Pyrene-Alkyne-Based Conjugated Porous Polymers with Skeleton Distortion-Mediated ⋠O2 - and 1O2 Generation for High-Selectivity Organic Photosynthesis.

Reactive oxygen species (ROS) play a crucial role in determining photocatalytic reaction pathways, intermediate species, and product selectivity. However, research on ROS regulation in polymer photocatalysts is still in its early stages. Herein, we successfully achieved series of modulations to the skeleton of Pyrene-alkyne-based (Tetraethynylpyrene (TEPY)) conjugated porous polymers (CPPs) by altering the linkers (1,4-dibromobenzene (BE), 4,4'-dibromobiphenyl (IP), and 3,3'-dibromobiphenyl (BP)). Experiments combined with theoretical calculations indicate that BE-TEPY exhibits a planar structure with minimal exciton binding energy, which favors exciton dissociation followed by charge transfer with adsorbed O2 to produce ⋅O2 -. Thus BE-TEPY shows optimal photocatalytic activity for phenylboronic acid oxidation and [3+2] cycloaddition. Conversely, the skeleton of BP-TEPY is significantly distorted. Its planar conjugation decreases, intersystem crossing (ISC) efficiency increases, which makes it more prone for resonance energy transfer to generate 1O2. Therefore, BP-TEPY displays best photocatalytic activity in [4+2] cycloaddition and thioanisole oxidation. Both above reactant conversion and its product selectivity exceed 99 %. This work systematically reveals the intrinsic structure-activity relationship among the skeleton structure of CPPs, excitonic behavior, and selective generation of ROS, providing new insights for the rational design of highly efficient and selective CPPs photocatalysts.

Rice false smut virulence protein subverts host chitin perception and signaling at lemma and palea for floral infection.

The flower-infecting fungus Ustilaginoidea virens causes rice false smut, which is a severe emerging disease threatening rice (Oryza sativa) production worldwide. False smut not only reduces yield, but more importantly produces toxins on grains, posing a great threat to food safety. U. virens invades spikelets via the gap between the 2 bracts (lemma and palea) enclosing the floret and specifically infects the stamen and pistil. Molecular mechanisms for the U. virens-rice interaction are largely unknown. Here, we demonstrate that rice flowers predominantly employ chitin-triggered immunity against U. virens in the lemma and palea, rather than in the stamen and pistil. We identify a crucial U. virens virulence factor, named UvGH18.1, which carries glycoside hydrolase activity. Mechanistically, UvGH18.1 functions by binding to and hydrolyzing immune elicitor chitin and interacting with the chitin receptor CHITIN ELICITOR BINDING PROTEIN (OsCEBiP) and co-receptor CHITIN ELICITOR RECEPTOR KINASE1 (OsCERK1) to impair their chitin-induced dimerization, suppressing host immunity exerted at the lemma and palea for gaining access to the stamen and pistil. Conversely, pretreatment on spikelets with chitin induces a defense response in the lemma and palea, promoting resistance against U. virens. Collectively, our data uncover a mechanism for a U. virens virulence factor and the critical location of the host-pathogen interaction in flowers and provide a potential strategy to control rice false smut disease.

Identification of NADPH Oxidase Genes Crucial for Rice Multiple Disease Resistance and Yield Traits.

Reactive oxygen species (ROS) act as a group of signaling molecules in rice functioning in regulation of development and stress responses. Respiratory burst oxidase homologues (Rbohs) are key enzymes in generation of ROS. However, the role of the nine Rboh family members was not fully understood in rice multiple disease resistance and yield traits. In this study, we constructed mutants of each Rboh genes and detected their requirement in rice multiple disease resistance and yield traits. Our results revealed that mutations of five Rboh genes (RbohA, RbohB, RbohE, RbohH, and RbohI) lead to compromised rice blast disease resistance in a disease nursery and lab conditions; mutations of five Rbohs (RbohA, RbohB, RbohC, RbohE, and RbohH) result in suppressed rice sheath blight resistance in a disease nursery and lab conditions; mutations of six Rbohs (RbohA, RbohB, RbohC, RbohE, RbohH and RbohI) lead to decreased rice leaf blight resistance in a paddy yard and ROS production induced by PAMPs and pathogen. Moreover, all Rboh genes participate in the regulation of rice yield traits, for all rboh mutants display one or more compromised yield traits, such as panicle number, grain number per panicle, seed setting rate, and grain weight, resulting in reduced yield per plant except rbohb and rbohf. Our results identified the Rboh family members involved in the regulation of rice resistance against multiple pathogens that caused the most serious diseases worldwide and provide theoretical supporting for breeding application of these Rbohs to coordinate rice disease resistance and yield traits.

