explore whether attenuated Salmonella carrying siRNA-PD-L1 could effectively enhance the antitumor effect of radiotherapy on HCC-bearing mice. Our results showed that a combination of siRNA-PD-L1 and radiotherapy had a synergistic antitumor effect by inhibiting the expression of PD-L1 induced by radiation therapy. Mechanistic insights indicated that the combination treatment significantly suppressed tumor cell proliferation, promoted cell apoptosis, and stimulated immune cell infiltration and activation in tumor tissues. Additionally, the combination treatment increased the ratios of CD4+ T, CD8+ T, and NK cells from the spleen in tumor-bearing mice. This study presents a novel therapeutic strategy for HCC treatment, especially for patients with RT resistance.

Artificial intelligence for the diagnosis of clinically significant prostate cancer based on multimodal data: a multicenter study.

BACKGROUND: The introduction of multiparameter MRI and novel biomarkers has greatly improved the prediction of clinically significant prostate cancer (csPCa). However, decision-making regarding prostate biopsy and prebiopsy examinations is still difficult. We aimed to establish a quick and economic tool to improve the detection of csPCa based on routinely performed clinical examinations through an automated machine learning platform (AutoML). METHODS: This study included a multicenter retrospective cohort and two prospective cohorts with 4747 cases from 9 hospitals across China. The multimodal data, including demographics, clinical characteristics, laboratory tests, and ultrasound reports, of consecutive participants were retrieved using extract-transform-load tools. AutoML was applied to explore potential data processing patterns and the most suitable algorithm to build the Prostate Cancer Artificial Intelligence Diagnostic System (PCAIDS). The diagnostic performance was determined by the receiver operating characteristic curve (ROC) for discriminating csPCa from insignificant prostate cancer (PCa) and benign disease. The clinical utility was evaluated by decision curve analysis (DCA) and waterfall plots. RESULTS: The random forest algorithm was applied in the feature selection, and the AutoML algorithm was applied for model establishment. The area under the curve (AUC) value in identifying csPCa was 0.853 in the training cohort, 0.820 in the validation cohort, 0.807 in the Changhai prospective cohort, and 0.850 in the Zhongda prospective cohort. DCA showed that the PCAIDS was superior to PSA or fPSA/tPSA for diagnosing csPCa with a higher net benefit for all threshold probabilities in all cohorts. Setting a fixed sensitivity of 95%, a total of 32.2%, 17.6%, and 26.3% of unnecessary biopsies could be avoided with less than 5% of csPCa missed in the validation cohort, Changhai and Zhongda prospective cohorts, respectively. CONCLUSIONS: The PCAIDS was an effective tool to inform decision-making regarding the need for prostate biopsy and prebiopsy examinations such as mpMRI. Further prospective and international studies are warranted to validate the findings of this study. TRIAL REGISTRATION: Chinese Clinical Trial Registry ChiCTR2100048428. Registered on 06 July 2021.

Genetic variation in ZmWAX2 confers maize resistance to Fusarium verticillioides.

Fusarium verticillioides (F. verticillioides) is a widely distributed phytopathogen that incites multiple destructive diseases in maize, posing a grave threat to corn yields and quality worldwide. However, there are few reports of resistance genes to F. verticillioides. Here, we reveal that a combination of two single nucleotide polymorphisms (SNPs) corresponding to ZmWAX2 gene associates with quantitative resistance variations to F. verticillioides in maize through a genome-wide association study. A lack of ZmWAX2 compromises maize resistance to F. verticillioides-caused seed rot, seedling blight and stalk rot by reducing cuticular wax deposition, while the transgenic plants overexpressing ZmWAX2 show significantly increased immunity to F. verticillioides. A natural occurrence of two 7-bp deletions within the promoter increases ZmWAX2 transcription, thus enhancing maize resistance to F. verticillioides. Upon Fusarium stalk rot, ZmWAX2 greatly promotes the yield and grain quality of maize. Our studies demonstrate that ZmWAX2 confers multiple disease resistances caused by F. verticillioides and can serve as an important gene target for the development of F. verticillioides-resistant maize varieties.

Discovery of novel sulfonamide chromone-oxime derivatives as potent indoleamine 2,3-dioxygenase 1 inhibitors.

