Multi-Omics profiling identifies aldehyde dehydrogenase 2 as a critical mediator in the crosstalk between Treg-mediated immunosuppression microenvironment and hepatocellular carcinoma.

Dysregulation of the aldehyde dehydrogenase (ALDH) family has been implicated in various pathological conditions, including cancer. However, a systematic evaluation of ALDH alterations and their therapeutic relevance in hepatocellular carcinoma (HCC) remains lacking. Herein, we found that 15 of 19 ALDHs were transcriptionally dysregulated in HCC tissues compared to normal liver tissues. A four gene signature, including ALDH2, ALDH5A1, ALDH6A1, and ALDH8A1, robustly predicted prognosis and defined a high-risk subgroup exhibiting immunosuppressive features like regulatory T cell (Tregs) infiltration. Single-cell profiling revealed selective overexpression of tumor necrosis factor receptor superfamily member 18 (TNFRSF18) on Tregs, upregulated in high-risk HCC patients. We identified ALDH2 as a tumor suppressor in HCC, with three novel phosphorylation sites mediated by protein kinase C zeta that enhanced enzymatic activity. Mechanistically, ALDH2 suppressed Tregs differentiation by inhibiting ß-catenin/TGF-ß1 signaling in HCC. Collectively, our integrated multi-omics analysis defines an ALDH-Tregs-TNFRSF18 axis that contributes to HCC pathogenesis and represents potential therapeutic targets for this aggressive malignancy.

Chiral coordination polymer nanowires boost radiation-induced in situ tumor vaccination.

Radiation-induced in situ tumor vaccination alone is very weak and insufficient to elicit robust antitumor immune responses. In this work, we address this issue by developing chiral vidarabine monophosphate-gadolinium nanowires (aAGd-NWs) through coordination-driven self-assembly. We elucidate the mechanism of aAGd-NW assembly and characterize their distinct features, which include a negative surface charge, ultrafine topography, and right-handed chirality. Additionally, aAGd-NWs not only enhance X-ray deposition but also inhibit DNA repair, thereby enhancing radiation-induced in situ vaccination. Consequently, the in situ vaccination induced by aAGd-NWs sensitizes radiation enhances CD8+ T-cell-dependent antitumor immunity and synergistically potentiates the efficacy immune checkpoint blockade therapies against both primary and metastatic tumors. The well-established aAGd-NWs exhibit exceptional therapeutic capacity and biocompatibility, offering a promising avenue for the development of radioimmunotherapy approaches.

Role and Mechanism of Growth Differentiation Factor 15 in Chronic Kidney Disease.

GDF-15 is an essential member of the transforming growth factor-beta superfamily. Its functions mainly involve in tissue injury, inflammation, fibrosis, regulation of appetite and weight, development of tumor, and cardiovascular disease. GDF-15 is involved in various signaling pathways, such as MAPK pathway, PI3K/AKT pathway, STAT3 pathway, RET pathway, and SMAD pathway. In addition, several factors such as p53, ROS, and TNF-α participate the regulation of GDF-15. However, the specific mechanism of these factors regulating GDF-15 is still unclear and more research is needed to explore them. GDF-15 mainly improves the function of kidneys in CKD and plays an important role in the prediction of CKD progression and cardiovascular complications. In addition, the role of GDF-15 in the kidney may be related to the SMAD and MAPK pathways. However, the specific mechanism of these pathways remains unclear. Accordingly, more research on the specific mechanism of GDF-15 affecting kidney disease is needed in the future. In conclusion, GDF-15 may be a therapeutic target for kidney disease.

Proteogenomic characterization of difficult-to-treat breast cancer with tumor cells enriched through laser microdissection.