Broad-spectrum resistance gene RPW8.1 balances immunity and growth via feedback regulation of WRKYs.

Arabidopsis RESISTANCE TO POWDERY MILDEW 8.1 (RPW8.1) is an important tool for engineering broad-spectrum disease resistance against multiple pathogens. Ectopic expression of RPW8.1 leads to enhanced disease resistance with cell death at leaves and compromised plant growth, implying a regulatory mechanism balancing RPW8.1-mediated resistance and growth. Here, we show that RPW8.1 constitutively enhances the expression of transcription factor WRKY51 and activates salicylic acid and ethylene signalling pathways; WRKY51 in turn suppresses RPW8.1 expression, forming a feedback regulation loop. RPW8.1 and WRKY51 are both induced by pathogen infection and pathogen-/microbe-associated molecular patterns. In ectopic expression of RPW8.1 background (R1Y4), overexpression of WRKY51 not only rescues the growth suppression and cell death caused by RPW8.1, but also suppresses RPW8.1-mediated broad-spectrum disease resistance and pattern-triggered immunity. Mechanistically, WRKY51 directly binds to and represses RPW8.1 promoter, thus limiting the expression amplitude of RPW8.1. Moreover, WRKY6, WRKY28 and WRKY41 play a role redundant to WRKY51 in the suppression of RPW8.1 expression and are constitutively upregulated in R1Y4 plants with WRKY51 being knocked out (wrky51 R1Y4) plants. Notably, WRKY51 has no significant effects on disease resistance or plant growth in wild type without RPW8.1, indicating a specific role in RPW8.1-mediated disease resistance. Altogether, our results reveal a regulatory circuit controlling the accumulation of RPW8.1 to an appropriate level to precisely balance growth and disease resistance during pathogen invasion.

Magnaporthe oryzae effector MoSPAB1 directly activates rice Bsr-d1 expression to facilitate pathogenesis.

Fungal pathogens typically use secreted effector proteins to suppress host immune activators to facilitate invasion. However, there is rarely evidence supporting the idea that fungal secretory proteins contribute to pathogenesis by transactivating host genes that suppress defense. We previously found that pathogen Magnaporthe oryzae induces rice Bsr-d1 to facilitate infection and hypothesized that a fungal effector mediates this induction. Here, we report that MoSPAB1 secreted by M. oryzae directly binds to the Bsr-d1 promoter to induce its expression, facilitating pathogenesis. Amino acids 103-123 of MoSPAB1 are required for its binding to the Bsr-d1 promoter. Both MoSPAB1 and rice MYBS1 compete for binding to the Bsr-d1 promoter to regulate Bsr-d1 expression. Furthermore, MoSPAB1 homologues are highly conserved among fungi. In particular, Colletotrichum fructicola CfSPAB1 and Colletotrichum sublineola CsSPAB1 activate kiwifruit AcBsr-d1 and sorghum SbBsr-d1 respectively, to facilitate pathogenesis. Taken together, our findings reveal a conserved module that may be widely utilized by fungi to enhance pathogenesis.

Unnatural activities and mechanistic insights of cytochrome P450 PikC gained from site-specific mutagenesis by non-canonical amino acids.

