Discovery of Imidazo[1,2-a]pyrazine Derivatives as Potent ENPP1 Inhibitors.

ENPP1 acts as a negative regulator of the cGAS-STING pathway through the hydrolysis of 2'3'-cGAMP. Inhibitors of ENPP1 are regarded as promising agents for stimulating the immune response in cancer immunotherapy. This study describes the identification and optimization of imidazo[1,2-a]pyrazine derivative 7 as a highly potent and selective ENPP1 inhibitor. Compound 7 demonstrated substantial inhibitory activity against ENPP1 with an IC50 value of 5.70 or 9.68 nM while showing weak inhibition against ENPP2 and ENPP3. Furthermore, compound 7 was shown to enhance the mRNA expression of cGAMP-induced STING pathway downstream target genes, such as IFNB1, CXCL10, and IL6. In vivo pharmacokinetic and antitumor studies showed promising results, with 7 not only exhibiting efficient pharmacokinetic properties but also enhancing the antitumor efficacy of the anti-PD-1 antibody. Treatment with 7 (80 mg/kg) combined with anti-PD-1 antibody achieved a tumor growth inhibition rate of 77.7% and improved survival in a murine model.

The diagnostic value of neutrophil to lymphocyte ratio, albumin to fibrinogen ratio, and lymphocyte to monocyte ratio in Parkinson's disease: a retrospective study.

Background: Parkinson's disease (PD) is a prevalent disorder of the central nervous system, marked by the degeneration of dopamine (DA) neurons in the ventral midbrain. In the pathogenesis of PD, inflammation hypothesis has been concerned. This study aims to investigate clinical indicators of peripheral inflammation in PD patients and to explore the diagnostic value of neutrophil-to-lymphocyte ratio (NLR), albumin-to-fibrinogen ratio (AFR), and lymphocyte-to-monocyte ratio (LMR) in assessing PD risk. Methods: This study included 186 patients with PD and 201 matched healthy controls (HC) with baseline data. Firstly, the differences of hematological indicators between PD group and healthy participants were compared and analyzed. Univariate and multivariate regression analyses were then conducted. Smooth curve fitting was applied to further validate the relationships between NLR, LMR, AFR, and PD. Subsequently, subgroup analysis was conducted in PD group according to different duration of disease and Hoehn and Yahr (H&Y) stage, comparing differences in clinical indicators. Finally, the receiver operating characteristic (ROC) curve was employed to assess the diagnostic value of NLR, LMR, and AFR in PD. Results: Compared to the HC group, the PD group showed significantly higher levels of hypertension, diabetes, neutrophil count, monocyte count, CRP, homocysteine, fibrinogen, and NLR. Conversely, levels of LMR, AFR, lymphocyte count, HDL, LDL, TG, TC, uric acid, and albumin were significantly lower. The multivariate regression model indicated that NLR (OR = 1.79, 95% CI: 1.39-2.31, p < 0.001), LMR (OR = 0.75, 95% CI: 0.66-0.85, p < 0.001), and AFR (OR = 0.79, 95% CI: 0.73-0.85, p < 0.001) were significant factors associated with PD. Smooth curve fitting revealed that NLR was positively linked to PD risk, whereas AFR and LMR were inversely associated with it. In ROC curve analysis, the AUC of AFR was 0.7290, the sensitivity was 63.98%, and the specificity was 76.00%. The AUC of NLR was 0.6200, the sensitivity was 50.54%, and the specificity was 71.50%. The AUC of LMR was 0.6253, the sensitivity was 48.39%, and the specificity was 73.00%. The AUC of the combination was 0.7498, the sensitivity was 74.19%, and the specificity was 64.00%. Conclusion: Our findings indicate that NLR, LMR, and AFR are significantly associated with Parkinson's disease and may serve as diagnostic markers.

Sodium silicate accelerates suberin accumulation at wounds of potato tuber by inducing phenylpropanoid pathway and fatty acid metabolism during healing.

