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Wheat leaf rust, caused by the obligate biotrophic fungus Puccinia triticina Eriks. (Pt), is one of the most common wheat foliar diseases that continuously threatens global wheat production. Currently, the approaches used to mitigate pathogen infestation include the application of fungicides and the deployment of resistance genes or cultivars. However, the continuous deployment of selected resistant varieties causes host selection pressures that drive Pt evolution and promote the incessant emergence of new virulent races, resulting in the demise of wheat-resistant cultivars after several years of planting. Intriguingly, diploid wheat accessions were found to confer haustorium formation-based resistance to leaf rust, which involves prehaustorial and posthaustorial resistance mechanisms. The prehaustorial resistance in the interaction between einkorn and wheat leaf rust is not influenced by specific races of the pathogen. The induced defense mechanism, known as systemic acquired resistance, also confers durable resistance against a wide array of pathogens. This review summarizes the host range, pathogenic profile, and evolutionary basis of Pt; the molecular basis underlying wheat-Pt interactions; the cloning and characterization of wheat leaf rust resistance genes; prehaustorial and posthaustorial resistance; systemic acquired resistance; and the role of reactive oxygen species. The interplay between climatic factors, genetic features, planting dates, and disease dynamics in imparting resistance is also discussed.

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Systemic acquired resistance (SAR) is a broad-spectrum plant defense phenomena controlled by the salicylic acid receptor NPR1. Key regulators of the SAR signaling pathway showed great potentials to improve crop resistance to various diseases. In our previous investigation, a barley transcription factor gene HvWRKY6 was identified as downstream of NPR1 during SAR. However, the broad-spectrum resistance features and molecular mechanisms of HvWRKY6 remain to be explored. In this study, a transgenic wheat line exogenously expressing HvWRKY6 showed improved resistance to leaf rust, Fusarium crown rot (FCR), and sharp eyespot. The model pathogen Pseudomonas syringae pv. tomato DC3000 was employed to induce the SAR response in wheat plants' leaf region adjacent to the infiltration area. Transcriptome sequencing revealed activation of broad-spectrum defense responses by expressing HvWRKY6 in a pathogen-independent manner. Based on the differentially expressed genes in plant hormone signal transduction, we speculated that the enhanced resistance in HvWRKY6-OE wheat transgenic line was associated with activation of the salicylic acid pathway and suppression of the abscisic acid and jasmonic acid pathways. These findings suggest that the transgenic line HvWRKY6-OE might be applied for the genetic improvement of wheat to several fungal diseases; the underlying resistance mechanism was clarified.

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Plant apoplast serves as the frontier battlefield of plant defense in response to different types of pathogens. Many pathogenesis-related (PR) proteins are accumulated in apoplastic space during the onset of plant-pathogen interaction, where they act to suppress pathogen infection. In this study, we found the expression of Triticum aestivum lipid transfer protein 3 (TaLTP3) gene was unregulated during incompatible interaction mediated by leaf rust resistance genes Lr39/41 at the early infection stage. Stable transgenic wheat lines overexpressing TaLTP3 exhibited enhanced resistance to leaf rust pathogen Puccinia triticina. Transcriptome analysis revealed that overexpression of TaLTP3 specifically activated the transcription of pathogenesis-related protein 1a (TaPR1a) and multiple plant hormone pathways, including salicylic acid (SA), jasmonic acid (JA), and auxin, in response to the infection of the model bacterial pathogen Pseudomonas syringae pv. tomato DC3000. Further investigation indicated that TaLTP3 physically associated with wheat TaPR1a protein in the apoplast. Transgenic wheat lines overexpressing TaLTP3 and TaPR1a showed higher accumulations of reactive oxygen species (ROS) during plant defense responses. All these findings suggested that TaLTP3 is involved in wheat resistance against leaf rust pathogen infection and forming a TaLTP3-TaPR1a complex in apoplast against this pathogen, which provides new insights into the functional roles of PR proteins.

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Due to soil changes, high density planting, and the use of straw-returning methods, wheat common root rot (spot blotch), Fusarium crown rot (FCR), and sharp eyespot (sheath blight) have become severe threats to global wheat production. Only a few wheat genotypes show moderate resistance to these root and crown rot fungal diseases, and the genetic determinants of wheat resistance to these devastating diseases are poorly understood. This review summarizes recent results of genetic studies of wheat resistance to common root rot, Fusarium crown rot, and sharp eyespot. Wheat germplasm with relatively higher resistance are highlighted and genetic loci controlling the resistance to each disease are summarized.

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Clofazimine (CLO) and TBI-166 belong to the riminophenazine class of antimicrobial agent. TBI-166 exhibited promising antituberculosis activity in vitro and in animal models and is currently under phase I clinical development for the treatment of tuberculosis in China. To identify an optimal dosing regimen to support further clinical development of TBI-166, the efficacies of CLO and TBI-166 were evaluated in two aerosol infection models utilizing BALB/c and C3HeB/FeJNju mice. TBI-166 and CLO were dosed at 20 mg/kg daily for 2 weeks, followed by QD (once daily), TIW (thrice weekly), and BIW (twice weekly) for an additional 10 weeks at the same dose level. The bactericidal activities of TBI-166 and clofazimine via QD, TIW, and BIW dosing regimens were determined after treatment. Once-daily administration of CLO and TBI-166 appeared to be more efficacious than the two intermittent dosing regimens. Once-daily administration of TBI-166 increased the bactericidal activity by approximately 1 log10 CFU in the lung and spleen compared with TIW or BIW dosing after 12 weeks of treatment, while once-daily administration of CLO increased the bactericidal activity by 1.27 to 1.90 log10 CFU/lung and by 1.61 to 2.22 log10 CFU/spleen in the BALB/c mouse model compared to the intermittent therapies. The differences between QD and TIW and between QD and BIW were significant (P < 0.05). The data suggest that accumulated total doses correlate with the log10 CFU reductions. Therefore, intermittent administration of TBI-166 and CLO should be further evaluated at the same accumulated total doses in preclinical and clinical studies.

