SLC7A11 as a therapeutic target to attenuate phthalates-driven testosterone level decline in mice.

INTRODUCTION: Phthalates exposure is a major public health concern due to the accumulation in the environment and associated with levels of testosterone reduction, leading to adverse pregnancy outcomes. However, the relationship between phthalate-induced testosterone level decline and ferroptosis remains poorly defined. OBJECTIVES: Herein, we aimed to explore the mechanisms of phthalates-induced testosterone synthesis disorder and its relationship to ferroptosis. METHODS: We conducted validated experiments in vivo male mice model and in vitro mouse Leydig TM3 cell line, followed by RNA sequencing and metabolomic analysis. We evaluated the levels of testosterone synthesis-associated enzymes and ferroptosis-related indicators by using qRT-PCR and Western blotting. Then, we analyzed the lipid peroxidation, ROS, Fe2+ levels and glutathione system to confirm the occurrence of ferroptosis. RESULTS: In the present study, we used di (2-ethylhexyl) phthalate (DEHP) to identify ferroptosis as the critical contributor to phthalate-induced testosterone level decline. It was demonstrated that DEHP caused glutathione metabolism and steroid synthesis disorders in Leydig cells. As the primary metabolite of DEHP, mono-2-ethylhexyl phthalate (MEHP) triggered testosterone synthesis disorder accompanied by a decrease in the expression of solute carri1er family 7 member 11 (SLC7A11) protein. Furthermore, MEHP synergistically induced ferroptosis with Erastin through the increase of intracellular and mitochondrial ROS, and lipid peroxidation production. Mechanistically, overexpression of SLC7A11 counteracts the synergistic effect of co-exposure to MEHP-Erastin. CONCLUSION: Our research results suggest that MEHP does not induce ferroptosis but synergizes Erastin-induced ferroptosis. These findings provide evidence for the role of ferroptosis in phthalates-induced testosterone synthesis disorder and point to SLC7A11 as a potential target for male reproductive diseases. This study established a correlation between ferroptosis and phthalates cytotoxicity, providing a novel view point for mitigating the issue of male reproductive disease and "The Global Plastic Toxicity Debt".

The novel selective TLR7 agonist GY101 suppresses colon cancer growth by stimulating immune cells.

Toll-like receptor (TLR) 7, a transmembrane signal transduction receptor expressed on the surface of endosomes, has become an attractive target for antiviral and cancer immunotherapies. TLR7 can induce signal transduction by recognizing single-stranded RNA or its analogs, leading to the release of cytokines such as IL-6, IL-12, TNF-α and type-I IFN. Activation of TLR7 helps to enhance immunogenicity and immune memory by stimulating immune cells. Herein, we identified a novel selective TLR7 agonist, GY101, and determined its ability to activate TLR7. In summary, in vitro, compound GY101 significantly induced the secretion of IL-6, IL-12, TNF-α and IFN-γ in mouse splenic lymphocytes; in vivo, peritumoral injection of GY101 significantly suppressed colon cancer CT26, as well as poorly immunogenic B16-F10 and 4T1 cancer cell-derived tumor growth by activating the infiltration of lymphocytes and polarization of M2-like macrophages into M1-like macrophages. These results demonstrate that GY101, as a potent TLR7 agonist, holds great potential for cancer immunotherapy.

Salvianolic acid A improve mitochondrial respiration and cardiac function via inhibiting apoptosis pathway through CRYAB in diabetic cardiomyopathy.

Salvianolic acid A (SAA) is a traditional Chinese medicine that has a good therapeutic effect on cardiovascular disease. However, the underlying mechanisms by which SAA improves mitochondrial respiration and cardiac function in diabetic cardiomyopathy (DCM) remain unknown. This study aims to elucidate whether SAA had any cardiovascular protection on the pathophysiology of DCM and explored the potential mechanisms. Diabetes was induced in rats by 30 mg/kg of streptozotocin (STZ) treatment. After a week of stability, 5 mg/kg isoprenaline (ISO) was injected into the rats subcutaneously. 3 mg/kg SAA was orally administered for six weeks and 150 mg/kg Metformin was selected as a positive group. At the end of this period, cardiac function was assessed by ultrasound, electrocardiogram, and relevant cardiac injury biomarkers testing. Treatment with SAA improved cardiac function, glucose, and lipid levels, mitochondrial respiration, and suppressed myocardial inflammation and apoptosis. Furthermore, SAA treatment inhibits the apoptosis pathway through CRYAB in diabetic cardiomyopathy rats. As a result, this study not only provides new insights into the mechanism of SAA against DCM but also provides new therapeutic ideas for the discovery of anti-DCM compounds in the clinic.