Although soluble silicate was reported to accelerate wound healing in muskmelon fruit through encouraging the deposition of lignin or free fatty acids, whether sodium silicate affects the biosynthesis, cross-linking and transport of suberin monomers during potato wound healing remains unknown. In this study, sodium silicate upregulated the expression and activity of 4-coumarate: coenzyme A ligase (4CL), phenylalanine ammonia lyase (PAL), and promoted the synthesis of phenolic acids (caffeic acid, p-coumaric acid, cinnamic acid, sinapic acid, and ferulic acid) in tuber wounds. Meanwhile, sodium silicate upregulated the expression of glycerol-3-phosphate acyltransferase (StGPAT), fatty acyl reductase (StFAR), long-chain acyl-CoA synthetase (StLACS), ß-ketoacyl-CoA synthase (StKCS), and cytochrome P450 (StCYP86A33), and thus increased the levels of α, ω-diacids, ω-hydroxy acids, and primary alcohols in wounds. Sodium silicate also induced the expression of ω-hydroxy acid/fatty alcohol hydroxycinnamoyl transferase (StFHT), ABC transporter (StABCG), and promoted the deposition of suberin in wound surface, hence reducing tuber disease index and weight loss during healing. Taken together, sodium silicate may accelerate suberin accumulation at potato tubers wound through inducing the phenylpropanoid pathway and fatty acid metabolism.

Cluster headache: understandings of current knowledge and directions for whole process management.

Cluster headache (CH) is a common primary headache that severely impacts patients' quality of life, characterized by recurrent, severe, unilateral headaches often centered around the eyes, temples, or forehead. Distinguishing CH from other headache disorders is challenging, and its pathogenesis remains unclear. Notably, patients with CH often experience high levels of depression and suicidal tendencies, necessitating increased clinical attention. This comprehensive assessment combines various reports and the latest scientific literature to evaluate the current state of CH research. It covers epidemiology, population characteristics, predisposing factors, and treatment strategies. Additionally, we provide strategic insights into the holistic management of CH, which involves continuous, individualized care throughout the prevention, treatment, and rehabilitation stages. Recent advances in the field have revealed new insights into the pathophysiology of CH. While these findings are still evolving, they offer a more detailed understanding of the neurobiological mechanisms underlying this disorder. This growing body of knowledge, alongside ongoing research efforts, promises to lead to the development of more targeted and effective treatments in the future.

Identifying compound-protein interactions with knowledge graph embedding of perturbation transcriptomics.

The emergence of perturbation transcriptomics provides a new perspective for drug discovery, but existing analysis methods suffer from inadequate performance and limited applicability. In this work, we present PertKGE, a method designed to deconvolute compound-protein interactions from perturbation transcriptomics with knowledge graph embedding. By considering multi-level regulatory events within biological systems that share the same semantic context, PertKGE significantly improves deconvoluting accuracy in two critical "cold-start" settings: inferring targets for new compounds and conducting virtual screening for new targets. We further demonstrate the pivotal role of incorporating multi-level regulatory events in alleviating representational biases. Notably, it enables the identification of ectonucleotide pyrophosphatase/phosphodiesterase-1 as the target responsible for the unique anti-tumor immunotherapy effect of tankyrase inhibitor K-756 and the discovery of five novel hits targeting the emerging cancer therapeutic target aldehyde dehydrogenase 1B1 with a remarkable hit rate of 10.2%. These findings highlight the potential of PertKGE to accelerate drug discovery.

SlLTPg1, a tomato lipid transfer protein, positively regulates in response to biotic stresses.

Late blight, caused by Phytophthora infestans (P. infestans), is among the most devastating diseases affecting tomato and other Solanaceae species. Lipid transfer proteins (LTPs) represent a class of small, basic proteins that play a crucial role in combating biotic stresses. Previous studies have shown that SlLTPg1 most strongly responds after P. infestans infestation among the LTPs family in tomato. However, the function of SlLTPg1 in disease resistance remains unclear. Here, we constructed transient overexpression and VIGS-silenced plants of SlLTPg1. Our results revealed that SlLTPg1 plays a regulatory role in enhancing tomato resistance against P. infestans. This enhancement was attributed to the upregulation of defense-related genes and reactive oxygen species (ROS) scavenging genes, as well as increased enzymatic antioxidant activities. Importantly, we found that the SlLTPg1 protein significantly inhibited the growth of Fusarium oxysporum (F. oxysporum) by observing the zone of inhibition. Interestingly, we found smaller lesion diameters and upregulated expression levels of PR genes in transient overexpression SlLTPg1 of tobacco. Therefore, we further constructed transgenic tobacco lines of SlLTPg1, presenting evidence that overexpression of SlLTPg1 could positively regulate the resistance of tobacco to F. oxysporum. These findings revealed the role of SlLTPg1 in tomato resistance to P. infestans and tobacco resistance to F. oxysporum. Moreover, we propose SlLTPg1 as a potential candidate gene for augmenting broad-spectrum plant resistance against pathogens.

