Extracellular pH sensing by plant cell-surface peptide-receptor complexes.

The extracellular pH is a vital regulator of various biological processes in plants. However, how plants perceive extracellular pH remains obscure. Here, we report that plant cell-surface peptide-receptor complexes can function as extracellular pH sensors. We found that pattern-triggered immunity (PTI) dramatically alkalinizes the acidic extracellular pH in root apical meristem (RAM) region, which is essential for root meristem growth factor 1 (RGF1)-mediated RAM growth. The extracellular alkalinization progressively inhibits the acidic-dependent interaction between RGF1 and its receptors (RGFRs) through the pH sensor sulfotyrosine. Conversely, extracellular alkalinization promotes the alkaline-dependent binding of plant elicitor peptides (Peps) to its receptors (PEPRs) through the pH sensor Glu/Asp, thereby promoting immunity. A domain swap between RGFR and PEPR switches the pH dependency of RAM growth. Thus, our results reveal a mechanism of extracellular pH sensing by plant peptide-receptor complexes and provide insights into the extracellular pH-mediated regulation of growth and immunity in the RAM.

TIR domains of plant immune receptors are 2',3'-cAMP/cGMP synthetases mediating cell death.

2',3'-cAMP is a positional isomer of the well-established second messenger 3',5'-cAMP, but little is known about the biology of this noncanonical cyclic nucleotide monophosphate (cNMP). Toll/interleukin-1 receptor (TIR) domains of nucleotide-binding leucine-rich repeat (NLR) immune receptors have the NADase function necessary but insufficient to activate plant immune responses. Here, we show that plant TIR proteins, besides being NADases, act as 2',3'-cAMP/cGMP synthetases by hydrolyzing RNA/DNA. Structural data show that a TIR domain adopts distinct oligomers with mutually exclusive NADase and synthetase activity. Mutations specifically disrupting the synthetase activity abrogate TIR-mediated cell death in Nicotiana benthamiana (Nb), supporting an important role for these cNMPs in TIR signaling. Furthermore, the Arabidopsis negative regulator of TIR-NLR signaling, NUDT7, displays 2',3'-cAMP/cGMP but not 3',5'-cAMP/cGMP phosphodiesterase activity and suppresses cell death activity of TIRs in Nb. Our study identifies a family of 2',3'-cAMP/cGMP synthetases and establishes a critical role for them in plant immune responses.

The ZAR1 resistosome is a calcium-permeable channel triggering plant immune signaling.

Nucleotide-binding, leucine-rich repeat receptors (NLRs) are major immune receptors in plants and animals. Upon activation, the Arabidopsis NLR protein ZAR1 forms a pentameric resistosome in vitro and triggers immune responses and cell death in plants. In this study, we employed single-molecule imaging to show that the activated ZAR1 protein can form pentameric complexes in the plasma membrane. The ZAR1 resistosome displayed ion channel activity in Xenopus oocytes in a manner dependent on a conserved acidic residue Glu11 situated in the channel pore. Pre-assembled ZAR1 resistosome was readily incorporated into planar lipid-bilayers and displayed calcium-permeable cation-selective channel activity. Furthermore, we show that activation of ZAR1 in the plant cell led to Glu11-dependent Ca2+ influx, perturbation of subcellular structures, production of reactive oxygen species, and cell death. The results thus support that the ZAR1 resistosome acts as a calcium-permeable cation channel to trigger immunity and cell death.

Substrate-induced condensation activates plant TIR domain proteins.

