Metabolomic analysis for asymptomatic hyperuricemia and gout based on a combination of dried blood spot sampling and mass spectrometry technology.

BACKGROUND: Gout is the most common inflammatory arthritis and closely related to metabolic syndrome, leading to excruciating pain and the decline in quality of patients' life. However, the pathogenesis of gout is still unclear, and novel biomarkers are demanded for the early prediction and diagnosis of gout. OBJECTIVE: This study aimed at profiling the dysregulated metabolic pathways in asymptomatic hyperuricemia (AHU) and gout and elucidating the associations between AHU, gout and metabolomics, which may aid in performing gout screening. METHODS: A total of 300 participants, including 114 healthy controls, 92 patients with AHU, and 94 patients with gout, were analyzed by using a combination of dried blood spot (DBS) sampling and mass spectrometry (MS) technology. Multiple algorithms were applied to characterize altered metabolic profiles in AHU and gout. The mainly altered metabolites were identified by random forest analysis. RESULTS: There were significant differences in AHU and gout compared with control group. The altered metabolites were involved in oxidation of fatty acids, carnitine synthesis, urea cycle, and amino acid metabolism in AHU and gout. Random forest classification of 16 metabolites yielded 3 important features to distinguish gout from AHU. CONCLUSIONS: Distinct metabolomic signatures were observed in AHU and gout. The selected metabolites may have the potential to improve the early detection of gout.

RAS signaling and immune cells: a sinister crosstalk in the tumor microenvironment.

The rat sarcoma virus (RAS) gene is the most commonly mutated oncogene in cancer, with about 19% of cancer patients carrying RAS mutations. Studies on the interaction between RAS mutation and tumor immune microenvironment (TIM) have been flourishing in recent years. More and more evidence has proved that RAS signals regulate immune cells' recruitment, activation, and differentiation while assisting tumor cells to evade immune surveillance. This review concluded the direct and indirect treatment strategies for RAS mutations. In addition, we updated the underlying mechanisms by which RAS signaling modulated immune infiltration and immune escape. Finally, we discussed advances in RAS-targeted immunotherapies, including cancer vaccines and adoptive cell therapies, with a particular focus on combination strategies with personalized therapy and great potential to achieve lasting clinical benefits.

A cancer-associated fibroblast subtypes-based signature enables the evaluation of immunotherapy response and prognosis in bladder cancer.

Bladder cancer (BLCA) is one of the most prevalent and heterogeneous urinary malignant tumors. Previous researches have reported a significant association between cancer-associated fibroblasts (CAFs) and poor prognosis of tumor patients. However, uncertainty surrounds the role of CAFs in the BLCA tumor microenvironment, necessitating further investigation into the CAFs-related gene signatures in BLCA. In this study, we identified three CAF subtypes in BLCA according to single-cell RNA-seq data and constructed CAFs-related risk score (CRRS) by screening 102,714 signatures. The survival analysis, ROC curves, and nomogram suggested that CRRS was a valuable predictor in 2,042 patients from 9 available public datasets and Xiangya real-world cohort. We further revealed the significant correlation between CRRS and clinicopathological characteristics, genome alterations, and epithelial-mesenchymal transition (EMT). A high CRRS indicated a non-inflamed phenotype and a lower remission rate of immunotherapy in BLCA. In conclusion, the CRRS had the potential to predict the prognosis and immunotherapy response of BLCA patients.

A retrospective study on expression and clinical significance of PHH3, Ki67 and P53 in bladder exophytic papillary urothelial neoplasms.