Targeting STING oligomerization with licochalcone D ameliorates STING-driven inflammatory diseases.

The development of STING inhibitors for the treatment of STING-related inflammatory diseases continues to encounter significant challenges. The activation of STING is a multi-step process that includes binding with cGAMP, self-oligomerization, and translocation from the endoplasmic reticulum to the Golgi apparatus, ultimately inducing the expression of IRF3 and NF-κB-mediated interferons and inflammatory cytokines. It has been demonstrated that disruption of any of these steps can effectively inhibit STING activation. Traditional structure-based drug screening methodologies generally focus on specific binding sites. In this study, a TransformerCPI model based on protein primary sequences and independent of binding sites is employed to identify compounds capable of binding to the STING protein. The natural product Licochalcone D (LicoD) is identified as a potent and selective STING inhibitor. LicoD does not bind to the classical ligand-binding pocket; instead, it covalently modifies the Cys148 residue of STING. This modification inhibits STING oligomerization, consequently suppressing the recruitment of TBK1 and the nuclear translocation of IRF3 and NF-κB. LicoD treatment ameliorates the inflammatory phenotype in Trex1-1- mice and inhibits the progression of DSS-induced colitis and AOM/DSS-induced colitis-associated colon cancer (CAC). In summary, this study reveals the potential of LicoD in treating STING-driven inflammatory diseases. It also demonstrates the utility of the TransformerCPI model in discovering allosteric compounds beyond the conventional binding pockets.

Regulatory Peptide Encoded by the Primary Transcript of miR396a Influences Gene Expression and Root Development in Solanum lycopersicum.

MicroRNAs (miRNAs) are the processing products of primary miRNAs (pri-miRNAs) that regulate the expression of target genes. Recent studies have demonstrated that some pri-miRNAs can encode small peptides (miPEPs) that perform significant biological functions. The function of miPEPs in tomatoes, an important model horticultural crop, remains to be investigated. Here, we characterized the primary sequence of tomato miR396a using 5' RACE and confirmed the presence of miPEP396a in tomato by verifying the translational activity of the start codon. It primarily resides in the nucleus to exert its function and additionally regulates the expression of pri-miR396a, miR396a, and its target genes. Transcriptomic and metabolomic analyses showed that in vitro synthesis of miPEP396a significantly increased the expression of genes related to phenylpropanoid biosynthesis and hormones in tomato. Meanwhile, our in vitro application of miPEP396a in tomato significantly inhibited the elongation of tomato primary roots. In conclusion, our results indicate that miPEP396a regulates root growth in tomato by specifically promoting miR396a expression, provide insight into the function of miPEPs in tomato and potential applications.

Essential role of ABA signaling and related transcription factors in phenolic acid and lignin synthesis during muskmelon wound healing.

Abscisic acid (ABA) is a key phytohormone involved in wound healing in fruits and vegetables, while fluridone (FLD) is its synthetic inhibitor. However, it is unknown whether ABA signaling and downstream transcription factors are involved in the synthesis of phenolic acids and lignin monomers in muskmelon wounds, and the underlying mechanisms. In our study, exogenous ABA promoted endogenous ABA synthesis by increasing the levels of ß-carotenoid and zeaxanthin, activating 9-cis-epoxycarotenoid dioxygenase (NCED) and zeaxanthin epoxidase (ZEP), facilitated ABA signaling by increasing the expression levels of protein phosphatases type 2C (CmPP2C) and ABA-responsive element binding factors (CmABF), upregulated the expression levels of CmMYB1 and CmWRKY1, and ABA induced phenylpropanoid metabolism by activating phenylalanine ammonia-lyase (PAL), 4-coenzyme A ligase (4CL), and cinnamyl alcohol dehydrogenase (CAD), which further increased the synthesis of phenolic acids and lignin monomers in muskmelon wounds during healing. Taken together, exogenous ABA induced phenylpropanoid metabolism and increased the synthesis of phenolic acid and lignin monomer in muskmelon wounds during healing, and may be involved in endogenous ABA synthesis and signaling and related transcription factors.