Plant nucleotide-binding leucine-rich repeat (NLR) immune receptors with an N-terminal Toll/interleukin-1 receptor (TIR) domain mediate recognition of strain-specific pathogen effectors, typically via their C-terminal ligand-sensing domains1. Effector binding enables TIR-encoded enzymatic activities that are required for TIR-NLR (TNL)-mediated immunity2,3. Many truncated TNL proteins lack effector-sensing domains but retain similar enzymatic and immune activities4,5. The mechanism underlying the activation of these TIR domain proteins remain unclear. Here we show that binding of the TIR substrates NAD+ and ATP induces phase separation of TIR domain proteins in vitro. A similar condensation occurs with a TIR domain protein expressed via its native promoter in response to pathogen inoculation in planta. The formation of TIR condensates is mediated by conserved self-association interfaces and a predicted intrinsically disordered loop region of TIRs. Mutations that disrupt TIR condensates impair the cell death activity of TIR domain proteins. Our data reveal phase separation as a mechanism for the activation of TIR domain proteins and provide insight into substrate-induced autonomous activation of TIR signalling to confer plant immunity.

NLR signaling in plants: from resistosomes to second messengers.

Nucleotide binding and leucine-rich repeat-containing receptors (NLRs) have a critical role in plant immunity through direct or indirect recognition of pathogen effectors. Recent studies have demonstrated that such recognition induces formation of large protein complexes called resistosomes to mediate NLR immune signaling. Some NLR resistosomes activate Ca2+ influx by acting as Ca2+-permeable channels, whereas others function as active NADases to catalyze the production of nucleotide-derived second messengers. In this review we summarize these studies on pathogen effector-induced assembly of NLR resistosomes and resistosome-mediated production of the second messengers of Ca2+ and nucleotide derivatives. We also discuss downstream events and regulation of resistosome signaling.

FoxO1 promotes ovarian cancer by increasing transcription and METTL14-mediated m6A modification of SMC4.

The transcription factor forkhead box protein O1 (FoxO1) is closely related to the occurrence and development of ovarian cancer (OC), however its role and molecular mechanisms remain unclear. Herein, we found that FoxO1 was highly expressed in clinical samples of OC patients and was significantly correlated with poor prognosis. FoxO1 knockdown inhibited the proliferation of OC cells in vitro and in vivo. ChIP-seq combined with GEPIA2 and Kaplan-Meier database analysis showed that structural maintenance of chromosome 4 (SMC4) is a downstream target of FoxO1, and FoxO1 promotes SMC4 transcription by binding to its -1400/-1390 bp promoter. The high expression of SMC4 significantly blocked the tumor inhibition effect of FoxO1 knockdown. Furtherly, FoxO1 increased SMC4 mRNA abundance by transcriptionally activating methyltransferase-like 14 (METTL14) and increasing SMC4 m6A methylation on its coding sequence region. The Cancer Genome Atlas dataset analysis confirmed a significant positive correlation between FoxO1, SMC4, and METTL14 expression in OC. In summary, this study revealed the molecular mechanisms of FoxO1 regulating SMC4 and established a clinical link between the expression of FoxO1/METTL14/SMC4 in the occurrence of OC, thus providing a potential diagnostic target and therapeutic strategy.

Phosphorylation at Ser724 of the ER stress sensor IRE1α governs its activation state and limits ER stress-induced hepatosteatosis.

Inositol-requiring enzyme 1 (IRE1) is an evolutionarily conserved sensor of endoplasmic reticulum (ER) stress and mediates a key branch of the unfolded protein response in eukaryotic cells. It is an ER-resident transmembrane protein that possesses Ser/Thr protein kinase and endoribonuclease (RNase) activities in its cytoplasmic region. IRE1 is activated through dimerization/oligomerization and autophosphorylation at multiple sites, acting through its RNase activity to restore the functional capacity of the ER. However, it remains poorly defined in vivo how the autophosphorylation events of endogenous IRE1 govern its dynamic activation and functional output. Here, we generated a mouse model harboring a S724A knock-in mutation (Ern1S724A/S724A) and investigated the importance of phosphorylation at Ser724 within the kinase activation loop of murine IRE1α. We found that in mouse embryonic fibroblast cells and in primary hepatocytes, S724A mutation resulted in markedly reduced IRE1α autophosphorylation in parallel with blunted activation of its RNase activity to catalyze X-box binding protein 1 (Xbp1) mRNA splicing. Furthermore, ablation of IRE1α phosphorylation at Ser724 exacerbated ER stress-induced hepatic steatosis in tunicamycin-treated Ern1S724A/S724A mice. This was accompanied by significantly decreased hepatic production of spliced XBP1 protein but increased CCAAT-enhancer-binding protein homologous protein (CHOP) level, along with suppressed expression of key metabolic regulators of fatty acid ß-oxidation and lipid secretion. These results demonstrate a critical role of phosphorylation at Ser724 of IRE1α in dynamically controlling its kinase activity, and thus its autophosphorylation state, which is coupled to activation of its RNase activity in counteracting hepatic steatosis under ER stress conditions.