Background: Exophytic papillary urothelial neoplasms (EPUN) are difficult to diagnose pathologically and are well-known for their heterogeneous prognoses. Thus, searching for an objective and accurate diagnostic marker is of great clinical value in improving the outcomes of EPUN patients. PHH3 was reported to be expressed explicitly in the mitotic phase of the cell cycle, and recent studies have shown that PHH3 expression was associated with the differential diagnosis and prognosis of many tumors. However, its significance in EPUN remains unclear. This study aimed to determine the expression of PHH3 in different EPUN, compare its expression with cell-cycle related proteins Ki67 and P53, and analyze its significance in the differential diagnosis and prognostic value for high-grade papillary urothelial carcinoma (HGPUC), low-grade papillary urothelial carcinoma (LGPUC), papillary urothelial neoplasm of low malignant potential (PUNLMP) and urothelial papilloma (UP). Methods: We retrospectively analyzed the pathological diagnosis and clinical features of 26 HGPUC cases, 43 LGPUC cases, 21 PUNLMP cases and 11 UP cases. PHH3, Ki67 and P53 were detected by immunohistochemistry in 101 EPUN cases samples. The cut-off values of PHH3 mitosis count (PHMC), HE mitosis count (HEMC), Ki67 and P53 in the different EPUN were determined using the ROC curve. The distribution of counts in each group and its relationship with clinical parameters and prognosis of EPUN patients were also analyzed. Results: The determination coefficient (R2 = 0.9980) of PHMC were more potent than those of HEMC (R2 = 0.9734) in the EPUN mitotic counts microscopically by both pathologists. Of the 101 EPUN cases investigated, significant positive linear correlations were found between PHMC and HEMC, PHMC and Ki67, and HEMC and Ki67 (P < 0.0001). In HGPUC, LGPUC, PUNLMP and UP, a decreasing trend was observed in the median and range of PHMC/10HPFs, HEMC/10HPFs, Ki67 (%) and P53 (%). PHMC, HEMC, Ki67 and P53 were associated with different clinical parameters of EPUN. PHMC, HEMC, Ki67 and P53 were found to exhibit substantial diagnostic values among different EPUN and tumor recurrence. Based on the ROC curve, when PHMC was >48.5/10HPFs, a diagnosis of HGPUC was more likely, and when PHMC was >13.5/10HPFs, LGPUC was more likely. In addition, when PHMC was >5.5/10HPFs, the possibility of non-infiltrating LGPUC was greater. Kaplan-Meier survival curve analysis showed that the median recurrence-free survival (RFS) for cases with PHMC > 13.5/10HPFs and HEMC > 14.5/10HPFs were 52.5 and 48 months, respectively, and their respective hazard ratio was significantly higher (Log-rank P < 0.05). Conclusion: PHH3 exhibited high specificity and sensitivity in diagnosing EPUN. Combined with HEMC, Ki67 and P53, it can assist in the differential diagnosis of EPUN and estimate its clinical progression with high predictive value to a certain extent.

MYB112 connects light and circadian clock signals to promote hypocotyl elongation in Arabidopsis.

Ambient light and the endogenous circadian clock play key roles in regulating Arabidopsis (Arabidopsis thaliana) seedling photomorphogenesis. PHYTOCHROME-INTERACTING FACTOR 4 (PIF4) acts downstream of both light and the circadian clock to promote hypocotyl elongation. Several members of the R2R3-MYB transcription factor (TF) family, the most common type of MYB TF family in Arabidopsis, have been shown to be involved in regulating photomorphogenesis. Nonetheless, whether R2R3-MYB TFs are involved in connecting the light and clock signaling pathways during seedling photomorphogenesis remains unknown. Here, we report that MYB112, a member of the R2R3-MYB family, acts as a negative regulator of seedling photomorphogenesis in Arabidopsis. The light signal promotes the transcription and protein accumulation of MYB112. myb112 mutants exhibit short hypocotyls in both constant light and diurnal cycles. MYB112 physically interacts with PIF4 to enhance the transcription of PIF4 target genes involved in the auxin pathway, including YUCCA8 (YUC8), INDOLE-3-ACETIC ACID INDUCIBLE 19 (IAA19), and IAA29. Furthermore, MYB112 directly binds to the promoter of LUX ARRHYTHMO (LUX), the central component of clock oscillators, to repress its expression mainly in the afternoon and relieve LUX-inhibited expression of PIF4. Genetic evidence confirms that LUX acts downstream of MYB112 in regulating hypocotyl elongation. Thus, the enhanced transcript accumulation and transcriptional activation activity of PIF4 by MYB112 additively promotes the expression of auxin-related genes, thereby increasing auxin synthesis and signaling and fine-tuning hypocotyl growth under diurnal cycles.