Zirconium­cerium modified polyvinyl alcohol/NaCMC biocomposite film: Synthesis of films through high-speed shear assisted technique and removal fluoride from water.

A new zirconium and cerium-modified polyvinyl alcohol (PVA) sodium carboxymethyl cellulose (NaCMC) film (PVA/CMC-Zr-Ce) was synthesized thru a high-speed shear-assisted method and its adsorption for the removal of fluoride was studied, in which the NaCMC provided -COONa for ion exchange between Na and Zr-Ce, thus the loading amount of Zr-Ce on films was accordingly increased. The morphology and structure of PVA/CMC-Zr-Ce were characterized using scanning electron microscopy (SEM), energy dispersive spectroscopy (EDS), and X-ray diffraction (XRD). Besides, the mechanical properties, water contact angle, and swelling ratio of film were also evaluated. The addition of high-speed shear improved the dispersion of the emulsion system, and PVA/CMC-Zr-Ce film with good adsorption performance and film stability was prepared. While, it was found that the adsorption capacity could reach 67.25 mg/g and equilibrium time could reach 20 min. The adsorption mechanism of PVA/CMC-Zr-Ce revealed that ion exchange between hydroxide and fluoride, electrostatic interactions and complexation were the dominating influencing factors. Based on these findings, it can be concluded that PVA/CMC-Zr-Ce film- synthesized with high-speed shear assistance technique is a promising adsorbent for fluoride removal from water.

Autophagy functions as a cytoprotective mechanism by regulating programmed cell death during desiccation in Syntrichia caninervis.

Desiccation is a state of extreme water loss that is lethal to many plant species. Some desert plants have evolved unique strategies to cope with desiccation stress in their natural environment. Here we present the remarkable stress management mechanism of Syntrichia caninervis, a desert moss species which exhibits an 'A' category of desiccation tolerance. Our research demonstrated that desiccation stress triggers autophagy in S. caninervis while inhibiting Programmed Cell Death (PCD). Silencing of two autophagy-related genes, ATG6 and ATG2, in S. caninervis promoted PCD. Desiccation treatment accelerated cell death in ATG6 and ATG2 gene-silenced S. caninervis. Notably, trehalose was not detected during desiccation, and exogenous application of trehalose cannot activate autophagy. These results suggested that S. caninervis is independent of trehalose accumulation to triggered autophagy. Our results showed that autophagy function as prosurvival mechanism to enhance desiccation tolerance of S. caninervis. Our findings enrich the knowledge of the role of autophagy in plant stress response and may provide new insight into understanding of plant desiccation tolerance.

Predictive value of prenatal ultrasound combined with long non-coding RNA CRNDE of women for their postpartum lower extremity deep venous thrombosis.

OBJECTIVE: Deep vein thrombosis (DVT) is a common complication in obstetrics that needs early interaction. The study examined the expression change and clinical value of long non-coding RNA (lncRNA) colorectal neoplasia differentially expressed (CRNDE) in DVT early diagnosis. METHODS: One hundred patients with DVT after delivery and 100 healthy parturients without DVT were enrolled. Serum samples were collected one day before delivery and received qRT-PCR for mRNA detection. Prenatal coagulation markers including prothrombin time (PT), activated partial prothrombin time (APTT), fibrinogen (FIB) and thrombin time (TT), D-dimer (D-D), thrombomodulin (TM), and peroxidase anti-peroxidase soluble complex (PAP) were tested. The receiver operating characteristic (ROC) curve was drawn for the diagnostic value assessment. RESULTS: LncRNA CRNDE levels increased remarkably in the serum of DVT patients compared with the healthy controls, which were negatively correlated with serum concentration of PT, APTT, and TT while positively correlated with FIB, D-D, TM, and PAP. Serum CRNDE (HR = 5.973, 95% CI = 2.990-11.933, p < .001) was independently related to the occurrence of DVT after delivery. Then, ROC curve using serum CRNDE showed a good diagnostic value for DVT with the AUC of 0.899. ROC curve of ultrasonography combined with CRNDE produced an AUC of 0.968, and both sensitivity and specificity were enhanced compared to a single indicator. CONCLUSIONS: The increase of CRNDE level was an independent risk factor for postpartum DVT. Prenatal ultrasonography combined with CRNDE can improve the predictive efficacy for DVT.