Cytochrome P450 enzymes play important roles in the biosynthesis of macrolide antibiotics by mediating a vast variety of regio- and stereoselective oxidative modifications, thus improving their chemical diversity, biological activities, and pharmaceutical properties. Tremendous efforts have been made on engineering the reactivity and selectivity of these useful biocatalysts. However, the 20 proteinogenic amino acids cannot always satisfy the requirement of site-directed/random mutagenesis and rational protein design of P450 enzymes. To address this issue, herein, we practice the semi-rational non-canonical amino acid mutagenesis for the pikromycin biosynthetic P450 enzyme PikC, which recognizes its native macrolide substrates with a 12- or 14-membered ring macrolactone linked to a deoxyamino sugar through a unique sugar-anchoring mechanism. Based on a semi-rationally designed substrate binding strategy, non-canonical amino acid mutagenesis at the His238 position enables the unnatural activities of several PikC mutants towards the macrolactone precursors without any sugar appendix. With the aglycone hydroxylating activities, the pikromycin biosynthetic pathway is rewired by the representative mutant PikCH238pAcF carrying a p-acetylphenylalanine residue at the His238 position and a promiscuous glycosyltransferase. Moreover, structural analysis of substrate-free and three different enzyme-substrate complexes of PikCH238pAcF provides significant mechanistic insights into the substrate binding and catalytic selectivity of this paradigm biosynthetic P450 enzyme.

A natural allele of proteasome maturation factor improves rice resistance to multiple pathogens.

Crops with broad-spectrum resistance loci are highly desirable in agricultural production because these loci often confer resistance to most races of a pathogen or multiple pathogen species. Here we discover a natural allele of proteasome maturation factor in rice, UMP1R2115, that confers broad-spectrum resistance to Magnaporthe oryzae, Rhizoctonia solani, Ustilaginoidea virens and Xanthomonas oryzae pv. oryzae. Mechanistically, this allele increases proteasome abundance and activity to promote the degradation of reactive oxygen species-scavenging enzymes including peroxidase and catalase upon pathogen infection, leading to elevation of H2O2 accumulation for defence. In contrast, inhibition of proteasome function or overexpression of peroxidase/catalase-encoding genes compromises UMP1R2115-mediated resistance. More importantly, introduction of UMP1R2115 into a disease-susceptible rice variety does not penalize grain yield while promoting disease resistance. Our work thus uncovers a broad-spectrum resistance pathway integrating de-repression of plant immunity and provides a valuable genetic resource for breeding high-yield rice with multi-disease resistance.

Golovinomyces cichoracearum effector-associated nuclear localization of RPW8.2 amplifies its expression to boost immunity in Arabidopsis.

Arabidopsis RESISTANCE TO POWDERY MILDEW 8.2 (RPW8.2) is specifically induced by the powdery mildew (PM) fungus (Golovinomyces cichoracearum) in the infected epidermal cells to activate immunity. However, the mechanism of RPW8.2-induction is not well understood. Here, we identify a G. cichoracearum effector that interacts with RPW8.2, named Gc-RPW8.2 interacting protein 1 (GcR8IP1), by a yeast two-hybrid screen of an Arabidopsis cDNA library. GcR8IP1 is physically associated with RPW8.2 with its REALLY INTERESTING NEW GENE finger domain that is essential and sufficient for the association. GcR8IP1 was secreted and translocated into the nucleus of host cell infected with PM. Association of GcR8IP1 with RPW8.2 led to an increase in RPW8.2 in the nucleus. In turn, the nucleus-localized RPW8.2 promoted the activity of the RPW8.2 promoter, resulting in transcriptional self-amplification of RPW8.2 to boost immunity at infection sites. Additionally, ectopic expression or host-induced gene silencing of GcR8IP1 supported its role as a virulence factor in PM. Altogether, our results reveal a mechanism of RPW8.2-dependent defense strengthening via altered partitioning of RPW8.2 and transcriptional self-amplification triggered by a PM fungal effector, which exemplifies an atypical form of effector-triggered immunity.

Overproduction of OsRACK1A, an effector-targeted scaffold protein promoting OsRBOHB-mediated ROS production, confers rice floral resistance to false smut disease without yield penalty.