Lipophagy-related gene RAB7A is involved in immune regulation and malignant progression in hepatocellular carcinoma.

BACKGROUND: RAB7A (RAS-related in Brain 7A) is an important member of the RAS oncogene family. However, the correlation between RAB7A and the development and immune infiltration of hepatocellular carcinoma (HCC) has rarely been studied. Here, we studied the role of RAB7A in HCC through bioinformatics analysis, real-world cohort validation, and in vitro experimental exploration. MATERIALS AND METHODS: The RAB7A expression level was analyzed through TCGA, HPA and TISIDB databases. TIMER and TISCH were used to analyze the correlation between RAB7A and tumor immune microenvironment. The expression of RAB7A was detected through real-time PCR and western blotting. The cell proliferation was detected by EdU and CCK8. Wound-healing and transwell assays were used to test the invasion and migration ability. Cell cycle distribution and reactive oxygen species (ROS) content were analyzed by flow cytometry. Identification of epithelial-mesenchymal transition (EMT) was performed by immunofluorescence double staining. Immunohistochemistry (IHC) was used to evaluate the correlation between RAB7A and immune checkpoints. RESULTS: RAB7A is upregulated in most of the tumor types, and the upregulation of RAB7A is associated with a poorer prognosis in many cancers. The results showed that RAB7A was significantly positively correlated with the infiltration of macrophages and cancer-associated fibroblasts (CAFs), but negatively correlated with M2-type macrophages in most tumors. The single-cell atlas also revealed the distribution and proportion of RAB7A in immune cells of HCC. The in vitro experiments suggested that RAB7A was increased in HCC tissue and cell lines. The knockdown of RAB7A inhibited the activation of the PIK3CA-AKT pathway and suppressed the expression of CDK4, CDK6 and CCNA2. Knockdown of RAB7A induced G0/G1 arrest and ROS accumulation in HCC. In addition, overexpression of RAB7A enhanced migration and invasion by inducing EMT. The real-world cohort showed that the expression level of RAB7A was positively correlated with the expression levels of TGFBR1 and PD-L1. CONCLUSIONS: RAB7A may serve as a potential tumor prognostic and immune infiltration-related biomarker, predicting immunotherapy efficacy in certain cancer types, especially in HCC. Besides, RAB7A was a multi-pathway target involved in the malignant progression of HCC.

A Multi-Omics Analysis of NASH-Related Prognostic Biomarkers Associated with Drug Sensitivity and Immune Infiltration in Hepatocellular Carcinoma.

Background: Nonalcoholic steatohepatitis (NASH)-driven hepatocellular carcinoma (HCC) is becoming a major health-related problem. The exploration of NASH-related prognostic biomarkers and therapeutic targets is necessary. Methods: Data were downloaded from the GEO database. The "glmnet" package was used to identify differentially expressed genes (DEGs). The prognostic model was constructed by the univariate Cox and LASSO regression analyses. Validation of the expression and prognosis by immunohistochemistry (IHC) in vitro. Drug sensitivity and immune cell infiltration were analyzed by CTR-DB and ImmuCellAI. Results: We constructed a prognostic model that identified the NASH-related gene set (DLAT, IDH3B, and MAP3K4), which was validated in a real-world cohort. Next, seven prognostic transcription factors (TFs) were identified. The prognostic ceRNA network included three mRNAs, four miRNAs, and seven lncRNAs. Finally, we found that the gene set was associated with drug response which was validated in six clinical trial cohorts. Moreover, the expression level of the gene set was inversely correlated with CD8 T cell infiltration in HCC. Conclusions: We established a NASH-related prognostic model. Upstream transcriptome analysis and the ceRNA network provided clues for mechanism exploration. The mutant profile, drug sensitivity, and immune infiltration analysis further guided precise diagnosis and treatment strategies.

RASGRP2 is a potential immune-related biomarker and regulates mitochondrial-dependent apoptosis in lung adenocarcinoma.

