Inhibitor of cardiolipin biosynthesis-related enzyme MoGep4 confers broad-spectrum anti-fungal activity.

Plant pathogens cause devastating diseases, leading to serious losses to agriculture. Mechanistic understanding of pathogenesis of plant pathogens lays the foundation for the development of fungicides for disease control. Mitophagy, a specific form of autophagy, is important for fungal virulence. The role of cardiolipin, mitochondrial signature phospholipid, in mitophagy and pathogenesis is largely unknown in plant pathogenic fungi. The functions of enzymes involved in cardiolipin biosynthesis and relevant inhibitors were assessed using a set of assays, including genetic deletion, plant infection, lipidomics, chemical-protein interaction, chemical inhibition, and field trials. Our results showed that the cardiolipin biosynthesis-related gene MoGEP4 of the rice blast fungus Magnaporthe oryzae regulates growth, conidiation, cardiolipin biosynthesis, and virulence. Mechanistically, MoGep4 regulated mitophagy and Mps1-MAPK phosphorylation, which are required for virulence. Chemical alexidine dihydrochloride (AXD) inhibited the enzyme activity of MoGep4, cardiolipin biosynthesis and mitophagy. Importantly, AXD efficiently inhibited the growth of 10 plant pathogens and controlled rice blast and Fusarium head blight in the field. Our study demonstrated that MoGep4 regulates mitophagy, Mps1 phosphorylation and pathogenesis in M. oryzae. In addition, we found that the MoGep4 inhibitor, AXD, displays broad-spectrum antifungal activity and is a promising candidate for fungicide development.

Trajectory of intrinsic capacity among community-dwelling older adults in China: The China health and retirement longitudinal study.

BACKGROUNDS: Intrinsic capacity (IC), the sum of individual mental and physical capabilities, as well as living environment and behavior, jointly determine the functional ability of older adults, shifting the focus from disease to function. At the population level, IC in older adults is associated with adverse health outcomes, such as disability, falls, and death. At the individual level, IC changes dynamically. However, studies on the longitudinal IC trajectory and the factors influencing IC deterioration are limited. We aimed to analyze the IC trajectory and explore the risk factors for IC deterioration in Chinese older adults. METHODS: Data were obtained from the baseline (2011-2012) and 4-year follow-up (2015) CHARLS surveys, including 1906 people aged 60 years and older. IC comprises six dimensions: locomotion, vitality, hearing, vision, cognition, and psychology. IC trajectory was categorized into three groups: improved, maintained, and deteriorated. Logistic regression analysis was used to analyze factors influencing the trajectory of IC deterioration. RESULTS: After 4 years, 32.1 % had deteriorated, 38.5 % remained stable, and 29.4 % had improved. Age, low level of education, widowed were independently associated with IC deterioration. CONCLUSIONS: Dynamic IC monitoring supports the development of individualized intervention policies to delay or prevent IC deterioration.

Association of Overweight and Inflammatory Indicators with Breast Cancer: A Cross-Sectional Study in Chinese Women.

Objective: This cross-sectional study aimed to explore the association of overweight and inflammatory indicators with breast cancer risk in Chinese patients. Methods: Weight, height, and peripheral blood inflammatory indicators, including white blood cell count (WBC), neutrophil count (NE), lymphocyte count (LY), platelet count (PLT) and the concentration of hypersensitivity C-reactive protein (hsCRP), were collected in 383 patients with benign breast lumps (non-cancer) and 358 patients with malignant breast tumors (cancer) at the First Affiliated Hospital of Soochow University, China, from March 2018 to July 2020. Body mass index (BMI), neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR) and systemic immune-inflammation index (SII) were determined according to the ratio equation. The correlations among overweight, inflammatory indicators, and the proportion of non-cancer or cancer cases were analyzed. Results: BMI is associated with an increased breast cancer risk. Compared with non-cancer patients, the average WBC count, NE count, NLR, and level of hsCRP were significantly higher in cancer patients. The level of hsCRP was closely associated with the size of malignant breast tumors. Conclusion: We conclude that overweight and high levels of hsCRP may serve as putative risk factors for malignant breast tumors in Chinese women.

Pituitary-related immune adverse events induced by programmed death Protein-1 inhibitors differ clinically from hypophysitis.