MYB24, MYB144, and MYB168 positively regulate suberin biosynthesis at potato tuber wounds during healing.

The essence of wound healing is the accumulation of suberin at wounds, which is formed by suberin polyphenolic (SPP) and suberin polyaliphatic (SPA). The biosynthesis of SPP and SPA monomers is catalyzed by several enzyme classes related to phenylpropanoid metabolism and fatty acid metabolism, respectively. However, how suberin biosynthesis is regulated at the transcriptional level during potato (Solanum tuberosum) tuber wound healing remains largely unknown. Here, 6 target genes and 15 transcription factors related to suberin biosynthesis in tuber wound healing were identified by RNA-seq technology and qRT-PCR. Dual luciferase and yeast one-hybrid assays showed that StMYB168 activated the target genes StPAL, StOMT, and St4CL in phenylpropanoid metabolism. Meanwhile, StMYB24 and StMYB144 activated the target genes StLTP, StLACS, and StCYP in fatty acid metabolism, and StFHT involved in the assembly of SPP and SPA domains in both native and wound periderms. More importantly, virus-induced gene silencing in S. tuberosum and transient overexpression in Nicotiana benthamiana assays confirmed that StMYB168 regulates the biosynthesis of free phenolic acids, such as ferulic acid. Furthermore, StMYB24/144 regulated the accumulation of suberin monomers, such as ferulates, α, ω-diacids, and ω-hydroxy acids. In conclusion, StMYB24, StMYB144, and StMYB168 have an elaborate division of labor in regulating the synthesis of suberin during tuber wound healing.

Molecular basis of hippopotamus ACE2 binding to SARS-CoV-2.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has a wide range of hosts, including hippopotami, which are semi-aquatic mammals and phylogenetically closely related to Cetacea. In this study, we characterized the binding properties of hippopotamus angiotensin-converting enzyme 2 (hiACE2) to the spike (S) protein receptor binding domains (RBDs) of the SARS-CoV-2 prototype (PT) and variants of concern (VOCs). Furthermore, the cryo-electron microscopy (cryo-EM) structure of the SARS-CoV-2 PT S protein complexed with hiACE2 was resolved. Structural and mutational analyses revealed that L30 and F83, which are specific to hiACE2, played a crucial role in the hiACE2/SARS-CoV-2 RBD interaction. In addition, comparative and structural analysis of ACE2 orthologs suggested that the cetaceans may have the potential to be infected by SARS-CoV-2. These results provide crucial molecular insights into the susceptibility of hippopotami to SARS-CoV-2 and suggest the potential risk of SARS-CoV-2 VOCs spillover and the necessity for surveillance. IMPORTANCE: The hippopotami are the first semi-aquatic artiodactyl mammals wherein SARS-CoV-2 infection has been reported. Exploration of the invasion mechanism of SARS-CoV-2 will provide important information for the surveillance of SARS-CoV-2 in hippopotami, as well as other semi-aquatic mammals and cetaceans. Here, we found that hippopotamus ACE2 (hiACE2) could efficiently bind to the RBDs of the SARS-CoV-2 prototype (PT) and variants of concern (VOCs) and facilitate the transduction of SARS-CoV-2 PT and VOCs pseudoviruses into hiACE2-expressing cells. The cryo-EM structure of the SARS-CoV-2 PT S protein complexed with hiACE2 elucidated a few critical residues in the RBD/hiACE2 interface, especially L30 and F83 of hiACE2 which are unique to hiACE2 and contributed to the decreased binding affinity to PT RBD compared to human ACE2. Our work provides insight into cross-species transmission and highlights the necessity for monitoring host jumps and spillover events on SARS-CoV-2 in semi-aquatic/aquatic mammals.

Hydrogen gas: A new fresh keeping agent of perishable horticultural products.

Hydrogen gas (H2), a gaseous signaling molecule, is involved in plant growth and development. This review collates emerging evidence to show that H2 regulates the postharvest senescence of horticultural products through critical biochemical processes, including the improvement of antioxidant systems, the activation of cell wall metabolism, the promotion of energy metabolism, the inhibition of ethylene biosynthesis and the regulation of bacterial communities. Additionally, the interactions between H2 and other signaling molecules are also discussed. This paper presents the current status of H2 research in terms of its biological effects and safety in postharvest products by combining the research results on the molecular mechanisms of biological effects and H2 signaling. The action mechanism of H2 for postharvest preservation is also proposed, and it reflects the complexity and diversity of the pathways involved. Furthermore, a growing body of evidence has found a large number of downstream pathways or targets for the medical effects of H2. Therefore, the scientific and practical aspects of H2 biology are proposed for the postharvest preservation of horticultural products.