A series of chromone-oxime derivatives containing piperazine sulfonamide moieties were designed, synthesized and evaluated for their inhibitory activities against IDO1. These compounds displayed moderate to good inhibitory activity against IDO1 with IC50 values in low micromolar range. Among them, compound 10m bound effectively to IDO1 with good inhibitory activities (hIDO1 IC50 = 0.64 µM, HeLa IDO1 IC50 = 1.04 µM) and were selected for further investigation. Surface plasmon resonance analysis confirmed the direct interaction between compound 10m and IDO1 protein. Molecular docking study of the most active compound 10m revealed key interactions between 10m and IDO1 in which the chromone-oxime moiety coordinated to the heme iron and formed several hydrogen bonds with the porphyrin ring of heme and ALA264, consistent with the observation by UV-visible spectra that 10m induced a Soret peak shift from 403 to 421 nm. Moreover, compound 10m exhibited no cytotoxicity at its effective concentration in MTT assay. Consistently, in vivo assays results demonstrated that 10m displayed potent antitumor activity with low toxicity in CT26 tumor-bearing Balb/c mice, in comparison with 1-methyl-l-tryptophan (1-MT) and 4-amino-N-(3-chloro-4-fluorophenyl)-N'-hydroxy-1,2,5-oxadiazole-3-carboximidamide (IDO5L). In brief, the results suggested that chromone-oxime derivatives containing sulfonamide moieties might serve as IDO1 inhibitors for the development of new antitumor agents.

Urinary exosomal prostate-specific antigen is a noninvasive biomarker to detect prostate cancer: Not only old wine in new bottles.

The study aimed at evaluating the performance of urinary exosomal prostate-specific antigen (UE-PSA) to predict the results of initial prostate biopsies and discriminate clinically significant prostate cancer (Gleason score ≥ 7, csPCa) from nonsignificant PCa (Gleason score < 7, nsPCa) plus benign patients. Two hundred seventy-two consecutive participants were admitted who underwent a prostate biopsy. The UE-PSA expression was detected by enzyme-linked immunosorbent assay (ELISA). The predictive power and clinical value of UE-PSA was assessed by receiver operating characteristic (ROC), decision curve analysis (DCA) and waterfall plots. UE-PSA was upregulated in PCa compared to benign patients (P < .001) and csPCa compared to nsPCa plus benign patients (P < .001). UE-PSA achieved an AUC of 0.953 (0.905-0.989) in distinguishing PCa from benign patients and an AUC of 0.879 (0.808-0.941) in predicting csPCa from nsPCa plus benign patients. These results were validated in an additional multicenter cohort. In addition, DCA showed that UE-PSA achieved the highest net benefit at almost any threshold probability compared to tPSA and %fPSA. As the waterfall plot showed, the UE-PSA assay could avoid 57.6% (155 cases) and 34.6% (93 cases) unnecessary biopsies while only missing 2.6% (7 cases) and 1.5% (4 cases) of the cases of csPCa at the cutoff value of 90% and 95% sensitivity, respectively. We validated that UE-PSA presented great diagnostic power and clinical utility to diagnose PCa and csPCa. UE-PSA could be a promising noninvasive biomarker to improve PCa detection.

HY5-HDA9 orchestrates the transcription of HsfA2 to modulate salt stress response in Arabidopsis.

Integration of light signaling and diverse abiotic stress responses contribute to plant survival in a changing environment. Some reports have indicated that light signals contribute a plant's ability to deal with heat, cold, and stress. However, the molecular link between light signaling and the salt-response pathways remains unclear. We demonstrate here that increasing light intensity elevates the salt stress tolerance of plants. Depletion of HY5, a key component of light signaling, causes Arabidopsis thaliana to become salinity sensitive. Interestingly, the small heat shock protein (sHsp) family genes are upregulated in hy5-215 mutant plants, and HsfA2 is commonly involved in the regulation of these sHsps. We found that HY5 directly binds to the G-box motifs in the HsfA2 promoter, with the cooperation of HISTONE DEACETYLASE 9 (HDA9), to repress its expression. Furthermore, the accumulation of HDA9 and the interaction between HY5 and HDA9 are significantly enhanced by salt stress. On the contrary, high temperature triggers HY5 and HDA9 degradation, which leads to dissociation of HY5-HDA9 from the HsfA2 promoter, thereby reducing salt tolerance. Under salt and heat stress conditions, fine tuning of protein accumulation and an interaction between HY5 and HDA9 regulate HsfA2 expression. This implies that HY5, HDA9, and HsfA2 play important roles in the integration of light signaling with salt stress and heat shock response.