Mineralocorticoid receptor deficiency in Treg cells ameliorates DSS-induced colitis in a gut microbiota-dependent manner.

Mineralocorticoid receptor (MR) is a classic nuclear receptor and an effective drug target in the cardiovascular system. The function of MR in immune cells such as macrophages and T cells has been increasingly appreciated. The aim of this study was to investigate the function of Treg MR in the process of inflammatory bowel disease (IBD). We treated Treg MR-deficient (MRflox/flox Foxp3YFP-Cre , KO) mice and control (Foxp3YFP-Cre , WT) mice with dextran sodium sulphate (DSS) to induce colitis and found that the severity of DSS-induced colitis was markedly alleviated in Treg MR-deficient mice, accompanied by reduced production of inflammatory cytokines, and relieved infiltration of monocytes, neutrophils and interferon γ+ T cells in colon lamina propria. Faecal microbiota of mice with colitis was analysed by 16S rRNA gene sequencing and the composition of gut microbiota was vastly changed in Treg MR-deficient mice. Furthermore, depletion of gut microbiota by antibiotics abolished the protective effects of Treg MR deficiency and resulted in similar severity of DSS-induced colitis in WT and KO mice. Faecal microbiota transplantation from KO mice attenuated DSS-induced colitis characterized by alleviated inflammatory infiltration compared to that from WT mice. Hence, our study demonstrates that Treg MR deficiency protects against DSS-induced colitis by attenuation of colonic inflammatory infiltration. Gut microbiota is both sufficient and necessary for Treg MR deficiency to exert the beneficial effects.

Anatomic characteristics of the knee influence the risk of suffering an isolated meniscal injury and the risk factors differ between women and men.

PURPOSE: To analyse the relationship between multiple anatomic characteristics of the knee (tibia and femur) and isolated meniscal injury in women and men. METHODS: Forty-seven patients with isolated medial meniscal injuries, 62 patients with isolated lateral meniscal injuries, and 70 control subjects were included. Medial posterior tibial slope (MTS), lateral posterior tibial slope (LTS), medial tibial plateau depth (MTD), coronal tibial slope (CTS), femoral notch width (NW), femoral condylar width (FCW), intercondylar notch depth (ND), femoral notch width index (NWI), intercondylar notch shape index (NSI), and cruciate ligaments tensity (CLT) were measured from magnetic resonance images. Anatomic characteristics differing between groups were compared, and risk factors for isolated meniscal injury were identified by multivariate forward stepwise logistic regression for men and women separately. RESULTS: Risk factors for an isolated medial meniscal injury were a steeper MTS and a lowered MTD in men, and a steeper MTS and an increased NWI in women. Risk factors for isolated lateral meniscal injury were a steeper LTS and an increased NW in men, and a steeper LTS and a lowered ND in women. Risk factors for both medial and lateral meniscal injuries were a higher CTS, an increased NWI, and a looser CLT in men, and a higher CTS, an increased NSI, and a looser CLT in women. CONCLUSION: The anatomic characteristics of the tibial plateau, femur, and cruciate ligaments influence the risk of suffering isolated meniscal injury, and the risk factors differ between men and women. This study provides a reference for developing identification criteria for those at risk of isolated meniscal injury. LEVEL OF EVIDENCE: III.

Emerging roles for the ER stress sensor IRE1α in metabolic regulation and disease.