BACKGROUND: Breast cancer (BC) is the most commonly diagnosed cancer and the leading cause of cancer death among women globally. Despite advances, there is considerable variation in clinical outcomes for patients with non-luminal A tumors, classified as difficult-to-treat breast cancers (DTBC). This study aims to delineate the proteogenomic landscape of DTBC tumors compared to luminal A (LumA) tumors. METHODS: We retrospectively collected a total of 117 untreated primary breast tumor specimens, focusing on DTBC subtypes. Breast tumors were processed by laser microdissection (LMD) to enrich tumor cells. DNA, RNA, and protein were simultaneously extracted from each tumor preparation, followed by whole genome sequencing, paired-end RNA sequencing, global proteomics and phosphoproteomics. Differential feature analysis, pathway analysis and survival analysis were performed to better understand DTBC and investigate biomarkers. RESULTS: We observed distinct variations in gene mutations, structural variations, and chromosomal alterations between DTBC and LumA breast tumors. DTBC tumors predominantly had more mutations in TP53, PLXNB3, Zinc finger genes, and fewer mutations in SDC2, CDH1, PIK3CA, SVIL, and PTEN. Notably, Cytoband 1q21, which contains numerous cell proliferation-related genes, was significantly amplified in the DTBC tumors. LMD successfully minimized stromal components and increased RNA-protein concordance, as evidenced by stromal score comparisons and proteomic analysis. Distinct DTBC and LumA-enriched clusters were observed by proteomic and phosphoproteomic clustering analysis, some with survival differences. Phosphoproteomics identified two distinct phosphoproteomic profiles for high relapse-risk and low relapse-risk basal-like tumors, involving several genes known to be associated with breast cancer oncogenesis and progression, including KIAA1522, DCK, FOXO3, MYO9B, ARID1A, EPRS, ZC3HAV1, and RBM14. Lastly, an integrated pathway analysis of multi-omics data highlighted a robust enrichment of proliferation pathways in DTBC tumors. CONCLUSIONS: This study provides an integrated proteogenomic characterization of DTBC vs LumA with tumor cells enriched through laser microdissection. We identified many common features of DTBC tumors and the phosphopeptides that could serve as potential biomarkers for high/low relapse-risk basal-like BC and possibly guide treatment selections.

Arbuscular mycorrhiza and plant growth promoting endophytes facilitates accumulation of saponin under moderate drought stress.

Objective: Paris polyphylla var. yunnanensis, one of the important medicinal plant resources in Yunnan, China, usually takes 6-8 years to be harvested. Therefore, it is urgent to find a method that can not only shorten its growth years, but also improve its quality. In this study, we examined the effects of a combination treatment of arbuscular mycorrhizal fungi (AMF) and plant growth-promoting endophytes (PGPE) and drought stress on the accumulation of saponins in it. Methods: P. polyphylla var. yunnanensis was infected with a mixture of AMF and PGPE under drought stress. The content of saponins, as well as morphological, physiological, and biochemical indicators, were all measured. The UGTs gene related to saponin synthesis was obtained from transcriptome data by homologous comparison, which were used for RT-PCR and phylogenetic analysis. Results: Regardless of water, AMF treatment could infect the roots of P. polyphylla var. yunnanensis, however double inoculation with AMF and PGPE (AMF + PGPE) would reduce the infection rate of AMF. Plant height, aboveground and underground fresh weight did not differ significantly between the single inoculation AMF and the double inoculation treatment under different water conditions, but the inoculation treatment significantly increased the plant height of P. polyphylla var. yunnanensis compared to the non-inoculation treatment. Single inoculation with AMF considerably increased the net photosynthetic rate, stomatal conductance, and transpiration rate of P. polyphylla var. yunnanensis leaves under various water conditions, but double inoculation with AMF + PGPE greatly increased the intercellular CO2 concentration and chlorophyll fluorescence parameter (Fv/Fm). Under diverse water treatments, single inoculation AMF had the highest proline content, whereas double inoculation AMF + PGPE may greatly improve the amount of abscisic acid (ABA) and indoleacetic acid (IAA) compared to normal water under moderate drought. Double inoculation AMF + PGPE treatment improved the proportion of N, P, and K in the rhizome of P. polyphylla var. yunnanensis under various water conditions. Under moderate drought stress, AMF + PGPE significantly enhanced the contents of P. polyphylla var. yunnanensis saponins I, II, VII, and total saponins as compared to normal water circumstances. Farnesyl diphosphate synthase (FPPS), Geranyl pyrophosphate synthase (GPPS), Cycloartenol synthase (CAS), and Squalene epoxidase (SE1) were the genes that were significantly up-regulated at the same time. The amount of saponins was favorably linked with the expression of CAS, GPPS, and SE1. Saponin VI content and glycosyl transferase (UGT) 010922 gene expression were found to be substantially associated, as was saponin II content and UGT010935 gene expression. Conclusion: Under moderate drought, AMF + PGPE was more conducive to the increase of hormone content, nutrient absorption, and total saponin content in P. polyphylla var. yunnanensis, and AMF + PGPE could up regulate the expression of key genes and UGTs genes in one or more steroidal saponin synthesis pathways to varying degrees, thereby stimulating the synthesis and accumulation of steroidal saponins in the rhizome of P. polyphylla var. yunnanensis. The combination of AMF and PGPE inoculation, as well as adequate soil drought, reduced the buildup of saponins in P. polyphylla var. yunnanensis and increased its quality.