Background: Ras guanine nucleotide-releasing protein 2 (RASGRP2), one of the guanine nucleotide exchange factors (GEFs), has attracted much attention in recent years. However, the correlation between RASGRP2 and immune infiltration and malignant features in lung adenocarcinoma (LUAD) has rarely been mentioned. Methods: The Limma package and the LASSO regression model were performed to screen for differentially expressed genes. Data from the TCGA and 5 GEO databases were used to explore the expression level of RASGRP2 in LUAD patients. A weighted co-expression network and LinkFinder module were established to find the related genes of RASGRP2. The ESTIMATE algorithm was used to analyze the correlation between RASGRP2 and immune infiltration in LUAD. Tumor-infiltrating immune cells were sorted and sequenced at the single-cell level to analyze differences in RASGRP2. Real-time PCR and immunohistochemistry were performed in the real-world cohort to verify the expression of RASGRP2 and its correlation with immune-related genes. Clone formation and EdU assays were used to verify the proliferation ability. The proportion of apoptotic cells was analyzed by flow cytometry. Observation of mitochondrial membrane potential (MMP) changes by fluorescence microscopy. Results: Our results suggested that decreased RASGRP2 was associated with worse clinical parameters and prognosis in LUAD patients. And we constructed a FLI1-HSA-miR-1976-RASGRP2 transcriptional network to support the role of RASGRP2. Enrichment analysis revealed that RASGRP2 was involved in lymphocyte activation and leukocyte adhesion. RASGRP2 was found to be positively correlated with the infiltration of most immune cells, immunoregulators, and chemokines in a subsequent study. Meanwhile, the real-world cohort confirmed that the expression levels of PDCD1, CTLA4, CD40LG, CCL14, CXCR5, and CCR7 were higher in the high-RASGRP2 expression group. Cytological experiments proved that RASGRP2 inhibited cell proliferation in LUAD by regulating mitochondrial-dependent apoptosis. Conclusion: RASGRP2 was a potential immune-related biomarker of LUAD. In addition, RASGRP2 was involved in the malignant progression of LUAD through the regulation of mitochondrial-dependent apoptosis.

MTFR2 shapes a barrier of immune microenvironment in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death in the world. Mitochondrial fission regulator 2 (MTFR2) is involved in the development of various cancers. However, the roles of MTFR2 in HCC remain unknown. In this study, we conducted a comprehensive analysis of MTFR2 in HCC, which was generated from integrative MTFR2 analyses of eight HCC cell lines, and three datasets (public dataset, real-world dataset, and immunotherapy dataset) derived from bulk HCC tissues, survival, and immunotherapy data. We demonstrated that the expression level of MTFR2 is upregulated in HCC, leading to poor prognosis. MTFR2 is positively correlated with the level of immune cell infiltration, multiple immune checkpoints and immunotherapy response prediction pathways, and acts as an important role in cancer-immunity cycle. In conclusion, our work indicates that MTFR2 can shape a barrier of immune microenvironment and result in poor prognosis in hepatocellular carcinoma, but the immune barrier may be broken by immunotherapy.

Evolutionary characteristics of ecosystem services and ecological risks at highly developed economic region: A case study on Yangtze River Delta, China.

Ecosystem services (ES) can mitigate ecological risks (ER), yet these services can also be affected by ER. Based on land use data, socioeconomic data, landscape index, and spatial analysis techniques such as spatial autocorrelation, we study the spatial and temporal characteristics of ES and ER in the Yangtze River Delta from 2000 to 2019. The conclusions are as follows: (1) During the study period, construction land has been growing rapidly, and the depth, complexity, and intensity of land use have been increasing. The reserve land resources in the Yangtze River Delta are scarce. (2) From 2000 to 2019, the ecosystem service value (ESV) has been declining, with a total loss of 107.562 billion RMB. The area of low ESV continues to grow rapidly, while the area of high ESV continues to shrink. High ecological risk potential exists in rivers, lakes, and coastal areas. (3) Although the ecological environment in economically developed areas is more fragile, the ecological risk potential can be reduced in two ways: strengthening urban clusters, thus improving cooperation and communication among them; and protecting ecosystems with high ES such as water area and forestland. When formulating regional development plans, in addition to socioeconomic benefits, managers and policy makers need to focus on natural benefits as well.