Inositol-requiring enzyme 1 (IRE1) is an endoplasmic reticulum (ER)-resident transmembrane protein that senses ER stress and is evolutionarily conserved from yeast to humans. IRE1 possesses both Ser/Thr protein kinase and endoribonuclease (RNase) activities within its cytoplasmic domain and is activated through autophosphorylation and dimerization/oligomerization. It mediates a critical arm of the unfolded protein response to manage ER stress provoked by lumenal overload of unfolded/misfolded proteins. Emerging lines of evidence have revealed that in mammals, IRE1α functions as a multifunctional signal transducer that responds to metabolic cues and nutrient stress conditions, exerting profound and broad effects on metabolic homeostasis. In this review, we cover recent advances in our understanding of how IRE1α integrates a variety of metabolic and stress signals and highlight its tissue-specific or context-dependent metabolic activities. We also discuss how dysregulation of this metabolic stress sensor during handling of excessive nutrients in cells contributes to the progression of obesity and metabolic disorders.

Mitochondrial activity related genes of mast cells identify poor prognosis and metastasis of ovarian cancer.

The pro-tumorigenic or anti-tumorigenic role of tumor infiltrating mast cells (TIMs) in tumors depends not only on the type of cancer and the degree of tumor progression, but also on their location in the tumor bulk. In our investigation, we employed immunohistochemistry to reveal that the mast cells (MCs) in the tumor stroma are positively correlated with metastasis of ovarian cancer (OC), but not in the tumor parenchyma. To delve deeper into the influence of different culture matrix stiffness on MCs' biological functions within the tumor parenchymal and stromal regions, we conducted a transcriptome analysis of the mouse MC line (P815) cultured in two-dimensional (2D) or three-dimensional (3D) culture system. Further research has found that the softer 3D extracellular matrix stiffness could improve the mitochondrial activity of MCs to promote proliferation by increasing the expression levels of mitochondrial activity-related genes, namely Pet100, atp5md, and Cox7a2. Furthermore, employing LASSO regression analysis, we identified that Pet100 and Cox7a2 were closely associated with the prognosis of OC patients. These two genes were subsequently employed to construct a risk score model, which revealed that the high-risk group model as one of the prognostic factors for OC patients. Additionally, the XCell algorithm analysis showed that the high-risk group displayed a broader spectrum of immune cell infiltrations. Our research revealed that TIMs in the tumor stroma could promote the metastasis of OC, and mitochondrial activity-related proteins Pet100/Cox7a2 can serve as biomarkers for prognostic evaluation of OC.

Risk Factors for Systemic Inflammatory Response Syndrome After Percutaneous Transhepatic Cholangioscopic Lithotripsy.

Background: There is a lack of validated predictive models for the occurrence of systemic inflammatory response syndrome (SIRS) after percutaneous transhepatic cholangioscopic lithotripsy (PTCSL) for the treatment of hepatolithiasis. This is the first study to estimate the incidence of SIRS after PTCSL. Methods: A retrospective analysis of 284 PTCSL sessions for the treatment of hepatolithiasis at our institution between January 2019 and January 2023 was performed. The development of SIRS after PTCSL was the primary study endpoint. Independent risk factors for SIRS after PTCSL were identified using univariate and multivariate logistic regression analyses. A nomogram prediction model was constructed using these independent risk factors, and the predictive value was assessed using receiver operating characteristic (ROC) curves. Results: The incidence of SIRS after PTCSL was 20.77%. According to multivariate analysis, the number of PTCSL sessions (odds ratio [OR]=0.399, 95% confidence interval [CI]=0.202-0.786, p=0.008), stone location (OR=2.194, 95% CI=1.107-4.347, p=0.024), intraoperative use of norepinephrine (OR=0.301, 95% CI=0.131-0.689, p=0.004), intraoperative puncture (OR=3.476, 95% CI=1.749-6.906, P<0.001), preoperative gamma-glutamyltransferase (OR=1.002, 95% CI=1.001-1.004, p=0.009), and preoperative total lymphocyte count (OR=1.820, 95% CI=1.110-2.985, p=0.018) were found to be independent risk factors for the development of SIRS after PTCSL. These six independent risk factors were used to construct a nomogram prediction model, which showed satisfactory accuracy with an area under the ROC curve of 0.776 (95% CI: 0.702-0.850). Conclusion: The number of PTCSL sessions, stone location, intraoperative use of norepinephrine, intraoperative puncture, preoperative gamma-glutamyltransferase, and preoperative total lymphocyte count may predict the occurrence of SIRS after PTCSL. This prediction model may help clinicians identify high-risk patients in advance.