Cell-free Nucleic Acid as Promising Diagnostic Biomarkers for Gastric Cancer: a Systematic Review.

Background: Gastric cancer (GC) is a common malignancy with early detection being crucial for survival. Liquid biopsy analysis using cell-free nucleic acid is a preferred method for detection. Hence, we conducted a systematic review to assess the diagnostic efficacy of cell-free nucleic acid markers for GC. Methods: We searched PubMed and ISI Web of Science databases for articles that conformed to our inclusion and exclusion criteria from 2012 to 2022. The following information was abstracted: first author, year of publication, country/region, age, male proportion, tumor stage for cases, specimen type, measurement method, targeted markers and diagnostic related indicators (including sensitivity, specificity, AUC, P-value). Results: Fifty-eight studies examined cell-free RNAs (cfRNAs) with a total of 62 individual circulating markers and 7 panels in serum or plasma, while 21 studies evaluated cell-free DNAs (cfDNAs) with 29 individual circulating markers and 7 panels. For individual cfRNAs, the median (range) sensitivity and specificity were 80% (21% - 98%) and 80% (54% - 99%), respectively. The median (range) sensitivity and specificity for cfRNA panels were 86% (83% - 90%) and 75% (60% - 98%), respectively. In comparison, the median (range) sensitivity and specificity reported for individual cfDNAs were 50% (18% - 96%) and 93% (57% - 100%), respectively, while cfDNA panels had a median (range) sensitivity and specificity of 85% (41% - 92%) and 73.5% (38% - 90%), respectively. The meta results indicate that cfRNA markers exhibit high sensitivity (80%) and low specificity (80%) for detecting GC, while cfDNA markers have lower sensitivity (59%) but higher specificity (92%). Conclusions: This review has demonstrated that cell-free nucleic acids have the potential to serve as useful diagnostic markers for GC. Given that both cfRNA and cfDNA markers have shown promising diagnostic performance for GC, the combination of the two may potentially enhance diagnostic efficiency.

Lysosomal-targeted fluorescent probe based pH regulating reactivity for tracking cysteine dynamics under oxidative stress.

The ability to detect and visualize cellular events and associated biological analytes is essential for the understanding of their physiological and pathological functions. Cysteine (Cys) plays a crucial role in biological systems and lysosomal homeostasis. This puts forward higher requirements on the performance of the probe. Herein, we rationally designed a coumarin-based probe for the reversible, specific, sensitive, and rapid detection of Cys based on pH regulating reactivity. The obtained probe (ECMA) introduces a morpholine moiety to target lysosomes, and α,ß-unsaturated-ketone with an electron-withdrawing CN group served as a reversible reaction site for Cys. Importantly, ECMA was successfully applied to the real-time monitoring of Cys dynamics in living cells. Furthermore, cell imaging clearly revealed that exogenous Cys could induce the up-regulation of lysosomal ROS, which provided a powerful tool for investigating the relationship between oxidative stress and lysosomal Cys.

Comparison of Different Fusion Radiomics for Predicting Benign and Malignant Sacral Tumors: A Pilot Study.