Grain formation is fundamental for crop yield but is vulnerable to abiotic and biotic stresses. Rice grain production is threatened by the false smut fungus Ustilaginoidea virens, which specifically infects rice floral organs, disrupting fertilization and seed formation. However, little is known about the molecular mechanisms of the U. virens-rice interaction and the genetic basis of floral resistance. Here, we report that U. virens secretes a cytoplasmic effector, UvCBP1, to facilitate infection of rice flowers. Mechanistically, UvCBP1 interacts with the rice scaffold protein OsRACK1A and competes its interaction with the reduced nicotinamide adenine dinucleotide phosphate oxidase OsRBOHB, leading to inhibition of reactive oxygen species (ROS) production. Although the analysis of natural variation revealed no OsRACK1A variants that could avoid being targeted by UvCBP1, expression levels of OsRACK1A are correlated with field resistance against U. virens in rice germplasm. Overproduction of OsRACK1A restores the OsRACK1A-OsRBOHB association and promotes OsRBOHB phosphorylation to enhance ROS production, conferring rice floral resistance to U. virens without yield penalty. Taken together, our findings reveal a new pathogenic mechanism mediated by an essential effector from a flower-specific pathogen and provide a valuable genetic resource for balancing disease resistance and crop yield.

Osa-miR160a confers broad-spectrum resistance to fungal and bacterial pathogens in rice.

Rice production is threatened by multiple pathogens. Breeding cultivars with broad-spectrum disease resistance is necessary to maintain and improve crop production. Previously we found that overexpression of miR160a enhanced rice blast disease resistance. However, it is unclear whether miR160a also regulates resistance against other pathogens, and what the downstream signaling pathways are. Here, we demonstrate that miR160a positively regulates broad-spectrum resistance against the causative agents of blast, leaf blight and sheath blight in rice. Mutations of miR160a-targeted Auxin Response Factors result in different alteration of resistance conferred by miR160a. miR160a enhances disease resistance partially by suppressing ARF8, as mutation of ARF8 in MIM160 background partially restores the compromised resistance resulting from MIM160. ARF8 protein binds directly to the promoter and suppresses the expression of WRKY45, which acts as a positive regulator of rice immunity. Mutation of WRKY45 compromises the enhanced blast resistance and bacterial leaf blight resistance conferred by arf8 mutant. Overall, our results reveal that a microRNA coordinates rice broad-spectrum disease resistance by suppressing multiple target genes that play different roles in disease resistance, and uncover a new regulatory pathway mediated by the miR160a-ARF8 module. These findings provide new resources to potentially improve disease resistance for breeding in rice.

miR167d-ARFs Module Regulates Flower Opening and Stigma Size in Rice.

Flower opening and stigma exertion are two critical traits for cross-pollination during seed production of hybrid rice (Oryza sativa L.). In this study, we demonstrate that the miR167d-ARFs module regulates stigma size and flower opening that is associated with the elongation of stamen filaments and the cell arrangement of lodicules. The overexpression of miR167d (OX167d) resulted in failed elongation of stamen filaments, increased stigma size, and morphological alteration of lodicule, resulting in cleistogamy. Blocking miR167d by target mimicry also led to a morphological alteration of the individual floral organs, including a reduction in stigma size and alteration of lodicule cell morphology, but did not show the cleistogamous phenotype. In addition, the four target genes of miR167d, namely ARF6, ARF12, ARF17, and ARF25, have overlapping functions in flower opening and stigma size. The loss-of-function of a single ARF gene did not influence the flower opening and stigma size, but arf12 single mutant showed a reduced plant height and aborted apical spikelets. However, mutation in ARF12 together with mutation in either ARF6, ARF17, or ARF25 led to the same defective phenotypes that were observed in OX167d, including the failed elongation of stamen filaments, increased stigma size, and morphological alteration of lodicule. These findings indicate that the appropriate expression of miR167d is crucial and the miR167d-ARFs module plays important roles in the regulation of flower opening and stigma size in rice.

Loss and Natural Variations of Blast Fungal Avirulence Genes Breakdown Rice Resistance Genes in the Sichuan Basin of China.