Study on the correlation between controlling nutritional status score and clinical biochemical indicators in patients with colorectal cancer.

Purpose: The controlling nutritional status (CONUT) score is an important tool for predicting the prognosis of colorectal cancer (CRC); however, its effectiveness is relatively insufficient. This study aimed to screen for more effective clinical indicators as supplements to the CONUT scoring system and improve the predictive value of CRC prognosis. Patients and methods: Between 2014 and 2020, the clinical information of all CRC patients in our unit was retrospectively collected, and the CONUT scores were calculated based on the levels of serum albumin (ALB), lymphocytes (LC), and total cholesterol. The included patients were divided into the following three groups: normal nutrition (0-1), mild malnutrition (2-4), and moderate-to-severe malnutrition (5-12). The correlations between the CONUT score and baseline characteristics and clinical indicators were evaluated. Results: This study ultimately included 5014 CRC patients. The nutritional status of patients with colon cancer (CC) was worse than that of rectal cancer (RC). The nutritional status was worse in men than in women. The older the patient, the poorer the nutritional status, and the poorer the nutritional status, the longer the hospital stay. In addition, poor nutritional status in patients is indicated by higher values of neutrophils (NE), monocytes (MC), eosinophils (EOS), alkaline phosphatase (ALP), lactate dehydrogenase (LDH), carcinoembryogenic antigen (CEA), and lower values of white blood cells (WBC), basophils (BAS), haemoglobin (HB), total protein (TP), triglycerides (TG), low density lipoprotein (LDL), aspartate transaminase (AST), and blood urea nitrogen (BUN), which was statistically significant (P < 0.05). Indicators that significantly correlated with the CONUT score reflected the immune nutritional status, including WBC (odds ratio [OR] = 0.036, P < 0.001), NE (OR = 30.815, P < 0.001), MC (OR = 41.388, P < 0.001), EOS (OR = 27.577, P < 0.001), BAS (OR = 0.006, P = 0.046), and LDL (OR = 0.319, P < 0.001). Conclusion: Additional variables such as WBC, NE, MC, EOS, BAS, and LDL may be used as supplementary indicators in the CONUT scoring system to more effectively predict the clinical prognosis of CRC patients.

Mammalian IRE1α dynamically and functionally coalesces with stress granules.

Upon endoplasmic reticulum (ER) stress, activation of the ER-resident transmembrane protein kinase/endoribonuclease inositol-requiring enzyme 1 (IRE1) initiates a key branch of the unfolded protein response (UPR) through unconventional splicing generation of the transcription factor X-box-binding protein 1 (XBP1s). Activated IRE1 can form large clusters/foci, whose exact dynamic architectures and functional properties remain largely elusive. Here we report that, in mammalian cells, formation of IRE1α clusters is an ER membrane-bound phase separation event that is coupled to the assembly of stress granules (SGs). In response to different stressors, IRE1α clusters are dynamically tethered to SGs at the ER. The cytosolic linker portion of IRE1α possesses intrinsically disordered regions and is essential for its condensation with SGs. Furthermore, disruption of SG assembly abolishes IRE1α clustering and compromises XBP1 mRNA splicing, and such IRE1α-SG coalescence engenders enrichment of the biochemical components of the pro-survival IRE1α-XBP1 pathway during ER stress. Our findings unravel a phase transition mechanism for the spatiotemporal assembly of IRE1α-SG condensates to establish a more efficient IRE1α machinery, thus enabling higher stress-handling capacity.