OBJECTIVE: We aimed to elucidate the clinical features of pituitary immune-related adverse events (irAEs) induced by PD-1 inhibitors in a Chinese cohort and the previous literatures. PATIENTS AND DESIGN AND MEASUREMENTS: We retrospectively analysed the clinical manifestations, laboratory examination findings, imaging features and treatments of 14 patients with pituitary irAEs caused by PD-1 inhibitors in our cohort. In addition, we searched PubMed for all English articles on pituitary irAEs induced by PD-1 inhibitors published from 1950 to 2023. A total of 47 articles were included, and the clinical characteristics of 94 patients with pituitary irAEs induced by PD-1 inhibitors in these literatures were compared to the characteristics of our cohort. RESULTS: Among the 14 patients in our cohort with pituitary irAEs induced by PD-1 inhibitors, 12 patients (85.71%, 12/14) exhibited isolated ACTH deficiency (IAD), 100.0% (14/14) of the central adrenocortical insufficiency, and 2 patients showed more than one hypothalamic-pituitary axis injury (14.29%, 2/14). Pituitary magnetic resonance imaging in all the 14 patients showed no pituitary enlargement. In previous studies we reviewed, 82.98% of the total (78/94) presented with pituitary irAEs as IAD, 100.0% (94/94) of the central adrenocortical insufficiency, and 78.33% of the patients showed no abnormality of the pituitary gland (47/60). The pituitary irAEs caused by PD-1 inhibitors did not involve typical manifestations of hypophysitis, such as pituitary enlargement, headache, visual field defects, and multiple pituitary function impairments in our cohort and the previous literatures. CONCLUSION: In our study, pituitary immune-related adverse reactions induced by PD-1 inhibitors mainly manifested isolated ACTH deficiency rather than hypophysitis.

Fine Mapping of Candidate Gene Controlling Anthocyanin Biosynthesis for Purple Peel in Solanum melongena L.

Fruit color is an intuitive quality of horticultural crops that can be used as an evaluation criterion for fruit ripening and is an important factor affecting consumers' purchase choices. In this study, a genetic population from the cross of green peel 'Qidong' and purple peel '8 guo' revealed that the purple to green color of eggplant peel is dominant and controlled by a pair of alleles. Bulked segregant analysis (BSA), SNP haplotyping, and fine genetic mapping delimited candidate genes to a 350 kb region of eggplant chromosome 10 flanked by markers KA2381 and CA8828. One ANS gene (EGP22363) was predicted to be a candidate gene based on gene annotation and sequence alignment of the 350-kb region. Sequence analysis revealed that a single base mutation of 'T' to 'C' on the exon green peel, which caused hydrophobicity to become hydrophilic serine, led to a change in the three-level spatial structure. Additionally, EGP22363 was more highly expressed in purple peels than in green peels. Collectively, EGP22363 is a strong candidate gene for anthocyanin biosynthesis in purple eggplant peels. These results provide important information for molecular marker-assisted selection in eggplants, and a basis for analyzing the regulatory pathways responsible for anthocyanin biosynthesis in eggplants.

gCTRP3 inhibits oophorectomy­induced osteoporosis by activating the AMPK/SIRT1/Nrf2 signaling pathway in mice.

C1q/tumor necrosis factor­related protein 3 (CTRP3) expression is markedly reduced in the serum of patients with osteoporosis. The present study aimed to investigate whether CTRP3 reduces bone loss in oophorectomy (OVX)­induced mice via the AMP­activated protein kinase (AMPK)/sirtuin 1 (SIRT1)/nuclear factor E2­related factor 2 (Nrf2) signaling pathway. Female C57BL/6J mice and MC3T3­E1 cells were used to construct in vivo and in vitro models of osteoporosis, respectively. The left femurs of mice were examined using micro­computed tomography scans and bone­related quantitative morphological evaluation was performed. Pathological changes and the number of osteoclasts in the left femurs of mice were detected using hematoxylin and eosin, and tartrate­resistant acid phosphatase (TRAP) staining. Runt­related transcription factor­2 (RUNX2) expression in the left femurs was detected using immunofluorescence analysis, and the serum levels of bone resorption markers (C­telopeptide of type I collagen and TRAP) and bone formation markers [osteocalcin (OCN) and procollagen type 1 N­terminal propeptide] were detected. In addition, osteoblast differentiation and calcium deposits were examined in MC3T3­E1 cells using alkaline phosphatase (ALP) and Alizarin red staining, respectively. Moreover, RUNX2, ALP and OCN expression levels were detected using reverse transcription­quantitative PCR, and the expression levels of proteins associated with the AMPK/SIRT1/Nrf2 signaling pathway were detected using western blot analysis. The results revealed that globular CTRP3 (gCTRP3) alleviated bone loss and promoted bone formation in OVX­induced mice. gCTRP3 also facilitated the osteogenic differentiation of MC3T3­E1 cells through the AMPK/SIRT1/Nrf2 signaling pathway. The addition of an AMPK inhibitor (Compound C), SIRT1 inhibitor (EX527) or Nrf2 inhibitor (ML385) reduced the osteogenic differentiation of MC3T3­E1 cells via inhibition of gCTRP3. In conclusion, gCTRP3 inhibits OVX­induced osteoporosis by activating the AMPK/SIRT1/Nrf2 signaling pathway.