Magnaporthe oryzae is the causative agent of rice blast, a devastating disease in rice worldwide. Based on the gene-for-gene paradigm, resistance (R) proteins can recognize their cognate avirulence (AVR) effectors to activate effector-triggered immunity. AVR genes have been demonstrated to evolve rapidly, leading to breakdown of the cognate resistance genes. Therefore, understanding the variation of AVR genes is essential to the deployment of resistant cultivars harboring the cognate R genes. In this study, we analyzed the nucleotide sequence polymorphisms of eight known AVR genes, namely, AVR-Pita1, AVR-Pii, AVR-Pia, AVR-Pik, AVR-Pizt, AVR-Pi9, AVR-Pib, and AVR-Pi54 in a total of 383 isolates from 13 prefectures in the Sichuan Basin. We detected the presence of AVR-Pik, AVR-Pi54, AVR-Pizt, AVR-Pi9, and AVR-Pib in the isolates of all the prefectures, but not AVR-Pita1, AVR-Pii, and AVR-Pia in at least seven prefectures, indicating loss of the three AVRs. We also detected insertions of Pot3, Mg-SINE, and indels in AVR-Pib, solo-LTR of Inago2 in AVR-Pizt, and gene duplications in AVR-Pik. Consistently, the isolates that did not harboring AVR-Pia were virulent to IRBLa-A, the monogenic line containing Pia, and the isolates with variants of AVR-Pib and AVR-Pizt were virulent to IRBLb-B and IRBLzt-t, the monogenic lines harboring Pib and Piz-t, respectively, indicating breakdown of resistance by the loss and variations of the avirulence genes. Therefore, the use of blast resistance genes should be alarmed by the loss and nature variations of avirulence genes in the blast fungal population in the Sichuan Basin.

Extracellular vesicle-mediated communication between hepatocytes and natural killer cells promotes hepatocellular tumorigenesis.

Hepatocellular carcinoma (HCC) is frequently characterized by metabolic and immune remodeling in the tumor microenvironment. We previously discovered that liver-specific deletion of fructose-1, 6-bisphosphatase 1 (FBP1), a gluconeogenic enzyme ubiquitously suppressed in HCC tissues, promotes liver tumorigenesis and induces metabolic and immune perturbations closely resembling human HCC. However, the underlying mechanisms remain incompletely understood. Here, we reported that FBP1-deficient livers exhibit diminished amounts of natural killer (NK) cells and accelerated tumorigenesis. Using the diethylnitrosamine-induced HCC mouse model, we analyzed potential changes in the immune cell populations purified from control and FBP1-depleted livers and found that NK cells were strongly suppressed. Mechanistically, FBP1 attenuation in hepatocytes derepresses an zeste homolog 2 (EZH2)-dependent transcriptional program to inhibit PKLR expression. This leads to reduced levels of PKLR cargo proteins sorted into hepatocyte-derived extracellular vesicles (EVs), dampened activity of EV-targeted NK cells, and accelerated liver tumorigenesis. Our study demonstrated that hepatic FBP1 depletion promotes HCC-associated immune remodeling, partly through the transfer of hepatocyte-secreted, PKLR-attenuated EVs to NK cells.

Blocking Osa-miR1871 enhances rice resistance against Magnaporthe oryzae and yield.

MicroRNAs (miRNAs) play vital roles in plant development and defence responses against various stresses. Here, we show that blocking miR1871 improves rice resistance against Magnaporthe oryzae and enhances grain yield simultaneously. The transgenic lines overexpressing miR1871 (OX1871) exhibit compromised resistance, suppressed defence responses and reduced panicle number resulting in slightly decreased yield. In contrast, the transgenic lines blocking miR1871 (MIM1871) show improved resistance, enhanced defence responses and significantly increased panicle number leading to enhanced yield per plant. The RNA-seq assay and defence response assays reveal that blocking miR1871 resulted in the enhancement of PAMP-triggered immunity (PTI). Intriguingly, miR1871 suppresses the expression of LOC_Os06g22850, which encodes a microfibrillar-associated protein (MFAP1) locating nearby the cell wall and positively regulating PTI responses. The mutants of MFAP1 resemble the phenotype of OX1871. Conversely, the transgenic lines overexpressing MFAP1 (OXMFAP1) or overexpressing both MFAP1 and miR1871 (OXMFAP1/OX1871) resemble the resistance of MIM1871. The time-course experiment data reveal that the expression of miR1871 and MFAP1 in rice leaves, panicles and basal internode is dynamic during the whole growth period to manipulate the resistance and yield traits. Our results suggest that miR1871 regulates rice yield and immunity via MFAP1, and the miR8171-MFAP1 module could be used in rice breeding to improve both immunity and yield.