Epigenetic repression of THBD transcription by BRG1 contributes to deep vein thrombosis.

BACKGROUND: Deep vein thrombosis (DVT) with its major complication, pulmonary embolism, is a global health problem. Endothelial dysfunction is involved in the pathogenesis of DVT. We have previously demonstrated that endothelial specific deletion of Brahma-related gene 1 (BRG1) ameliorates atherosclerosis and aneurysm in animal models. Whether endothelial BRG1 contributes to DVT development remains undetermined. METHODS: DVT was induced in mice by ligation of inferior vena cava. Deletion of BRG1 in endothelial cells was achieved by crossing the Cdh5-ERT-Cre mice with the Brg1loxp/loxp mice. RESULTS: Here we report that compared to the wild type mice, BRG1 conditional knockout (CKO) mice displayed substantially decreased DVT susceptibility characterized by decreased weight and size of thrombus and reduced immune infiltration. In endothelial cells, thrombomodulin (THBD) expression was significantly decreased by TNF-α stimulation, while BRG1 knockdown or inhibition recovered THBD expression. Further analysis revealed that BRG1 deficiency decreased the CpG methylation levels of the THBD promoter induced by TNF-α. Mechanistically, BRG1 directly upregulated DNMT1 expression after TNF-α treatment in endothelial cells. More importantly, administration of a small-molecule BRG1 inhibitor PFI-3 displayed potent preventive and therapeutic potentials in the DVT model. CONCLUSIONS: Our findings implicate BRG1 as an important regulator of DVT pathogenesis likely through epigenetic regulation of THBD expression in endothelial cells and provide translational proof-of-concept for targeting BRG1 in DVT intervention.

Ongoing Clinical Trials in Aging-Related Tissue Fibrosis and New Findings Related to AhR Pathways.

Fibrosis is a pathological manifestation of wound healing that replaces dead/damaged tissue with collagen-rich scar tissue to maintain homeostasis, and complications from fibrosis contribute to nearly half of all deaths in the industrialized world. Ageing is closely associated with a progressive decline in organ function, and the prevalence of tissue fibrosis dramatically increases with age. Despite the heavy clinical and economic burden of organ fibrosis as the population ages, to date, there is a paucity of therapeutic strategies that are specifically designed to slow fibrosis. Aryl hydrocarbon receptor (AhR) is an environment-sensing transcription factor that exacerbates aging phenotypes in different tissues that has been brought back into the spotlight again with economic development since AhR could interact with persistent organic pollutants derived from incomplete waste combustion. In addition, gut microbiota dysbiosis plays a pivotal role in the pathogenesis of numerous diseases, and microbiota-associated tryptophan metabolites are dedicated contributors to fibrogenesis by acting as AhR ligands. Therefore, a better understanding of the effects of tryptophan metabolites on fibrosis modulation through AhR may facilitate the exploitation of new therapeutic avenues for patients with organ fibrosis. In this review, we primarily focus on how tryptophan-derived metabolites are involved in renal fibrosis, idiopathic pulmonary fibrosis, hepatic fibrosis and cardiac fibrosis. Moreover, a series of ongoing clinical trials are highlighted.

Proteomic analysis of early-stage incompatible and compatible interactions between grapevine and P. viticola.

Wild grapevines can show strong resistance to the downy mildew pathogen P. viticola, but the associated mechanisms are poorly described, especially at early stages of infection. Here, we performed comparative proteomic analyses of grapevine leaves from the resistant genotype V. davidii "LiuBa-8" (LB) and susceptible V. vinifera "Pinot Noir" (PN) 12 h after inoculation with P. viticola. By employing the iTRAQ technique, a total of 444 and 349 differentially expressed proteins (DEPs) were identified in LB and PN, respectively. The majority of these DEPs were related to photosynthesis, respiration, cell wall modification, protein metabolism, stress, and redox homeostasis. Compared with PN, LB showed fewer downregulated proteins associated with photosynthesis and more upregulated proteins associated with metabolism. At least a subset of PR proteins (PR10.2 and PR10.3) was upregulated upon inoculation in both genotypes, whereas HSP (HSP70.2 and HSP90.6) and cell wall-related XTH and BXL1 proteins were specifically upregulated in LB and PN, respectively. In the incompatible interaction, ROS signaling was evident by the accumulation of H2O2, and multiple APX and GST proteins were upregulated. These DEPs may play crucial roles in the grapevine response to downy mildew. Our results provide new insights into molecular events associated with downy mildew resistance in grapevine, which may be exploited to develop novel protection strategies against this disease.