Differentiating between benign and malignant sacral tumors is crucial for determining appropriate treatment options. This study aims to develop two benchmark fusion models and a deep learning radiomic nomogram (DLRN) capable of distinguishing between benign and malignant sacral tumors using multiple imaging modalities. We reviewed axial T2-weighted imaging (T2WI) and non-contrast computed tomography (NCCT) of 134 patients pathologically confirmed as sacral tumors. The two benchmark fusion models were developed using fusion deep learning (DL) features and fusion classical machine learning (CML) features from multiple imaging modalities, employing logistic regression, K-nearest neighbor classification, and extremely randomized trees. The two benchmark models exhibiting the most robust predictive performance were merged with clinical data to formulate the DLRN. Performance assessment involved computing the area under the receiver operating characteristic curve (AUC), sensitivity, specificity, accuracy, negative predictive value (NPV), and positive predictive value (PPV). The DL benchmark fusion model demonstrated superior performance compared to the CML fusion model. The DLRN, identified as the optimal model, exhibited the highest predictive performance, achieving an accuracy of 0.889 and an AUC of 0.961 in the test sets. Calibration curves were utilized to evaluate the predictive capability of the models, and decision curve analysis (DCA) was conducted to assess the clinical net benefit of the DLR model. The DLRN could serve as a practical predictive tool, capable of distinguishing between benign and malignant sacral tumors, offering valuable information for risk counseling, and aiding in clinical treatment decisions.

circ_WASF2 regulates ferroptosis by miR-634/ GPX4 signaling in pancreatic cancer.

PURPOSE: Pancreatic cancer (PC) is one of the most lethal malignant gastrointestinal tumors (GI) characterized by a poor prognosis. Ferroptosis is an emerging programmed cell death that plays an essential role in the progression of various cancers. Ferroptosis is driven by iron-dependent phospholipid peroxidation and is regulated by mitochondrial activity, lipid peroxidation, and reactive oxygen species (ROS). The function and mechanism of ferroptosis in PC need more research. METHODS: The levels of circRNAs, miRNAs, and mRNAs were detected by quantitative real-time polymerase chain reaction (qRT-PCR). Western blot was used for protein detection. CCK8 assays were used to detect cell proliferation. Cell death, lipid peroxidation, ROS, and Fe2+ were detected by indicted kits. Dual-luciferase reporter and RNA pull-down assays were conducted to confirm the interaction between circRNAs, miRNAs, and mRNAs. RESULTS: In this research, we found that circular RNA hsa_circ_0000003(circ_WASF2) was upregulated in pancreatic cancer cells. The silence of circ_WASF2 inhibited cancer proliferation and increased cell death by increasing ferroptosis accompanied by up-regulation of lipid peroxidation, ROS, and Fe2+. Further studies showed that circ_WASF2 could attenuate ferroptosis by targeting miR-634 and the downstream glutathione peroxidase 4 (GPX4). GPX4 has been well-reported as a central factor in ferroptosis. Our research revealed a new pathway for regulating ferroptosis in PC. CONCLUSION: In summary, we have determined that circ_WASF2/miR-634/GPX4 contributed to ferroptosis-induced cell death, and provided a possible therapeutic target in PC.

AKAP8 promotes ovarian cancer progression and antagonizes PARP inhibitor sensitivity through regulating hnRNPUL1 transcription.

Ovarian cancer (OC) is the highest worldwide cancer mortality cause among gynecologic tumors, but its underlying molecular mechanism remains largely unknown. Here, we report that the RNA binding protein A-kinase anchoring protein 8 (AKAP8) is highly expressed in ovarian cancer and predicts poor prognosis for ovarian cancer patients. AKAP8 promotes ovarian cancer progression through regulating cell proliferation and metastasis. Mechanically, AKAP8 is enriched at chromatin and regulates the transcription of the specific hnRNPUL1 isoform. Moreover, AKAP8 phase separation modulates the hnRNPUL1 short isoform transcription. Ectopic expression of the hnRNPUL1 short isoform could partially rescue the growth inhibition effect of AKAP8-knockdown in ovarian cancer cells. In addition, AKAP8 modulates PARP1 expression through hnRNPUL1, and AKAP8 inhibition enhances PAPR inhibitor cytotoxicity in ovarian cancer. Together, our study uncovers the crucial function of AKAP8 condensation-mediated transcription regulation, and targeting AKAP8 could be potential for improvement of ovarian cancer therapy.