Palmitoylation of KSHV pORF55 is required for Golgi localization and efficient progeny virion production.

Kaposi's sarcoma-associated herpesvirus (KSHV) is a double-stranded DNA virus etiologically associated with multiple malignancies. Both latency and sporadic lytic reactivation contribute to KSHV-associated malignancies, however, the specific roles of many KSHV lytic gene products in KSHV replication remain elusive. In this study, we report that ablation of ORF55, a late gene encoding a tegument protein, does not impact KSHV lytic reactivation but significantly reduces the production of progeny virions. We found that cysteine 10 and 11 (C10 and C11) of pORF55 are palmitoylated, and the palmytoilation is essential for its Golgi localization and secondary envelope formation. Palmitoylation-defective pORF55 mutants are unstable and undergo proteasomal degradation. Notably, introduction of a putative Golgi localization sequence to these palmitoylation-defective pORF55 mutants restores Golgi localization and fully reinstates KSHV progeny virion production. Together, our study provides new insight into the critical role of pORF55 palmitoylation in KSHV progeny virion production and offers potential therapeutic targets for the treatment of related malignancies.

Prevalence and incidence of mobility limitation in Chinese older adults: evidence from the China health and retirement longitudinal study.

BACKGROUND: Mobility limitation, a manifestation of impaired intrinsic capacity, is the first obvious sign of functional decline. However, few studies have been conducted on the prevalence and incidence of mobility limitation. This study aimed to estimate the prevalence and incidence of mobility limitation in Chinese older adults (over 60 years old) and evaluate its impact on mortality. METHODS: The study used two waves of data from China Health and Retirement Longitudinal Study (CHARLS) in 2011 and 2013. The prevalence and incidence of mobility limitation were assessed using the methods recommended by the World Health Organization in the integrated care for older people guidelines, using the five-time sit-to-stand test as a screening and then the Short Physical Performance Battery assessment for diagnosis. Multivariable logistic regression was used to analyze the association between mobility limitation and death. RESULTS: Of the 5507 participants with complete baseline data, 1486 had limited mobility, and 4021 had intact mobility at baseline; 4093 participants completed follow-up assessment 2 years later, and 189 died between the baseline and follow-up assessments. Of the 2828 participants with intact mobility at baseline who completed the follow-up mobility assessment, 408 developed mobility limitation. The standardized prevalence was 30.4% (95% CI = 28.8-32.1 %). The standardized incidence of mobility limitation in 2 years was 18.1% (95% CI = 15.8-20.4 %). A total of 189 patients died during the follow-up period. After adjusting for sociodemographic factors and chronic diseases, mobility limitation was associated with an increased risk of death (odds ratio = 1.84, 95% CI = 1.33-2.55, P < .001). CONCLUSIONS: The standardized prevalence of mobility limitation in Chinese older adults living in the community was 30.4%, and the standardized incidence was 18.1%. Mobility limitation significantly predicts 2-year death in older adults. This suggests that early screening, assessment of intrinsic capacity (particularly locomotion domain) as well as tailored interventions to tackle mobility limitation in older adults might reduce mortality.

Non-canonical regulation of the reactivation of an oncogenic herpesvirus by the OTUD4-USP7 deubiquitinases.