Hsa_Circ_0066351 Acts as a Prognostic and Immunotherapeutic Biomarker in Colorectal Cancer.

Circular RNA (circRNA), a novel class of non-coding RNA, has been reported in various diseases, especially in tumors. However, the key signatures of circRNA-competitive endogenous RNA (ceRNA) network are largely unclear in colorectal cancer (CRC). We first characterized circRNAs profile by using circRNA-seq analysis from real-word dataset. The expression level of hsa_circ_0066351 in CRC tissues and cell lines was detected by quantitative real-time PCR. Then, cell proliferation assay was used to confirm the proliferation function of hsa_circ_0066351. Next, Cytoscape was used to construct circRNA-miRNA-mRNA networks. Last but not least, the landscape of hsa_circ_0066351-miRNA-mRNA in CRC had been investigated in the bulk tissue RNA-Seq level and single-cell Seq level. We proved that hsa_circ_0066351 was significantly downregulated in CRC cell lines and tissues (P < 0.001), and was negatively associated with distant metastasis (P < 0.01). Significantly, the expression of hsa_circ_0066351 was associated with better survival in patients with CRC. Function assays showed that hsa_circ_0066351 could inhibit CRC cells proliferation. In addition, a ceRNA network, including hsa_circ_0066351, two miRNAs, and ten mRNAs, was constructed. Our analyses showed that these ten mRNAs were consistently downregulated in pan-cancer and enriched in tumor suppressive function. A risk score model constructed by these ten downstream genes also indicated that they were related to the prognosis and immune response in CRC. In conclusion, we demonstrated that a novel circRNA (hsa_circ_0066351) inhibited CRC proliferation, and revealed a potential prognostic and immunotherapeutic biomarker in CRC.

The optimal first-line treatment for patients with left-sided RAS wild-type metastatic colorectal cancer: Double-drug regimen or triple-drug regimen therapy.

There are many treatments for metastatic colorectal cancer (mCRC). Among them, uncertainty remains especially concerning the clinical benefit of different regimens for left-sided RAS wild-type (WT) mCRC in the triple-drug therapy era. No studies have been conducted to answer this critical clinical issue. We performed a comprehensive analysis of published data and real-world data. First, we conducted analyses of the published trials to show the landscape of efficacy and safety in the treatments of left-sided RAS WT mCRC. Then, we initiated a multicenter real-world study as the validation dataset. This study included six published randomized controlled trials (RCTs) and a total of 1925 patients. The double-drug regimen plus cetuximab/panitumumab (D + C/P) achieved the longest overall survival (OS) in patients with left-sided mCRC (HR = 0.74, 95%CI: 0.57-0.98), while triple-drug regimen with bevacizumab (T + B, HR = 1.1, 95%CI: 0.63-2.0), compared with double-drug with bevacizumab (D + B). The D + C/P had the highest overall response rate (ORR) in patients with left-sided mCRC (OR = 1.8, 95%CI: 0.89-3.8), while T + B (OR = 1.8, 95%CI: 0.70-4.8), compared with D + B. The multicenter real-world cohort showed the double-drug regimen plus cetuximab had longer progression-free survival (PFS) in left-sided mCRC patients than the triple-drug regimen with bevacizumab. The safety analysis showed the incidence of the adverse events (grade≥3) in the triple-drug therapy plus bevacizumab was higher than that in the double-drug therapy plus cetuximab/panitumumab. This work demonstrates the ranking of three regimens for therapeutic efficacy and safety in patients with left-sided RAS WT mCRC. The double-drug regimen plus cetuximab/panitumumab appears more effective and safer than double-drug and triple-drug based regimens with bevacizumab. Further trials and cohort analyses on this topic would increase confidence in these results.

Prognostic stratification based on m5C regulators acts as a novel biomarker for immunotherapy in hepatocellular carcinoma.