Transcatheter arterial perfusion chemotherapy combined with lipiodol chemoembolization for advanced colorectal cancer complicated by obstruction.

Background: Obstruction is a common complication of advanced colorectal cancer. This study was aimed at investigating the safety, efficacy, and feasibility of transcatheter arterial perfusion chemotherapy combined with lipiodol chemoembolization for treating advanced colorectal cancer complicated by obstruction. Patients and methods: This retrospective analysis was conducted using clinical data of patients with advanced colorectal cancer who received arterial infusion chemotherapy combined with lipiodol chemoembolization treatment at our center. Treatment efficacy was evaluated in terms of obstruction-free survival and overall survival, and treatment complications were monitored. Results: Fifty-four patients with colorectal cancer complicated by obstruction were included. All patients successfully underwent transcatheter arterial infusion combined with lipiodol chemoembolization treatment. The average lipiodol dose administered was 2.62 ± 1.45 ml (0.5-5.5 ml). No serious complications such as perforation or tumor dissemination occurred. The clinical success rate was 83.3% (45/54). One month after treatment, the objective response rate (ORR) and disease control rate (DCR) were 66.67% and 88.9%, respectively. The median obstruction-free survival was 5.0 months. No serious adverse events occurred. As of the last follow-up, 6 patients survived, 44 died, and 4 were lost to follow-up. Conclusion: Our findings revealed that transcatheter arterial infusion chemotherapy combined with lipiodol chemoembolization is safe and effective for treating advanced colorectal cancer complicated by obstruction. It may serve as a new treatment strategy for patients with advanced colorectal cancer complicated by obstruction.

Engineering non-conventional yeast Rhodotorula toruloides for ergothioneine production.

BACKGROUND: Ergothioneine (EGT) is a distinctive sulfur-containing histidine derivative, which has been recognized as a high-value antioxidant and cytoprotectant, and has a wide range of applications in food, medical, and cosmetic fields. Currently, microbial fermentation is a promising method to produce EGT as its advantages of green environmental protection, mild fermentation condition, and low production cost. However, due to the low-efficiency biosynthetic process in numerous cell factories, it is still a challenge to realize the industrial biopreparation of EGT. The non-conventional yeast Rhodotorula toruloides is considered as a potential candidate for EGT production, thanks to its safety for animals and natural ability to synthesize EGT. Nevertheless, its synthesis efficiency of EGT deserves further improvement. RESULTS: In this study, out of five target wild-type R. toruloides strains, R. toruloides 2.1389 (RT1389) was found to accumulate the highest EGT production, which could reach 79.0 mg/L at the shake flask level on the 7th day. To achieve iterative genome editing in strain RT1389, CRISPR-assisted Cre recombination (CACR) method was established. Based on it, an EGT-overproducing strain RT1389-2 was constructed by integrating an additional copy of EGT biosynthetic core genes RtEGT1 and RtEGT2 into the genome, the EGT titer of which was 1.5-fold increase over RT1389. As the supply of S-adenosylmethionine was identified as a key factor determining EGT production in strain RT1389, subsequently, a series of gene modifications including S-adenosylmethionine rebalancing were integrated into the strain RT1389-2, and the resulting mutants were rapidly screened according to their EGT production titers with a high-throughput screening method based on ergothionase. As a result, an engineered strain named as RT1389-3 was selected with a production titer of 267.4 mg/L EGT after 168 h in a 50 mL modified fermentation medium. CONCLUSIONS: This study characterized the EGT production capacity of these engineered strains, and demonstrated that CACR and high-throughput screening method allowed rapid engineering of R. toruloides mutants with improved EGT production. Furthermore, this study provided an engineered RT1389-3 strain with remarkable EGT production performance, which had potential industrial application prospects.

Cascade Nanoreactor Employs Mitochondrial-Directed Chemodynamic and δ-ALA-Mediated Photodynamic Synergy for Deep-Seated Oral Cancer Therapy.