A plant mechanism of hijacking pathogen virulence factors to trigger innate immunity.

Polygalacturonase-inhibiting proteins (PGIPs) interact with pathogen-derived polygalacturonases to inhibit their virulence-associated plant cell wall-degrading activity but stimulate immunity-inducing oligogalacturonide production. Here we show that interaction between Phaseolus vulgaris PGIP2 (PvPGIP2) and Fusarium phyllophilum polygalacturonase (FpPG) enhances substrate binding, resulting in inhibition of the enzyme activity of FpPG. This interaction promotes FpPG-catalyzed production of long-chain immunoactive oligogalacturonides, while diminishing immunosuppressive short oligogalacturonides. PvPGIP2 binding creates a substrate binding site on PvPGIP2-FpPG, forming a new polygalacturonase with boosted substrate binding activity and altered substrate preference. Structure-based engineering converts a putative PGIP that initially lacks FpPG-binding activity into an effective FpPG-interacting protein. These findings unveil a mechanism for plants to transform pathogen virulence activity into a defense trigger and provide proof of principle for engineering PGIPs with broader specificity.

Alterations of oral and gut viromes in hypertension and/or periodontitis.

The microbiota plays an important role in both hypertension (HTN) and periodontitis (PD), and PD exacerbates the development of HTN by oral and gut microbiota. Previous studies have focused on exploring the importance of the bacteriome in HTN and PD but overlooked the impact of the virome, which is also a member of the microbiota. We collected 180 samples of subgingival plaques, saliva, and feces from a cohort of healthy subjects (nHTNnPD), subjects with HTN (HTNnPD) or PD (PDnHTN), and subjects with both HTN and PD (HTNPD). We performed metagenomic sequencing to assess the roles of the oral and gut viromes in HTN and PD. The HTNnPD, PDnHTN, and HTNPD groups all showed significantly distinct beta diversity from the nHTNnPD group in saliva. We analyzed alterations in oral and gut viral composition in HTN and/or PD and identified significantly changed viruses in each group. Many viruses across three sites were significantly associated with blood pressure and other clinical parameters. Combined with these clinical associations, we found that Gillianvirus in subgingival plaques was negatively associated with HTN and that Torbevirus in saliva was positively associated with HTN. We found that Pepyhexavirus from subgingival plaques was indicated to be transferred to the gut. We finally evaluated viral-bacterial transkingdom interactions and found that viruses and bacteria may cooperate to affect HTN and PD. Correspondingly, HTN and PD may synergize to improve communications between viruses and bacteria.IMPORTANCEPeriodontitis (PD) and hypertension (HTN) are both highly prevalent worldwide and cause serious adverse outcomes. Increasing studies have shown that PD exacerbates HTN by oral and gut microbiota. Previous studies have focused on exploring the importance of the bacteriome in HTN and PD but overlooked the impact of the virome, even though viruses are common inhabitants in humans. Alterations in oral and gut viral diversity and composition contribute to diseases. The present study, for the first time, profiled the oral and gut viromes in HTN and/or PD. We identified key indicator viruses and their clinical implications in HTN and/or PD. We also investigated interactions between viruses and bacteria. This work improved the overall understanding of the viromes in HTN and PD, providing vital insights into the role of the virome in the development of HTN and PD.

Lysine acetyltransferase 6A maintains CD4+ T cell response via epigenetic reprogramming of glucose metabolism in autoimmunity.