Deubiquitinases (DUBs) remove ubiquitin from substrates and play crucial roles in diverse biological processes. However, our understanding of deubiquitination in viral replication remains limited. Employing an oncogenic human herpesvirus Kaposi's sarcoma-associated herpesvirus (KSHV) to probe the role of protein deubiquitination, we found that Ovarian tumor family deubiquitinase 4 (OTUD4) promotes KSHV reactivation. OTUD4 interacts with the replication and transcription activator (K-RTA), a key transcription factor that controls KSHV reactivation, and enhances K-RTA stability by promoting its deubiquitination. Notably, the DUB activity of OTUD4 is not required for K-RTA stabilization; instead, OTUD4 functions as an adaptor protein to recruit another DUB, USP7, to deubiquitinate K-RTA and facilitate KSHV lytic reactivation. Our study has revealed a novel mechanism whereby KSHV hijacks OTUD4-USP7 deubiquitinases to promote lytic reactivation, which could be potentially harnessed for the development of new antiviral therapies.

Identification of propranolol and derivatives that are chemical inhibitors of phosphatidate phosphatase as potential broad-spectrum fungicides.

Plant diseases cause enormous economic losses in agriculture and threaten global food security, and application of agrochemicals is an important method of crop disease control. Exploration of disease-resistance mechanisms and synthesis of highly bioactive agrochemicals are thus important research objectives. Here, we show that propranolol, a phosphatidate phosphatase (Pah) inhibitor, effectively suppresses fungal growth, sporulation, sexual reproduction, and infection of diverse plants. The MoPah1 enzyme activity of the rice blast fungus Magnaporthe oryzae is inhibited by propranolol. Alterations in lipid metabolism are associated with inhibited hyphal growth and appressorium formation caused by propranolol in M. oryzae. Propranolol inhibits a broad spectrum of 12 plant pathogens, effectively inhibiting infection of barley, wheat, maize, tomato, and pear. To improve antifungal capacity, we synthesized a series of propranolol derivatives, one of which shows a 16-fold increase in antifungal ability and binds directly to MoPah1. Propranolol and its derivatives can also reduce the severity of rice blast and Fusarium head blight of wheat in the field. Taken together, our results demonstrate that propranolol suppresses fungal development and infection through mechanisms involved in lipid metabolism. Propranolol and its derivatives may therefore be promising candidates for fungicide development.

Association of plasma galectin-3 and fetuin-A levels with diabetic retinopathy in type 2 diabetes mellitus patients.

INTRODUCTION: Galectin-3 (Gal-3) and fetuin-A (Fet-A) are cytokines that participate in inflammation and insulin resistance. Previous studies have found that altered Gal-3 and Fet-A levels in circulation correlate with diabetic complications. However, whether they are all associated with diabetic retinopathy (DR) has been little investigated. The aim of this study was to assess plasma Gal-3 and Fet-A concentrations, and to investigate their associations with the presence of DR in type 2 diabetes mellitus (T2DM) patients. MATERIAL AND METHODS: A total of 100 T2DM patients were enrolled, among which there were 50 patients without DR (non diabetic retinopathy, NDR group) and 50 patients with DR (DR group). Clinical parameters were collected, and plasma Gal-3 and Fet-A levels were measured by enzyme-linked immunosorbent assay (ELISA). RESULTS: Both Gal-3 and Fet-A were found to be increased in DR patients with respect to NDR controls, and Gal-3 correlated positively with Fet-A. Bivariate correlation analysis revealed that Gal-3 levels were positively correlated with haemoglobin A1c (HbA1c), while Fet-A correlated negatively with fasting C peptide (FC-P) and positively with homocysteine (Hcy). Binary logistic regression suggested that elevated Gal-3 and Fet-A levels were related to increased risk of DR. ROC curve displayed that the combination of Fet-A and Gal-3 exhibited better diagnostic value for DR. CONCLUSIONS: Both Gal-3 and Fet-A were elevated in the circulation of DR patients, and they were positively associated with the occurrence of DR. The combination of 2 indicators showed better diagnostic value for DR.

Hypophysitis Induced by Sintilimab in the Treatment of Bladder Cancer: A Case Report.