The management of oral squamous cell carcinoma (OSCC) poses significant challenges, leading to organ impairment and ineffective treatment of deep-seated tumors, adversely affecting patient prognosis. A cascade nanoreactor that integrates photodynamic therapy (PDT) and chemodynamic therapy (CDT) for comprehensive multimodal OSCC treatment is introduced. Utilizing iron oxide and mesoporous silica, the FMMSH drug delivery system, encapsulating the photosensitizer prodrug δ-aminolevulinic acid (δ-ALA), is developed. Triphenylphosphine (TPP) modification facilitates mitochondrial targeting, while tumor cell membrane (TCM) coating provides homotypic targeting. The dual-targeting δ-ALA@FMMSH-TPP-TCM demonstrate efficacy in eradicating both superficial and deep tumors through synergistic PDT/CDT. Esterase overexpression in OSCC cells triggers δ-ALA release, and excessive hydrogen peroxide in tumor mitochondria undergoes Fenton chemistry for CDT. The synergistic interaction of PDT and CDT increases cytotoxic ROS levels, intensifying oxidative stress and enhancing apoptotic mechanisms, ultimately leading to tumor cell death. PDT/CDT-induced apoptosis generates δ-ALA-containing apoptotic bodies, enhancing antitumor efficacy in deep tumor cells. The anatomical accessibility of oral cancer emphasizes the potential of intratumoral injection for precise and localized treatment delivery, ensuring focused therapeutic agent delivery to maximize efficacy while minimizing side effects. Thus, δ-ALA@FMMSH-TPP-TCM, tailored for intratumoral injection, emerges as a transformative modality in OSCC treatment.

Integration analysis of single-cell transcriptome reveals specific monocyte subsets associated with melanoma brain and leptomeningeal metastasis.

BACKGROUND: Melanoma central nervous system (CNS) metastasis remains a leading cause of patient mortality, and the underlying pathological mechanism has not been fully elucidated, leading to a lack of effective therapeutic strategies. MATERIALS AND METHODS: In this study, we conducted an integrated analysis of single-cell transcriptomic data related to melanoma brain metastasis (MBM) and leptomeningeal metastasis (LMM). We focused on differences of subset composition and molecular expression of monocytes in blood, primary tumor, brain metastases, and leptomeningeal metastases. RESULTS: Significant differences were observed among monocytes in blood, primary tumor, and different CNS metastatic tissues, particularly in terms of subset differentiation and gene expression patterns. Subsequent analysis revealed the upregulation of cell proportions of six monocyte subsets in brain metastasis and leptomeningeal metastasis. Based on differential gene analysis, four of these subsets exhibited increased expression of factors promoting tumor migration and survival, including AREG+ monocytes (AREG, EREG, THBS1), FABP5+ monocytes (SPP1, CCL2, CTSL), and CXCL3+ monocytes (CXCL3, IL8, IL1B). The proportions of TPSB2+ monocytes (IL32, CCL5) were notably elevated in melanoma leptomeningeal metastasis tissues. Pathway analysis indicated the activation of signaling pathways such as NOD-like receptors, NFκB, and Toll-like receptors in these metastasis-related subsets. CONCLUSION: Our findings elucidate that AREG+, FABP5+ and CXCL3+ monocytes are associated with brain metastasis and TPSB2+ monocytes are associated with leptomeningeal metastasis in melanoma, which may be contribute to the development of therapeutic strategies focusing on monocytes or cytokines for melanoma CNS metastasis.

Proteome-wide association study and functional validation identify novel protein markers for pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) remains a lethal malignancy, largely due to the paucity of reliable biomarkers for early detection and therapeutic targeting. Existing blood protein biomarkers for PDAC often suffer from replicability issues, arising from inherent limitations such as unmeasured confounding factors in conventional epidemiologic study designs. To circumvent these limitations, we use genetic instruments to identify proteins with genetically predicted levels to be associated with PDAC risk. Leveraging genome and plasma proteome data from the INTERVAL study, we established and validated models to predict protein levels using genetic variants. By examining 8,275 PDAC cases and 6,723 controls, we identified 40 associated proteins, of which 16 are novel. Functionally validating these candidates by focusing on 2 selected novel protein-encoding genes, GOLM1 and B4GALT1, we demonstrated their pivotal roles in driving PDAC cell proliferation, migration, and invasion. Furthermore, we also identified potential drug repurposing opportunities for treating PDAC. SIGNIFICANCE: PDAC is a notoriously difficult-to-treat malignancy, and our limited understanding of causal protein markers hampers progress in developing effective early detection strategies and treatments. Our study identifies novel causal proteins using genetic instruments and subsequently functionally validates selected novel proteins. This dual approach enhances our understanding of PDAC etiology and potentially opens new avenues for therapeutic interventions.