IGSF10 inhibits the metastasis of lung adenocarcinoma via the Spi-B/Integrin-ß1 signaling pathway.

IGSF10, a protein that belongs to the immunoglobulin superfamily, is involved in regulating the early migration of neurons that produce gonadotropin-releasing hormone and performs a fundamental function in development. Our previous study confirmed that the mRNA expression level of IGSF10 may be a protective prognosis factor for lung adenocarcinoma (LUAD) patients. However, the specific mechanisms of IGSF10 are still unclear. In this research, it was shown that the protein level of IGSF10 was down-modulated in LUAD tissues and had a link to the clinical and pathological characteristics as well as the patient's prognosis in LUAD. Importantly, IGSF10 regulates the metastatic ability of LUAD cells in vitro and in vivo. It was proven in a mechanistic sense that IGSF10 inhibits the capacity of LUAD cells to metastasize through the Spi-B/Integrin-ß1 signaling pathway. These findings gave credence to the premise that IGSF10 performed a crucial function in LUAD.

Grape Seed Proanthocyanidins Protect Pancreatic ß Cells Against Ferroptosis via the Nrf2 Pathway in Type 2 Diabetes.

Pancreatic ß cell damage is the primary contributor to type 2 diabetes mellitus (T2DM); however, the underlying mechanism remains nebulous. This study explored the role of ferroptosis in pancreatic ß cell damage and the protective effects of grape seed proanthocyanidin extract (GSPE). In T2DM model rats, the blood glucose, water intake, urine volume, HbA1c, and homeostasis model assessment-insulin resistance were significantly increased, while the body weight and the insulin level were significantly decreased, indicating the successful establishment of the T2DM model. MIN6 mouse insulinoma ß cells were cultured in high glucose and sodium palmitate conditions to obtain a glycolipid damage model, which was administered with GSPE, ferrostatin-1 (Fer-1), or nuclear factor erythroid 2-related factor 2 (Nrf2) small interfering (si) RNA. GSPE and Fer-1 treatment significantly improved pancreatic ß-cell dysfunction and protected against cell death. Both treatments increased the superoxide dismutase and glutathione activity, reduced the malondialdehyde and reactive oxygen species levels, and improved iron metabolism. Furthermore, the treatments reversed the expression of ferroptosis markers cysteine/glutamate transporter (XCT) and glutathione peroxidase 4 (GPX4) caused by glycolipid toxicity. GSPE treatments activated the expression of Nrf2 and related proteins. These effects were reversed when co-transfected with si-Nrf2. GSPE inhibits ferroptosis by activating the Nrf2 signaling pathway, thus reducing ß-cell damage and dysfunction in T2DM. Therefore, GSPE is a potential treatment strategy against T2DM.

Targeting JMJD1C to selectively disrupt tumor Treg cell fitness enhances antitumor immunity.

Regulatory T (Treg) cells are critical for immune tolerance but also form a barrier to antitumor immunity. As therapeutic strategies involving Treg cell depletion are limited by concurrent autoimmune disorders, identification of intratumoral Treg cell-specific regulatory mechanisms is needed for selective targeting. Epigenetic modulators can be targeted with small compounds, but intratumoral Treg cell-specific epigenetic regulators have been unexplored. Here, we show that JMJD1C, a histone demethylase upregulated by cytokines in the tumor microenvironment, is essential for tumor Treg cell fitness but dispensable for systemic immune homeostasis. JMJD1C deletion enhanced AKT signals in a manner dependent on histone H3 lysine 9 dimethylation (H3K9me2) demethylase and STAT3 signals independently of H3K9me2 demethylase, leading to robust interferon-γ production and tumor Treg cell fragility. We have also developed an oral JMJD1C inhibitor that suppresses tumor growth by targeting intratumoral Treg cells. Overall, this study identifies JMJD1C as an epigenetic hub that can integrate signals to establish tumor Treg cell fitness, and we present a specific JMJD1C inhibitor that can target tumor Treg cells without affecting systemic immune homeostasis.