Rice miR1432 Fine-Tunes the Balance of Yield and Blast Disease Resistance via Different Modules.

microRNAs act as fine-tuners in the regulation of plant growth and resistance against biotic and abiotic stress. Here we demonstrate that rice miR1432 fine-tunes yield and blast disease resistance via different modules. Overexpression of miR1432 leads to compromised resistance and decreased yield, whereas blocking miR1432 using a target mimic of miR1432 results in enhanced resistance and yield. miR1432 suppresses the expression of LOC_Os03g59790, which encodes an EF-hand family protein 1 (OsEFH1). Overexpression of OsEFH1 leads to enhanced rice resistance but decreased grain yield. Further study revealed that miR1432 and OsEFH1 are differentially responsive to chitin, a fungus-derived pathogen/microbe-associated molecular pattern (PAMP/MAMP). Consistently, blocking miR1432 or overexpression of OsEFH1 improves chitin-triggered immunity responses. In contrast, overexpression of ACOT, another target gene regulating rice yield traits, has no significant effects on rice blast disease resistance. Altogether, these results indicate that miR1432 balances yield and resistance via different target genes, and blocking miR1432 can simultaneously improve yield and resistance.

Blocking miR530 Improves Rice Resistance, Yield, and Maturity.

MicroRNAs fine-tune plant growth and resistance against multiple biotic and abiotic stresses. The trade-off between biomass and resistance can penalize crop yield. In this study, we have shown that rice miR530 regulates blast disease resistance, yield, and growth period. While the overexpression of miR530 results in compromised blast disease resistance, reduced grain yield, and late maturity, blocking miR530 using a target mimic (MIM530) leads to enhanced resistance, increased grain yield, and early maturity. Further study revealed that the accumulation of miR530 was decreased in both leaves and panicles along with the increase of age. Such expression patterns were accordant with the enhanced resistance from seedlings to adult plants, and the grain development from panicle formation to fully-filled seeds. Divergence analysis of miR530 precursor with upstream 1,000-bp promoter sequence in 11 rice species revealed that miR530 was diverse in Oryza sativa japonica and O. sativa indica group, which was consistent with the different accumulation of miR530 in japonica accessions and indica accessions. Altogether, our results indicate that miR530 coordinates rice resistance, yield, and maturity, thus providing a potential regulatory module for breeding programs aiming to improve yield and disease resistance.

The Flower-Infecting Fungus Ustilaginoidea virens Subverts Plant Immunity by Secreting a Chitin-Binding Protein.

Ustilaginoidea virens is a biotrophic fungal pathogen specifically colonizing rice floral organ and causes false smut disease of rice. This disease has emerged as a serious problem that hinders the application of high-yield rice cultivars, by reducing grain yield and quality as well as introducing mycotoxins. However, the pathogenic mechanisms of U. virens are still enigmatic. Here we demonstrate that U. virens employs a secreted protein UvCBP1 to manipulate plant immunity. In planta expression of UvCBP1 led to compromised chitin-induced defense responses in Arabidopsis and rice, including burst of reactive oxygen species (ROS), callose deposition, and expression of defense-related genes. In vitro-purified UvCBP1 protein competes with rice chitin receptor OsCEBiP to bind to free chitin, thus impairing chitin-triggered rice immunity. Moreover, UvCBP1 could significantly promote infection of U. virens in rice flowers. Our results uncover a mechanism of a floral fungus suppressing plant immunity and pinpoint a universal role of chitin-battlefield during plant-fungi interactions.

MYCN mediates TFRC-dependent ferroptosis and reveals vulnerabilities in neuroblastoma.