The Relationship Between Human Papillomavirus, OFD1 and Primary Ciliogenesis in the Progression of Oropharyngeal Cancer: A Retrospective Cohort Study.

PURPOSE: Infection with human papillomavirus (HPV) has been indicated to be a important risk factor for oropharyngeal squamous cell carcinoma (OPSCC). Primary ciliogenesis defects contribute to tumorigenesis, and OFD1 at centriolar satellites is a crucial suppressor of primary ciliogenesis. To identify novel markers associated with HPV-induced carcinogenesis, the interactions between HPV infection and primary ciliogenesis in the tumorigenesis and progression of OPSCC were investigated in this study. PATIENTS AND METHODS: The 1530 OPSCC patients recruited in this research were treated from 2000 to 2017. Immunohistochemistry and RT-PCR were performed on tissue samples to compare the expression of p16, TSLP, TGFß1, IFNγ, OFD1, and their relationship with clinical characteristics of patients. RESULTS: We speculate that the positive expression of p16 is related to early primary OPSCC, and the survival rate of p16 positive patients after radiotherapy and surgery is higher. Expression of TSLP on dendritic cells in HPV-positive OPSCC correlated with the expression of OFD1. HPV-positive OPSCC showed increased expression of OFD1 combined with reduced ciliogenesis. Hence, TSLP induced by HPV infection may reduce the invasive potential of OPSCC cells by promoting OFD1 expression, thereby inhibiting primary ciliogenesis. CONCLUSION: Our study demonstrated that HPV may be related to the progression of OPSCC by regulating OFD1 expression and primary ciliogenesis, making this protein a potential therapeutic target.

Long Noncoding RNA TINCR-Mediated Regulation of Acetyl-CoA Metabolism Promotes Nasopharyngeal Carcinoma Progression and Chemoresistance.

Frontier evidence suggests that dysregulation of long noncoding RNAs (lncRNA) is ubiquitous in all human tumors, indicating that lncRNAs might have essential roles in tumorigenesis. Therefore, an in-depth study of the roles of lncRNA in nasopharyngeal carcinoma (NPC) carcinogenesis might be helpful to provide novel therapeutic targets. Here we report that lncRNA TINCR was significantly upregulated in NPC and was associated positively with poor survival. Silencing TINCR inhibited NPC progression and cisplatin resistance. Mechanistically, TINCR bound ACLY and protected it from ubiquitin degradation to maintain total cellular acetyl-CoA levels. Accumulation of cellular acetyl-CoA promoted de novo lipid biosynthesis and histone H3K27 acetylation, which ultimately regulated the peptidyl arginine deiminase 1 (PADI1)-MAPK-MMP2/9 pathway. In addition, insulin-like growth factor 2 mRNA-binding protein 3 interacted with TINCR and slowed its decay, which partially accounted for TINCR upregulation in NPC. These findings demonstrate that TINCR acts as a crucial driver of NPC progression and chemoresistance and highlights the newly identified TINCR-ACLY-PADI1-MAPK-MMP2/9 axis as a potential therapeutic target in NPC. SIGNIFICANCE: TINCR-mediated regulation of a PADI1-MAPK-MMP2/9 signaling pathway plays a critical role in NPC progression and chemoresistance, marking TINCR as a viable therapeutic target in this disease.

Pathological Mechanism of Photodynamic Therapy and Photothermal Therapy Based on Nanoparticles.

The ultimate goal of phototherapy based on nanoparticles, such as photothermal therapy (PTT) which generates heat and photodynamic therapy (PDT) which not only generates reactive oxygen species (ROS) but also induces a variety of anti-tumor immunity, is to kill tumors. In addition, due to strong efficacy in clinical treatment with minimal invasion and negligible side effects, it has received extensive attention and research in recent years. In this paper, the generations of nanomaterials in PTT and PDT are described separately. In clinical application, according to the different combination pathway of nanoparticles, it can be used to treat different diseases such as tumors, melanoma, rheumatoid and so on. In this paper, the mechanism of pathological treatment is described in detail in terms of inducing apoptosis of cancer cells by ROS produced by PDT, immunogenic cell death to provoke the maturation of dendritic cells, which in turn activate production of CD4+ T cells, CD8+T cells and memory T cells, as well as inhibiting heat shock protein (HSPs), STAT3 signal pathway and so on.