Background: Immunotherapy is a promising anti-cancer strategy in hepatocellular carcinoma (HCC). However, a limited number of patients can benefit from it. There are currently no reliable biomarkers available to find the potential beneficiaries. Methylcytosine (m5C) is crucial in HCC, but its role in forecasting clinical responses to immunotherapy has not been fully clarified. Methods: In this study, we analyzed 371 HCC patients from The Cancer Genome Atlas (TCGA) database and investigated the expression of 18 m5C regulators. We selected 6 differentially expressed genes (DEGs) to construct a prognostic risk model as well as 2 m5C-related diagnostic models. Results: The 1-, 3-, and 5-year area under the curve (AUC) of m5C scores for the overall survival (OS) was 0.781/0.762/0.711, indicating the m5C score system had an ideal distinction of prognostic prediction for HCC. The survival analysis showed that patients with high-risk scores present a worse prognosis than the patients with low-risk scores (p< 0.0001). We got consistent results in 6 public cohorts and validated them in Xiangya real-world cohort by quantitative real-time PCR and immunohistochemical (IHC) assays. The high-m5C score group was predicted to be in an immune evasion state and showed low sensitivity to immunotherapy, but high sensitivity to chemotherapy and potential targeted drugs and agents, such as sepantronium bromide (YM-155), axitinib, vinblastine and docetaxel. Meanwhile, we also constructed two diagnostic models to distinguish HCC tumors from normal liver tissues or liver cirrhosis. Conclusion: In conclusion, our study helps to early screen HCC patients and select patients who can benefit from immunotherapy. Step forwardly, for the less likely beneficiaries, this study provides them with new potential targeted drugs and agents for choice to improve their prognosis.

A metabolomics strategy to identify potential biomarkers associated with human laryngeal cancer based on dried blood spot mass spectrometry approach.

ABSTRACT: Laryngeal cancer (LC) as one of common malignant tumors in the head and neck region accounted for 1% to 5% of new cancer cases and was ranked as the third otolaryngology cancer. However, some patients with LC were diagnosed at the advanced stage, which can cause delayed diagnosis and treatment. It is an urgent task to seek effective biomarkers for the early diagnosis of LC aimed at alleviating suffering.A combination of dried blood spot sampling and direct infusion mass spectrometry technology was applied to 39 patients with LC and 53 healthy individuals. Multiple algorithms towards 93 metabolites including amino acids and carnitine/acylcarnitines were run for selecting differential metabolites. Furthermore, leave-one-out cross-validation method was used to evaluate diagnostic performance of selected metabolite biomarkers.A biomarker panel consisting of arginine, proline, hexacosanoic carnitine, ornithine /citrulline, and 3-hydroxy-octadecenoylcarnitine exhibited potential to distinguish patients with LC from healthy individuals, with a sensitivity of 0.8974 and a specificity of 0.8302 in leave-one-out cross-validation model.The metabolomic analysis of LC patients is beneficial to screen disease-associated biomarkers and develop new diagnostic approaches.

In respond to commensal bacteria: γδT cells play a pleiotropic role in tumor immunity.

γδT cells are a mixture of innate programming and acquired adaptability that bridge the adaptive and innate immune systems. γδT cells are mainly classified as tissue-resident Vδ1 or circulating Vδ2 γδT cells. In the tumor microenvironment, tumor immunity is influenced by the increased quantity and phenotype plasticity of γδT cells. Commensal bacteria are ubiquitous in the human body, and they have been confirmed to exist in various tumor tissues. With the participation of commensal bacteria, γδT cells maintain homeostasis and are activated to affect the development and progression of tumors. Here, we summarize the relationship between γδT cells and commensal bacteria, the potential protumor and antitumor effects underlying γδT cells, and the new developments in γδT cell-based tumor therapy which is expected to open new opportunities for tumor immunotherapy.

Efficient hyperentanglement purification for three-photon systems with the fidelity-robust quantum gates and hyperentanglement link.