MYCN amplification is tightly associated with the poor prognosis of pediatric neuroblastoma (NB). The regulation of NB cell death by MYCN represents an important aspect, as it directly contributes to tumor progression and therapeutic resistance. However, the relationship between MYCN and cell death remains elusive. Ferroptosis is a newly identified cell death mode featured by lipid peroxide accumulation that can be attenuated by GPX4, yet whether and how MYCN regulates ferroptosis are not fully understood. Here, we report that MYCN-amplified NB cells are sensitive to GPX4-targeting ferroptosis inducers. Mechanically, MYCN expression reprograms the cellular iron metabolism by upregulating the expression of TFRC, which encodes transferrin receptor 1 as a key iron transporter on the cell membrane. Further, the increased iron uptake promotes the accumulation of labile iron pool, leading to enhanced lipid peroxide production. Consistently, TFRC overexpression in NB cells also induces selective sensitivity to GPX4 inhibition and ferroptosis. Moreover, we found that MYCN fails to alter the general lipid metabolism and the amount of cystine imported by System Xc(-) for glutathione synthesis, both of which contribute to ferroptosis in alternative contexts. In conclusion, NB cells harboring MYCN amplification are prone to undergo ferroptosis conferred by TFRC upregulation, suggesting that GPX4-targeting ferroptosis inducers or TFRC agonists can be potential strategies in treating MYCN-amplified NB.

Plasma Metabolic Profiling of Pediatric Sepsis in a Chinese Cohort.

Sepsis represents one of the most pressing problems in pediatrics, characterized by pathogenic bacteria invading the blood, growing and multiplying in the blood circulation, and ultimately causing severe infections. Most children with sepsis have a rapid disease onset and frequently exhibit sudden high fever or first chills. Here we performed comprehensive metabolomic profiling of plasma samples collected from pediatric sepsis patients to identify specific metabolic alterations associated with these patients (n = 84, designated as case subjects) as compared to healthy cohorts (n = 59, designated as control subjects). Diagnostic models were constructed using MetaboAnalyst, R packages, and multiple statistical methods, such as orthogonal partial least squares-discriminant analysis, principal component analysis, volcano plotting, and one-way ANOVA. Our study revealed a panel of metabolites responsible for the discrimination between case and control subjects with a high predictive value of prognosis. Moreover, significantly altered metabolites in sepsis survivors versus deceased patients (non-survivors) were identified as those involved in amino acids, fatty acids, and carbohydrates metabolism. Nine metabolites including organic acids and fatty acids were also identified with significantly higher abundance in sepsis patients with related microbes, implicating greater potentials to distinguish bacterial species using metabolomic analysis than blood culture. Pathway enrichment analysis further revealed that fatty acid metabolism might play an important role in the pathogenesis of sepsis.

A natural antisense transcript acts as a negative regulator for the maize drought stress response gene ZmNAC48.

Although plant-specific NAC transcription factors play crucial roles in response to abiotic stress, few reports describe the regulation of NAC genes in maize (Zea mays) by the cis-natural antisense transcripts (cis-NATs). In this study, 521 NAC genes from Gramineae were classified, of which 51 NAC genes contained cis-NATs. ZmNAC48 and cis-NATZmNAC48 co-localized to the same cell nucleus, and both transcripts responded to drought stress. Arabidopsis plants overexpressing ZmNAC48 had improved drought tolerance, lower rate of water loss, enhanced stomatal closure, and higher rates of survival. Transient expression in both maize protoplasts and tobacco leaves indicated that cis-NATZmNAC48 reduced ZmNAC48 expression. Western blotting and ribosome profiling analyses confirmed that cis-NATZmNAC48 lacked protein coding potential. Furthermore, the cis-NAT-derived small-interfering RNAs (nat-siRNAs) generated from the overlapping regions of ZmNAC48 and cis-NATZmNAC48 were detected in maize and transgenic Arabidopsis. Cis-NATZmNAC48 overexpressing maize showed higher water loss rate, increased stomatal opening, and had more dead leaves. Expression of ZmNAC48 and nat-siRNA was decreased in these plants. Taken together, our study indicates that both ZmNAC48 and cis-NATZmNAC48 are involved in plant drought stress responses, and that the double-stranded RNA-dependent mechanism is involved in the interaction between cis-NATZmNAC48 and ZmNAC48. Additionally, cis-NATZmNAC48 may negatively regulate ZmNAC48 to affect stomatal closure of maize.