Lactic acid induced defense responses in tobacco against Phytophthora nicotianae.

Induced resistance is considered an eco-friendly disease control strategy, which can enhance plant disease resistance by inducing the plant's immune system to activate the defense response. In recent years, studies have shown that lactic acid can play a role in plant defense against biological stress; however, whether lactic acid can improve tobacco resistance to Phytophthora nicotianae, and its molecular mechanism remains unclear. In our study, the mycelial growth and sporangium production of P. nicotianae were inhibited by lactic acid in vitro in a dose-dependent manner. Application of lactic acid could reduce the disease index, and the contents of total phenol, salicylic acid (SA), jasmonic acid (JA), lignin and H2O2, catalase (CAT) and phenylalanine ammonia-lyase (PAL) activities were significantly increased. To explore this lactic acid-induced protective mechanism for tobacco disease resistance, RNA-Seq analysis was used. Lactic acid enhances tobacco disease resistance by activating Ca2+, reactive oxygen species (ROS) signal transduction, regulating antioxidant enzymes, SA, JA, abscisic acid (ABA) and indole-3-acetic acid (IAA) signaling pathways, and up-regulating flavonoid biosynthesis-related genes. This study demonstrated that lactic acid might play a role in inducing resistance to tobacco black shank disease; the mechanism by which lactic acid induces disease resistance includes direct antifungal activity and inducing the host to produce direct and primed defenses. In conclusion, this study provided a theoretical basis for lactic acid-induced resistance and a new perspective for preventing and treating tobacco black shank disease.

Pore structure characterization and its influence on aqueous phase trapping damage in tight gas sandstone reservoirs.

Aqueous phase trapping (APT), which is one of the most prominent damages, seriously restricts the natural gas production in tight gas sandstone with low permeability. Pore size and microscopic pore structures are the most important factors to determine the water blocking damage. In this paper, 9 core samples from tight gas sandstone with various physical properties were employed, and the pore size distribution (PSD) of the core samples were investigated by high pressure mercury intrusion tests (HPMI). Results showed that the porosity of core samples ranges from 5.68% to 13.7%, and the permeability ranges from 0.00456 to 7.86 mD, which is a typical tight reservoir with strong heterogeneity. According to the HPMI capillary curve, the cores can be divided into two types: Type I and Type II, and the pore sizes of type I are larger than that of type II. Fractal distributions were obtained using HPMI data to further determine the pore structure characteristics of tight reservoirs. The pore structures of tight sandstones display the multifractal fractal feature: D1 corresponding to macro-pores, and D2 corresponding to fractal dimension of micro-pores. Furthermore, APT damage was determined by the permeability recovery ratios (Kr) after gas flooding tests. The correlation of Kr and PSD and fractal dimensions were jointly analyzed in tight gas sandstone. Although positive correlations between pore size parameters and the permeability recovery ratios were observed with relatively weak correlations, for those core samples with very close permeability, pore size parameters (both permeability and PSD) is inadequate in clarifying this damage. The fractal dimension can well describe the complexity and heterogeneity of flow channels in pores, which can become the determining factor to distinguish the flow capacity of tight sandstone. The D2 for samples of type I and type II exhibited a good negative relation with Kr with a correlation coefficient of 0.9878 and 0.7723, respectively. The significance of this finding is that for tight gas sandstone, fractal dimensions, especially the small pore fractal dimension (D2), can be used to predict the possible APT damage very well.

Correction: Identification of serum prognostic marker miRNAs and construction of microRNA-mRNA networks of esophageal cancer.

[This corrects the article DOI: 10.1371/journal.pone.0255479.].