BACKGROUND: Immune checkpoint inhibitors (ICIs), as novel antitumor drugs, have been widely used in the clinic and have shown good antitumor effects. However, their widespread use has also led to the emergence of various immune-related adverse events (IrAEs). Hypophysitis is a rare but serious IrAE. Due to its complex and changeable clinical manifestations, hypophysitis may be easily overlooked, leading to delayed diagnosis and treatment. CASE PRESENTATION: A 68-year-old male patient was diagnosed with bladder cancer (T2bNXM0) in October 2021. He received two cycles of immunotherapy with sintilimab and chemotherapy with gemcitabine and cisplatin (GC). One month after the second treatment, he gradually developed recurrent fever, anorexia, drowsiness, and delirium. Laboratory examination revealed hyponatremia, decreased adrenocorticotropic hormone, and hypocortisolemia. The pituitary MRI showed no abnormality. The patient was diagnosed with immunotherapy-induced hypophysitis (IH) caused by sintilimab, leading to downstream endocrine disorders. With hormone replacement therapy, he was in a good mood, had a good appetite, and made an overall recovery. CONCLUSION: Immunotherapy-induced hypophysitis (IH) can result in a severe adrenal crisis, and prompt recognition and diagnosis are crucial. Clinicians must remain vigilant for the possibility of IH in patients who exhibit recurrent fever, anorexia, cognitive decline, and personality changes following ICI treatment. It is imperative to consider this diagnosis early to initiate appropriate management promptly.

Rethinking terrestrial dissolved organic matter in dam reservoirs before mixing: Linking photodegradation and biodegradation and the phenanthrene binding behavior.

With the increased construction of dam reservoirs and the demand for water security, terrestrial dissolved organic matter (DOM) has received attention because of its role in regulating water quality, ecological functions, and the fate and transport of pollutants in dam reservoirs. This study investigated the transformations of soil DOM and vegetation DOM of dam reservoirs following photodegradation and biodegradation before conservative mixing, as well as the resultant effects on phenanthrene binding. Based on the results, terrestrial DOM could undergo transformation via photodegradation and biodegradation before conservative mixing in dam reservoirs. Although both processes resulted in substantial decreases in DOM concentrations, the changes in chromophoric DOM and fluorescent DOM depended on the original DOM sources. Furthermore, the photodegradation of terrestrial DOM resulted in more pronounced photobleaching than photomineralization. In addition, photodegradation of terrestrial DOM resulted in the generation of DOM-derived by-products with low molecular weight and low aromaticity, whereas the biodegradation of terrestrial DOM resulted in DOM-derived by-products with low molecular weight and high aromaticity. Subsequently, the photodegradation and biodegradation of terrestrial DOM substantially enhanced the binding affinity of phenanthrene. Soil DOM is prior to vegetation DOM when predicting the ecological risk of HOCs. These results indicate that the terrestrial DOM in dam reservoirs should be reconsidered before conservative mixing. Further studies on the coupling effects of both biogeochemical processes, as well as on the relative contributions of soil DOM and vegetation DOM after transformation to the aquatic DOM in dam reservoirs, are required. This study provides information on the environmental effects of dam construction from the perspective of biogeochemical processes.

The prevalence and treatment rate trends of osteoporosis in postmenopausal women.

BACKGROUND: To evaluate the prevalence and treatment of postmenopausal women with osteoporosis in recent years, analyze differences between the prevalence diagnosed by physicians and the prevalence detected by bone mineral density (BMD), and observe the trends of prevalence and treatment rate of osteoporosis in postmenopausal women over time are of great value for the management of osteoporosis. METHODS: This cross-sectional study collected the data of 4012 postmenopausal women from the National Health and Nutrition Examination Survey (NHANES) from 2005 to 2010, 2013 to 2014 and 2017 to 2018. The prevalence of osteoporosis and osteopenia as well as the treatment rate of osteoporosis were analyzed using Mann-Kendall trend test. Subgroup analysis was conducted in different age, race, body mass index (BMI), diabetes, hypertension, or glucocorticoid use groups. RESULTS: The overall prevalence of physician diagnosed of osteoporosis was 17.4% and was fluctuated in a small range and remained relatively stable within a certain range (Mann-Kendall trend test: Z = 2.20, P = 0.027) during 2005-2018. The prevalence of osteoporosis in postmenopausal women determined by bone mineral density (BMD) examination reached 9.2% during the five cycles. From 2005 to 2018, the prevalence of physician diagnosed osteoporosis fluctuated in a small range. For osteopenia measured by BMD, the prevalence was 59.6% and a gradual increasing trend was found between 2005 and 2018 (Mann-Kendall trend test: Z = 2.20, P = 0.027). Among patients with physician diagnosed osteoporosis, the treatment rate reached 70.49%. The treatment rate of physician diagnosed osteoporosis was decreased from 2005 to 2008, and further decreased from 2009 to 2018 (Mann-Kendall trend test: Z = -2.20, P = 0.027). The actual treatment rate of osteoporosis patients was 55.53%. During 2005-2018, the actual treatment rate of osteoporosis showed a continuous decline (Mann-Kendall trend test: Z = -2.20, P = 0.027). CONCLUSION: Osteoporosis management might be insufficient and more efforts are needed to improve the diagnosis and treatment rates of osteoporosis in postmenopausal women.