Metagenomic Sequencing Revealed Differences in the Composition of Cecal Microbes in Different Breeds of Chickens.

Intestinal microorganisms are closely related to the health, development, and production performance of animals and can also provide basic information for us to fully understand and explore the germplasm characteristics and traits of local chicken breeds. In this experiment, we used five local Chinese chicken breeds as research materials; metagenomic sequencing technology was used to explore the differences in the composition of intestinal microorganisms in different breeds, and it was found that each local chicken breed had unique unigenes, of which Silkies had the most, with a total of 12,948. GO and KEGG analyses found that the biological processes most enriched by differential functional genes include genetic coding, macromolecular transport, protein synthesis, and molecular functions such as glycoprotein binding, protein hydrolysis, etc. Each breed is enriched with specific pathways, such as Anyi tile-like gray chickens, which are enriched with pathways related to disease resistance, while Gamecocks' enrichment is related to amino acid metabolism. Random Forest and LEfSe analyses revealed specific species of intestinal microorganisms in the cecum of different breeds, such as Exiguobacterium, which is associated with melanin deposition in Silkies. Therefore, we infer that gut microorganisms are closely related to the formation of chicken breed characteristics, and the results of this experiment can provide a theoretical basis for the discovery of high-quality traits and the improvement of feeding conditions in the future.

CTLs: Killers of intracellular bacteria.

Many microbial pathogens have evolved a range of capabilities to evade host immune defense mechanisms and to survive and multiply in host cells. The presence of host intracellular bacteria makes it difficult for specific antibodies to function. After the intracellular bacteria escape the attack of the innate immune system, such as phagocytes, they survive in cells, and then adaptive immunity comes into play. Cytotoxic T lymphocytes (CTLs) play an important role in eliminating intracellular bacteria. The regulation of key transcription factors could promote CD4+/CD8+ T cells to acquire cytolytic ability. The TCR-CD3 complex transduces activation signals generated by TCR recognition of antigen and promotes CTLs to generate multiple pathways to kill intracellular bacteria. In this review, the mechanism of CD4/CD8 CTLs differentiation and how CD4/CD8 CTLs kill intracellular bacteria are introduced. In addition, their application and prospects in the treatment of bacterial infections are discussed.

Predictors for Treatment Outcomes in Patients with Multi-drug Resistant Tuberculosis - China, 2018-2020.

What is already known about this topic?: Multi-drug resistant tuberculosis (MDR-TB) is a critical global public health problem. What is added by this report?: Sputum cultures and lung images show a strong association with treatment outcomes, serving as a multi-dimensional approach to identify MDR-TB patients with poor outcomes. What are the implications for public health practice?: The results imply that funds and policy investments should be increased by early monitoring of MDR-TB patients, especially regarding imaging and sputum bacterium. By informing physicians on changes to the therapeutic schedule, treatment outcomes can be improved.

Analysis of genome and methylation changes in Chinese indigenous chickens over time provides insight into species conservation.

Conservation of natural resources is a vital and challenging task. Numerous animal genetic resources have been effectively conserved worldwide. However, the effectiveness of conservation programmes and the variation information of species have rarely been evaluated. Here, we performed whole-genome and whole-genome bisulfite sequencing of 90 Chinese indigenous chickens, which belonged to the Tibetan, Wenchang and Bian chicken breeds, and have been conserved under different conservation programmes. We observed that low genetic diversity and high DNA methylation variation occurs during ex situ in vivo conservation, while higher genetic diversity and differentiation occurs during in situ conservation. Further analyses revealed that most DNA methylation signatures are unique within ex situ in vivo conservation. Moreover, a high proportion of differentially methylated regions is found in genomic selection regions, suggesting a link between the effects of genomic variation and DNA methylation. Altogether our findings provide valuable information about genetic and DNA methylation variations during different conservation programmes, and hold practical relevance for species conservation.

Circulating exosomal mRNA signatures for the early diagnosis of clear cell renal cell carcinoma.