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A piperazine-containing benzothiazinones lead compound PBTZ169, served as DprE1 inhibitor, displays nanomolar bactericidal activity against Mycobacteria tuberculosis. Here, we systematically evaluate anti-tuberculosis activity of one of PBTZ169 analogues, TZY-5-84, in vitro and in vivo. The MIC value of TZY-5-84 against M. tuberculosis H37Rv ranged from 0.014 to 0.015 mg/L, lower than those of INH, RFP and BDQ. Five susceptible and thirteen drug-resistant clinical isolates were also susceptive to TZY-5-84. It had anti-tuberculosis activity against intracellular bacilli in infected macrophage model. It exhibited its activity in time-dependent manner and against intracellular bacilli in infected macrophage cells. However, the MIC of TZY-5-84 against three laboratory PBTZ169-induced resistant isolates increased four-fold increment compared to that of H37Rv. No antagonism was observed in any combination between TZY-5-84 and seven commonly used anti-tuberculosis drugs in an in vitro checkerboard assay. In murine infection model, TZY-5-84 at lower dosage (12.5 mg/kg) was found to be comparatively efficacious as PBTZ169 at 25 mg/kg. Our research suggests TZY-5-84 can be a promising preclinical candidate for further study on TB treatment.

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PURPOSE: Linezolid (LZD) and pretomanid (PA-824) are promising candidates in regimens for the treatment of drug-resistant tuberculosis. However, research on LZD and PA-824 dual drug-resistant (LPDR) strains is rarely reported. This study aimed to investigate the genotypic and virulence characteristics of LPDR strains. METHODS: To obtain the LPDR strains (marked as LP or PL strains), we used a two-way induction method, namely, we first induced LZD- or PA-824-resistant mutants from the parental Mycobacterium tuberculosis (MTB) strain H37Rv in vitro, then we obtained the LPDR strains from induction of LZD- or PA-824-resistant mutants. Mutations in rplC, rrl, or ddn and fgd1 were identified in all mutants. To investigate the virulence of these strains, six strains were selected as representative strains, including LZD-resistant strains, PA-824-resistant strains and LPDR strains. We performed the animal survival study as virulence of MTB can be measured as survival time of an animal after being infected. RESULTS: We induced 38 mutant strains of LZD and PA-824 mono or dual drug resistance from H37Rv in vitro. The mutation frequency of rplC (C154R) gene in LPDR strains was 100% and 86%, respectively. In the animal survival study, animals infected with different drug-resistant strains survived significantly longer than those infected with H37Rv; animals infected with LPDR strains and PA-824-resistant strains survived similarly and both of which survived significantly shorter than those infected with LZD-resistant strains. CONCLUSION: Our study showed that rplC gene had a high mutation frequency in LPDR strains. The virulence of LPDR strains was similar to PA-824-resistant strains, and the virulence of the LZD-resistant strains was weaker than PA-824-resistant strains.

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Puccinia triticina (Pt), the causal agent of wheat leaf rust, is one of the most destructive fungal pathogens threatening global wheat cultivations. The rational utilization of leaf rust resistance (Lr) genes is still the most efficient method for the control of such diseases. The Lr47 gene introgressed from chromosome 7S of Aegilops speltoides still showed high resistance to the majority of Pt races collected in China. However, the Lr47 gene has not been cloned yet, and the regulatory network of the Lr47-mediated resistance has not been explored. In the present investigation, transcriptome analysis was applied on RNA samples from three different wheat lines ("Yecora Rojo", "UC1037", and "White Yecora") carrying the Lr47 gene three days post-inoculation with the epidemic Pt race THTT. A comparison between Pt-inoculated and water-inoculated "Lr47-Yecora Rojo" lines revealed a total number of 863 upregulated (q-value < 0.05 and log2foldchange > 1) and 418 downregulated (q-value < 0.05 and log2foldchange < -1) genes. Specifically, differentially expressed genes (DEGs) located on chromosomes 7AS, 7BS, and 7DS were identified, ten of which encoded receptor-like kinases (RLKs). The expression patterns of these RLK genes were further determined by a time-scale qRT-PCR assay. Moreover, heatmaps for the expression profiles of pathogenesis-related (PR) genes and several transcription factor gene families were generated. Using a transcriptomic approach, we initially profiled the transcriptional changes associated with the Lr47-mediated resistance. The identified DEGs, particularly those genes encoding RLKs, might serve as valuable genetic resources for the improvement of wheat resistance to Pt.

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Autophagy is an evolutionarily conserved pathway in which cytoplasmic contents are degraded and recycled. This study found that submicromolar concentrations of urolithin A, a major polyphenol metabolite, induced autophagy in SW620 colorectal cancer (CRC) cells. Exposure to urolithin A also dose-dependently decreased cell proliferation, delayed cell migration, and decreased matrix metalloproteinas-9 (MMP-9) activity. In addition, inhibition of autophagy by Atg5-siRNA, caspases by Z-VAD-FMK suppressed urolithin A-stimulated cell death and anti-metastatic effects. Micromolar urolithin A concentrations induced both autophagy and apoptosis. Urolithin A suppressed cell cycle progression and inhibited DNA synthesis. These results suggest that dietary consumption of urolithin A could induce autophagy and inhibit human CRC cell metastasis. Urolithins may thus contribute to CRC treatment and offer an alternative or adjunct chemotherapeutic agent to combat this disease.

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