Updates on RPE cell damage in diabetic retinopathy (Review).

Diabetic retinopathy (DR) is a microvascular complication of diabetes. The retinal pigment epithelium (RPE) forms the outer layer of the blood­retinal barrier and serves a role in maintaining retinal function. RPE cell injury has been revealed in diabetic animal models, and high glucose (HG) levels may cause damage to RPE cells by increasing the levels of oxidative stress, promoting pro­inflammatory gene expression, disrupting cell proliferation, inducing the endothelial­mesenchymal transition, weakening tight conjunctions and elevating cell death mechanisms, such as apoptosis, ferroptosis and pyroptosis. Non­coding RNAs including microRNAs, long non­coding RNAs and circular RNAs participate in RPE cell damage caused by HG levels, which may provide targeted therapeutic strategies for the treatment of DR. Plant extracts such as citrusin and hesperidin, and a number of hypoglycemic drugs, such as sodium­glucose co­transporter 2 inhibitors, metformin and glucagon­like peptide­1 receptor agonists, exhibit potential RPE protective effects; however, the detailed mechanisms behind these effects remain to be fully elucidated. An in­depth understanding of the contribution of the RPE to DR may provide novel perspectives and therapeutic targets for DR.

Omentin-1 and diabetes: more evidence but far from enough.

AIMS AND BACKGROUND: Omentin-1 (oment-1) is a type of adipokines that is mainly expressed in visceral fat tissue. Based on accumulating evidence, oment-1 is closely related to diabetes and its complications. However, so far data about oment-1 and diabetes is fragmented. In this review, we focus on the role of oment-1 on diabetes, including its possible signalling pathways, the correlation of circulating omens-1 levels with diabetes and its complications. METHODS: The web of PubMed was searched for articles of relevant studies published until February, 2023. RESULTS AND CONCLUSIONS: Oment-1 might exert its effects by inhibiting the NF-κB pathway and activating the Akt and AMPK-dependent pathways. The level of circulating oment-1 is negatively correlated with the occurrence of type 2 diabetes and some complications, including diabetic vascular disease, cardiomyopathy, and retinopathy, which can be affected by anti-diabetic therapies. Oment-1 could be a promising marker for screening and targeted therapy for diabetes and its complications; however, more studies are still needed.

Melatonin targets MoIcl1 and works synergistically with fungicide isoprothiolane in rice blast control.

Melatonina natural harmless molecule-displays versatile roles in human health and crop disease control such as for rice blast. Rice blast, caused by the filamentous fungus Magnaporthe oryzae, is one devastating disease of rice. Application of fungicides is one of the major measures in the control of various crop diseases. However, fungicide resistance in the pathogen and relevant environmental pollution are becoming serious problems. By screening for possible synergistic combinations, here, we discovered an eco-friendly combination for rice blast control, melatonin, and the fungicide isoprothiolane. These compounds together exhibited significant synergistic inhibitory effects on vegetative growth, conidial germination, appressorium formation, penetration, and plant infection by M. oryzae. The combination of melatonin and isoprothiolane reduced the effective concentration of isoprothiolane by over 10-fold as well as residual levels of isoprothiolane. Transcriptomics and lipidomics revealed that melatonin and isoprothiolane synergistically interfered with lipid metabolism by regulating many common targets, including the predicted isocitrate lyase-encoding gene MoICL1. Furthermore, using different techniques, we show that melatonin and isoprothiolane interact with MoIcl1. This study demonstrates that melatonin and isoprothiolane function synergistically and can be used to reduce the dosage and residual level of isoprothiolane, potentially contributing to the environment-friendly and sustainable control of crop diseases.