We present an efficient and faithful hyperentanglement purification protocol (hyper-EPP) for three-photon system in mixed hyperentangled Greenberger-Horne-Zeilinger states with bit-flip errors in both spatial-mode and polarization degrees of freedom (DOFs), resorting to the fidelity-robust quantum gates and hyperentanglement link. Our high-efficiency hyper-EPP comes from two aspects. One is to pump the higher-fidelity hyperentanglement from different three-photon systems into the same three-photon system with fidelity-robust swap gates, the other is to reproduce some hyperentangled three-photon systems from hyperentangled two-photon subsystems based on hyperentanglement link. Moreover, as the infidelity originating from imperfect single-photon scattering can be heralded as a failure by triggering a detector, our hyper-EPP operates faithfully with the present quantum circuits. Furthermore, our hyper-EPP can be directly extended to purify multiple photon systems entangled in one DOF or hyperentangled in multiple DOFs.

[Research progress on neural mechanism of peripheral inflammation in Parkinson's disease].

Parkinson's disease (PD) is the second most common neurodegenerative disease, characterized by loss of dopaminergic (DA) neurons in the dense part of the substantia nigra (SNpc). Postmortem analysis of PD patients and experimental animal studies found that microglial cell activation and increased levels of pro-inflammatory factors were common features of PD brain tissue. At the same time, the invasion and accumulation of peripheric immune cells were detected in the brain of PD patients. In this paper, peripheral inflammation across the blood-brain barrier (BBB), the misfolded α-synuclein (α-syn)-induced microglial cell activation and intracerebral inflammation in PD are summarized, providing potential therapeutic measures for delaying the onset of PD.

Xanthomonas oryzae pv. oryzae type III effector PthXo3JXOV suppresses innate immunity, induces susceptibility and binds to multiple targets in rice.

Transcription activator-like (TAL) effectors encoded by tal genes were recognized as a key virulence strategy used by Xanthomonas oryzae pv. oryzae (Xoo) to cause bacterial leaf blight of rice. TAL effector PthXo3 is a major virulence factor identified in a Philippine Xoo strain PXO61, and it can induce the expression of susceptibility gene OsSWEET14 by binding to the effector-binding element (EBE) in the promoter region. In this study, pthXo3 homologous genes were also identified and isolated from Xoo Chinese strain OS198 and Japanese strain JXOV, which were named as pthXo3OS198 and pthXo3JXOV, respectively. When pthXo3JXOV was delivered into PXO99A, the resulting strain PXO99A/pthXo3JXOV significantly increased virulence in 18 out of 23 rice varieties tested, with the most prominent increase in lesion length and bacteria propagation in rice IRBB13. PthXo3JXOV suppresses the plant's innate immunity by inhibiting hypersensitive response (HR) and callose deposition. The Agrobacterium tumefaciens-mediated transient expression assays showed that, besides OsSWEET14, PthXo3JXOV also interacts with other targets by binding to the EBEs in their promoter regions. Our results suggest that PthXo3JXOV may interact with multiple targets to execute its virulence functions.

Xanthomonas oryzae pv. oryzae requires H-NS-family protein XrvC to regulate virulence during rice infection.

Histone-like nucleoid-structuring (H-NS) proteins, which are conserved in Gram-negative bacteria, bind DNA and act as the global transcriptional repressors. In this study, we identified and characterized the xrvC gene encoding a H-NS protein in Xathomonas oryzae pv. oryzae (Xoo) Philippines strain PXO99(A) Compared with the wild type, the xrvC-deficient mutant of PXO99(A) (named PXO99ΔxrvC) showed a reduced growth rate in both nutrient-rich and nutrient-limited media. Interestingly, PXO99ΔxrvC exhibited significantly reduced virulence on rice cultivar IRBB214, but its virulence on 31 other rice cultivars was not affected. Transcriptional analysis revealed that the expression of hrpG, hrpX and hpa1 and of 15 out of 18 tested non-TAL (transcription activator-like) effector genes was decreased significantly in the xrvC mutant compared with that in the wild type. In addition, loss of xrvC also impaired the induction of the rice susceptibility gene Os8N3 in IRBB214 by PXO99(A) Our results suggest that the xrvC gene is involved in bacterial growth, and it plays a vital role in virulence by positively regulating the expression of hrp genes and non-TAL effector genes in PXO99(A) and the susceptibility gene Os8N3 in rice.