CRISPR/Cas9-mediated VvPR4b editing decreases downy mildew resistance in grapevine (Vitis vinifera L.).

Downy mildew of grapevine (Vitis vinifera L.), caused by the oomycete pathogen Plasmopara viticola, is one of the most serious concerns for grape production worldwide. It has been widely reported that the pathogenesis-related 4 (PR4) protein plays important roles in plant resistance to diseases. However, little is known about the role of PR4 in the defense of grapevine against P. viticola. In this study, we engineered loss-of-function mutations in the VvPR4b gene from the cultivar "Thompson Seedless" using the CRISPR/Cas9 system and evaluated the consequences for downy mildew resistance. Sequencing results showed that deletions were the main type of mutation introduced and that no off-target events occurred. Infection assays using leaf discs showed that, compared to wild-type plants, the VvPR4b knockout lines had increased susceptibility to P. viticola. This was accompanied by reduced accumulation of reactive oxygen species around stomata. Measurement of the relative genomic abundance of P. viticola in VvPR4b knockout lines also demonstrated that the mutants had increased susceptibility to the pathogen. Our results confirm that VvPR4b plays an active role in the defense of grapevine against downy mildew.

[Study on mechanisms of anti-Alzheimer's disease action of absorbed components of Gardeniae Fructus based on network pharmacology].

Gardeniae Fructus has the traditional effects of promoting intelligence and inducing resuscitation, but its mechanism is unclear. In this study, the relationship between Gardeniae Fructus's traditional effect of promoting intelligence and inducing resuscitation and anti-Alzheimer's disease effect was taken as the starting point to investigate the anti-Alzheimer's disease mechanism of the major absorbed components in Gardeniae Fructus by the network pharmacology method. The network pharmacology research model of "absorbed composition-target-pathway-disease" was adopted. In this study, the active components screening and target prediction technology were used to determine the active components and targets of Gardeniae Fructus in treatment of Alzheimer's disease. The enrichment pathway and biological process of Gardeniae Fructus were studied by using the bioinformatics annotation database(DAVID), and the results of molecular docking validation network analysis were used to elaborate the mechanism of Gardeniae Fructus in treatment of Alzheimer's disease. It was found that 35 absorbed components of Gardeniae Fructus not only regulated 48 targets such as cholines-terase(BCHE) and carbonic anhydrase 2(CA2), but also affected 11 biological processes(e.g. transcription factor activity, nuclear receptor activity, steroid hormone receptor activity, amide binding and peptide binding) and 7 metabolic pathways(MAPK signaling pathway, Alzheimer disease and estrogen signaling pathway, etc.). Molecular docking results showed that more than 60% of the active components could be well docked with key targets, and the relevant literature also showed that the active components could inhibit the MAPK1 expression of key targets, indicating a high reliability of results. These results indicated that Gardeniae Fructus may play its anti-Alzheimer's disease action via a "multi-ingredients-multi-targets and multi-pathways" mode, providing a scientific basis for further drug research and development.

Chromatin accessibility analysis reveals that TFAP2A promotes angiogenesis in acquired resistance to anlotinib in lung cancer cells.

Anlotinib, a multitarget tyrosine kinase inhibitor, is effective as a third-line treatment against non-small cell lung cancer (NSCLC). However, acquired resistance occurs during its administration. To understand the molecular mechanisms of anlotinib resistance, we characterized chromatin accessibility in both the parental and anlotinib-resistant lung cancer cell line NCI-H1975 through ATAC-seq. Compared with the parental cells, we identified 2666 genomic regions with greater accessibility in anlotinib-resistant cells, in which angiogenesis-related processes and the motifs of 21 transcription factors were enriched. Among these transcription factors, TFAP2A was upregulated. TFAP2A knockdown robustly diminished tumor-induced angiogenesis and partially rescued the anti-angiogenic activity of anlotinib. Furthermore, transcriptome analysis indicated that 2280 genes were downregulated in anlotinib-resistant cells with TFAP2A knocked down, among which the PDGFR, TGF-ß, and VEGFR signaling pathways were enriched. Meanwhile, we demonstrated that TFAP2A binds to accessible sites within BMP4 and HSPG2. Collectively, this study suggests that TFAP2A accelerates anlotinib resistance by promoting tumor-induced angiogenesis.

Comprehensive characterization of the alternative splicing landscape in head and neck squamous cell carcinoma reveals novel events associated with tumorigenesis and the immune microenvironment.