Augmented CD4+ T cell response in autoimmunity is characterized by extensive metabolic reprogramming. However, the epigenetic molecule that drives the metabolic adaptation of CD4+ T cells remains largely unknown. Here, we show that lysine acetyltransferase 6A (KAT6A), an epigenetic modulator that is clinically associated with autoimmunity, orchestrates the metabolic reprogramming of glucose in CD4+ T cells. KAT6A is required for the proliferation and differentiation of proinflammatory CD4+ T cell subsets in vitro, and mice with KAT6A-deficient CD4+ T cells are less susceptible to experimental autoimmune encephalomyelitis and colitis. Mechanistically, KAT6A orchestrates the abundance of histone acetylation at the chromatin where several glycolytic genes are located, thus affecting glucose metabolic reprogramming and subsequent CD4+ T cell responses. Treatment with KAT6A small-molecule inhibitors in mouse models shows high therapeutic value for targeting KAT6A in autoimmunity. Our study provides novel insights into the epigenetic programming of immunometabolism and suggests potential therapeutic targets for patients with autoimmunity.

DSGN++: Exploiting Visual-Spatial Relation for Stereo-Based 3D Detectors.

Camera-based 3D object detectors are welcome due to their wider deployment and lower price than LiDAR sensors. We first revisit the prior stereo detector DSGN for its stereo volume construction ways for representing both 3D geometry and semantics. We polish the stereo modeling and propose the advanced version, DSGN++, aiming to enhance effective information flow throughout the 2D-to-3D pipeline in three main aspects. First, to effectively lift the 2D information to stereo volume, we propose depth-wise plane sweeping (DPS) that allows denser connections and extracts depth-guided features. Second, for grasping differently spaced features, we present a novel stereo volume - Dual-view Stereo Volume (DSV) that integrates front-view and top-view features and reconstructs sub-voxel depth in the camera frustum. Third, as the foreground region becomes less dominant in 3D space, we propose a multi-modal data editing strategy - Stereo-LiDAR Copy-Paste, which ensures cross-modal alignment and improves data efficiency. Without bells and whistles, extensive experiments in various modality setups on the popular KITTI benchmark show that our method consistently outperforms other camera-based 3D detectors for all categories. Code is available at https://github.com/chenyilun95/DSGN2.

TIR-catalyzed nucleotide signaling molecules in plant defense.

Toll and interleukin-1 receptor (TIR) domain is a conserved immune module in prokaryotes and eukaryotes. Signaling regulated by TIR-only proteins or TIR domain-containing intracellular immune receptors is critical for plant immunity. Recent studies demonstrated that TIR domains function as enzymes encoding a variety of activities, which manifest different mechanisms for regulation of plant immunity. These enzymatic activities catalyze metabolism of NAD+, ATP and other nucleic acids, generating structurally diversified nucleotide metabolites. Signaling roles have been revealed for some TIR enzymatic products that can act as second messengers to induce plant immunity. Herein, we summarize our current knowledge about catalytic production of these nucleotide metabolites and their roles in plant immune signaling. We also highlight outstanding questions that are likely to be the focus of future investigations about TIR-produced signaling molecules.

Assessment of bidirectional relationships between circulating cytokines and periodontitis: Insights from a mendelian randomization analysis.

Background: The purpose of this Mendelian randomization (MR) study was to assess the causal relationship between circulating cytokines and periodontitis. Materials and methods: Based on the aggregated statistics of the largest publicly available genome-wide association study (GWAS), we applied a bidirectional two-sample MR. MR analyses were conducted using Inverse variance weighted (IVW), Robust Adjusted Profile Score (RAPS), Maximum likelihood (ML), Weighted median and MR-Egger, and results obtained from IVW served as the primary outcome. Cochran Q test was used to test the heterogeneity. MR-Egger intercept test and MR polymorphism residual and outlier test (MR-PRESSO) were used for polymorphism analysis. Leave-one-out sensitivity and funnel plots were used for sensitivity analysis. Results: The IVW method indicated that interleukin 9 (IL9) had a positive causal relationship with periodontitis [odds ratio (OR) = 1.199, 95% confidence interval (CI) = 1.049-1.372, p = 0.008], and interleukin 17 (IL17) had a negative causal relationship with periodontitis (OR = 0.847, 95% CI = 0.735-0.976, p = 0.022). In bidirectional MR, periodontitis was not causally related to any of the cytokines in our study. Conclusion: Our findings provided evidence in support of potential causal associations between circulating IL9/IL17 and periodontitis.