The lncRNA20718-miR6022-RLPs module regulates tomato resistance to Phytophthora infestans.

KEY MESSAGE: Sl-lncRNA20718 acts as an eTM of Sl-miR6022 regulating its expression thereby affecting SlRLP6/10 expression. SlRLP6/10 regulate PRs expression, ROS accumulation, and JA/ET content thereby affecting tomato resistance to P. infestans. Tomato (Solanum lycopersicum) is an important horticultural and cash crop whose yield and quality can be severely affected by Phytophthora infestans (P. infestans). Long non-coding RNAs (lncRNAs) and microRNAs (miRNAs) are widely involved in plant defense responses against pathogens. The involvement of Sl-lncRNA20718 and Sl-miR6022 in tomato resistance to P. infestans as well as the targeting of Sl-miR6022 to receptor-like protein genes (RLPs) were predicted in our previous study. However, uncertainty exists regarding their potential interaction as well as the molecular processes regulating tomato resistance. Here, we found that Sl-lncRNA20718 and Sl-miR6022 are positive and negative regulators of tomato resistance to P. infestans by gain- and loss-of-function experiments, respectively. Overexpression of Sl-lncRNA20718 decreased the expression of Sl-miR6022, induced the expression of PRs, reduced the diameter of lesions (DOLs), thereby enhanced disease resistance. A six-point mutation in the binding region of Sl-lncRNA20718 to Sl-miR6022 disabled the interaction, indicating that Sl-lncRNA20718 acts as an endogenous target mimic (eTM) of Sl-miR6022. We demonstrated that Sl-miR6022 cleaves SlRLP6/10. Overexpression of Sl-miR6022 decreases the expression levels of SlRLP6/10, induces the accumulation of reactive oxygen species (ROS) and reduces the content of JA and ET, thus inhibiting tomato resistance to P. infestans. In conclusion, our study provides detailed information on the lncRNA20718-miR6022-RLPs module regulating tomato resistance to P. infestans by affecting the expression of disease resistance-related genes, the accumulation of ROS and the phytohormone levels, providing a new reference for tomato disease resistance breeding.

Transcriptome Profiles Reveals ScDREB10 from Syntrichia caninervis Regulated Phenylpropanoid Biosynthesis and Starch/Sucrose Metabolism to Enhance Plant Stress Tolerance.

Desiccation is a kind of extreme form of drought stress and desiccation tolerance (DT) is an ancient trait of plants that allows them to survive tissue water potentials reaching -100 MPa or lower. ScDREB10 is a DREB A-5 transcription factor gene from a DT moss named Syntrichia caninervis, which has strong comprehensive tolerance to osmotic and salt stresses. This study delves further into the molecular mechanism of ScDREB10 stress tolerance based on the transcriptome data of the overexpression of ScDREB10 in Arabidopsis under control, osmotic and salt treatments. The transcriptional analysis of weight gene co-expression network analysis (WGCNA) showed that "phenylpropanoid biosynthesis" and "starch and sucrose metabolism" were key pathways in the network of cyan and yellow modules. Meanwhile, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis of differentially expressed genes (DEGs) also showed that "phenylpropanoid biosynthesis" and "starch and sucrose metabolism" pathways demonstrate the highest enrichment in response to osmotic and salt stress, respectively. Quantitative real-time PCR (qRT-PCR) results confirmed that most genes related to phenylpropanoid biosynthesis" and "starch and sucrose metabolism" pathways in overexpressing ScDREB10 Arabidopsis were up-regulated in response to osmotic and salt stresses, respectively. In line with the results, the corresponding lignin, sucrose, and trehalose contents and sucrose phosphate synthase activities were also increased in overexpressing ScDREB10 Arabidopsis under osmotic and salt stress treatments. Additionally, cis-acting promoter element analyses and yeast one-hybrid experiments showed that ScDREB10 was not only able to bind with classical cis-elements, such as DRE and TATCCC (MYBST1), but also bind with unknown element CGTCCA. All of these findings suggest that ScDREB10 may regulate plant stress tolerance by effecting phenylpropanoid biosynthesis, and starch and sucrose metabolism pathways. This research provides insights into the molecular mechanisms underpinning ScDREB10-mediated stress tolerance and contributes to deeply understanding the A-5 DREB regulatory mechanism.