BACKGROUND: There are no proven tumor biomarkers for the early diagnosis of clear cell renal cell carcinoma (ccRCC) thus far. This study aimed to identify novel biomarkers of ccRCC based on exosomal mRNA (emRNA) profiling and develop emRNA-based signatures for the early detection of ccRCC. METHODS: Four hundred eighty-eight participants, including 226 localized ccRCCs, 73 patients with benign renal masses, and 189 healthy controls, were recruited. Circulating emRNA sequencing was performed in 12 ccRCCs and 22 healthy controls in the discovery phase. The candidate emRNAs were evaluated with 108 ccRCCs and 70 healthy controls in the test and training phases. The emRNA-based signatures were developed by logistic regression analysis and validated with additional cohorts of 106 ccRCCs, 97 healthy controls, and 73 benign individuals. RESULTS: Five emRNAs, CUL9, KMT2D, PBRM1, PREX2, and SETD2, were identified as novel potential biomarkers of ccRCC. We further developed an early diagnostic signature that comprised KMT2D and PREX2 and a differential diagnostic signature that comprised CUL9, KMT2D, and PREX2 for RCC detection. The early diagnostic signature displayed high accuracy in distinguishing ccRCCs from healthy controls, with areas under the receiver operating characteristic curve (AUCs) of 0.836 and 0.830 in the training and validation cohorts, respectively. The differential diagnostic signature also showed great performance in distinguishing ccRCCs from benign renal masses (AUC = 0.816), including solid masses (AUC = 0.810) and cystic masses (AUC = 0.832). CONCLUSIONS: We established and validated novel emRNA-based signatures for the early detection of ccRCC and differential diagnosis of uncertain renal masses. These signatures could be promising and noninvasive biomarkers for ccRCC detection and thus improve the prognosis of ccRCC patients.

SICKLE represses photomorphogenic development of Arabidopsis seedlings via HY5- and PIF4-mediated signaling.

Arabidopsis CONSTITUTIVELY PHOTOMORPHOGENIC1 (COP1) and PHYTOCHROME INTERACTING FACTORs (PIFs) are negative regulators, and ELONGATED HYPOCOTYL5 (HY5) is a positive regulator of seedling photomorphogenic development. Here, we report that SICKLE (SIC), a proline rich protein, acts as a novel negative regulator of photomorphogenesis. HY5 directly binds the SIC promoter and activates SIC expression in response to light. In turn, SIC physically interacts with HY5 and interferes with its transcriptional regulation of downstream target genes. Moreover, SIC interacts with PIF4 and promotes PIF4-activated transcription of itself. Interestingly, SIC is targeted by COP1 for 26S proteasome-mediated degradation in the dark. Collectively, our data demonstrate that light-induced SIC functions as a brake to prevent exaggerated light response via mediating HY5 and PIF4 signaling, and its degradation by COP1 in the dark avoid too strong inhibition on photomorphogenesis at the beginning of light exposure.

A novel maize microRNA negatively regulates resistance to Fusarium verticillioides.

Although microRNAs (miRNAs) regulate the defence response against multiple pathogenic fungi in diverse plant species, few efforts have been devoted to deciphering the involvement of miRNA in resistance to Fusarium verticillioides, a major pathogenic fungus affecting maize production. In this study, we discovered a novel F. verticillioides-responsive miRNA designated zma-unmiR4 in maize kernels. The expression of zma-unmiR4 was significantly repressed in the resistant maize line but induced in the susceptible lines upon exposure to F. verticillioides exposure, whereas its target gene ZmGA2ox4 exhibited the opposite pattern of expression. Heterologous overexpression of zma-unmiR4 in Arabidopsis resulted in enhanced growth and compromised resistance to F. verticillioides. By contrast, transgenic plants overexpressing ZmGA2ox4 or the homologue AtGA2ox7 showed impaired growth and enhanced resistance to F. verticillioides. Moreover, zma-unmiR4-mediated suppression of AtGA2ox7 disturbed the accumulation of bioactive gibberellin (GA) in transgenic plants and perturbed the expression of a set of defence-related genes in response to F. verticillioides. Exogenous application of GA or a GA biosynthesis inhibitor modulated F. verticillioides resistance in different plants. Taken together, our results suggest that the zma-unmiR4-ZmGA2ox4 module might act as a major player in balancing growth and resistance to F. verticillioides in maize.