STING is a cell-intrinsic metabolic checkpoint restricting aerobic glycolysis by targeting HK2.

Evasion of antitumour immunity is a hallmark of cancer. STING, a putative innate immune signalling adaptor, has a pivotal role in mounting antitumour immunity by coordinating innate sensing and adaptive immune surveillance in myeloid cells. STING is markedly silenced in various human malignancies and acts as a cell-intrinsic tumour suppressor. How STING exerts intrinsic antitumour activity remains unclear. Here, we report that STING restricts aerobic glycolysis independent of its innate immune function. Mechanistically, STING targets hexokinase II (HK2) to block its hexokinase activity. As such, STING inhibits HK2 to restrict tumour aerobic glycolysis and promote antitumour immunity in vivo. In human colorectal carcinoma samples, lactate, which can be used as a surrogate for aerobic glycolysis, is negatively correlated with STING expression level and antitumour immunity. Taken together, this study reveals that STING functions as a cell-intrinsic metabolic checkpoint that restricts aerobic glycolysis to promote antitumour immunity. These findings have important implications for the development of STING-based therapeutic modalities to improve antitumour immunotherapy.

Genome editing of a rice CDP-DAG synthase confers multipathogen resistance.

The discovery and application of genome editing introduced a new era of plant breeding by giving researchers efficient tools for the precise engineering of crop genomes1. Here we demonstrate the power of genome editing for engineering broad-spectrum disease resistance in rice (Oryza sativa). We first isolated a lesion mimic mutant (LMM) from a mutagenized rice population. We then demonstrated that a 29-base-pair deletion in a gene we named RESISTANCE TO BLAST1 (RBL1) caused broad-spectrum disease resistance and showed that this mutation caused an approximately 20-fold reduction in yield. RBL1 encodes a cytidine diphosphate diacylglycerol synthase that is required for phospholipid biosynthesis2. Mutation of RBL1 results in reduced levels of phosphatidylinositol and its derivative phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2). In rice, PtdIns(4,5)P2 is enriched in cellular structures that are specifically associated with effector secretion and fungal infection, suggesting that it has a role as a disease-susceptibility factor3. By using targeted genome editing, we obtained an allele of RBL1, named RBL1Δ12, which confers broad-spectrum disease resistance but does not decrease yield in a model rice variety, as assessed in small-scale field trials. Our study has demonstrated the benefits of editing an LMM gene, a strategy relevant to diverse LMM genes and crops.

Doxorubicin inhibits phosphatidylserine decarboxylase and confers broad-spectrum antifungal activity.

As phospholipids of cell membranes, phosphatidylethanolamine (PE) and phosphatidylserine (PS) play crucial roles in glycerophospholipid metabolism. Broadly, some phospholipid biosynthesis enzymes serve as potential fungicide targets. Therefore, revealing the functions and mechanism of PE biosynthesis in plant pathogens would provide potential targets for crop disease control. We performed analyses including phenotypic characterizations, lipidomics, enzyme activity, site-directed mutagenesis, and chemical inhibition assays to study the function of PS decarboxylase-encoding gene MoPSD2 in rice blast fungus Magnaporthe oryzae. The Mopsd2 mutant was defective in development, lipid metabolism, and plant infection. The PS level increased while PE decreased in Mopsd2, consistent with the enzyme activity. Furthermore, chemical doxorubicin inhibited the enzyme activity of MoPsd2 and showed antifungal activity against 10 phytopathogenic fungi including M. oryzae and reduced disease severity of two crop diseases in the field. Three predicted doxorubicin-interacting residues are important for MoPsd2 functions. Our study demonstrates that MoPsd2 is involved in de novo PE biosynthesis and contributes to the development and plant infection of M. oryzae and that doxorubicin shows broad-spectrum antifungal activity as a fungicide candidate. The study also implicates that bacterium Streptomyces peucetius, which biosynthesizes doxorubicin, could be potentially used as an eco-friendly biocontrol agent.