Alternative splicing (AS) has emerged as a key event in tumor development and microenvironment formation. However, comprehensive analysis of AS and its clinical significance in head and neck squamous cell carcinoma (HNSC) is urgently required. Methods: Genome-wide profiling of AS events using RNA-Seq data from The Cancer Genome Atlas (TCGA) program was performed in a cohort of 464 patients with HNSC. Cancer-associated AS events (CASEs) were identified between paired HNSC and adjacent normal tissues and evaluated in functional enrichment analysis. Splicing networks and prognostic models were constructed using bioinformatics tools. Unsupervised clustering of the CASEs identified was conducted and associations with clinical, molecular and immune features were analyzed. Results: We detected a total of 32,309 AS events and identified 473 CASEs in HNSC; among these, 91 were validated in an independent cohort (n = 15). Functional protein domains were frequently altered, especially by CASEs affecting cancer drivers, such as PCSK5. CASE parent genes were significantly enriched in pathways related to HNSC and the tumor immune microenvironment, such as the viral carcinogenesis (FDR < 0.001), Human Papillomavirus infection (FDR < 0.001), chemokine (FDR < 0.001) and T cell receptor (FDR < 0.001) signaling pathways. CASEs enriched in immune-related pathways were closely associated with immune cell infiltration and cytolytic activity. AS regulatory networks suggested a significant association between splicing factor (SF) expression and CASEs and might be regulated by SF methylation. Eighteen CASEs were identified as independent prognostic factors for overall and disease-free survival. Unsupervised clustering analysis revealed distinct correlations between AS-based clusters and prognosis, molecular characteristics and immune features. Immunogenic features and immune subgroups cooperatively depict the immune features of AS-based clusters. Conclusion: This comprehensive genome-wide analysis of the AS landscape in HNSC revealed novel AS events related to carcinogenesis and immune microenvironment, with implications for prognosis and therapeutic responses.

Long Noncoding RNA FAM225A Promotes Nasopharyngeal Carcinoma Tumorigenesis and Metastasis by Acting as ceRNA to Sponge miR-590-3p/miR-1275 and Upregulate ITGB3.

Long noncoding RNAs (lncRNA) play important roles in the tumorigenesis and progression of cancers. However, the clinical significance of lncRNAs and their regulatory mechanisms in nasopharyngeal carcinogenesis (NPC) are largely unknown. Here, based on a microarray analysis, we identified 384 dysregulated lncRNAs, of which, FAM225A was one of the most upregulated lncRNAs in NPC. FAM225A significantly associated with poor survival in NPC. N(6)-Methyladenosine (m6A) was highly enriched within FAM225A and enhanced its RNA stability. FAM225A functioned as an oncogenic lncRNA that promoted NPC cell proliferation, migration, invasion, tumor growth, and metastasis. Mechanistically, FAM225A functioned as a competing endogenous RNA (ceRNA) for sponging miR-590-3p and miR-1275, leading to the upregulation of their target integrin ß3 (ITGB3), and the activation of FAK/PI3K/Akt signaling to promote NPC cell proliferation and invasion. In summary, our study reveals a potential ceRNA regulatory pathway in which FAM225A modulates ITGB3 expression by binding to miR-590-3p and miR-1275, ultimately promoting tumorigenesis and metastasis in NPC. SIGNIFICANCE: These findings demonstrate the clinical significance of the lncRNA FAM225A in nasopharyngeal carcinoma (NPC) and the regulatory mechanism involved in NPC development and progression, providing a novel prognostic indicator and promising therapeutic target.

XPG rs873601 G>A contributes to uterine leiomyoma susceptibility in a Southern Chinese population.

XPG gene contributes to DNA repair defects and genomic instability, which may lead to the initiation of uterine leiomyoma. We hypothesized that genetic variants of XPG gene may alter the carriers' susceptibility to leiomyoma. The association between five potential functional single nucleotide polymorphisms (SNPs), i.e. rs2094258 C>T, rs751402 C>T, rs2296147 T>C, rs1047768 T>C, rs873601 G>A, and uterine leiomyoma risk in Chinese, was investigated in this case-control study, which included 398 incident leiomyoma cases and 733 controls. We found that rs873601 was significantly associated with tumor risk in a recessive genetic model after being adjusting for age and menopause. When compared with rs873601 GG/GA genotypes, the AA genotype had an increased leiomyoma risk (adjusted OR = 1.59, 95% CI = 1.16-2.18, P=0.004; Bonferroni adjusted P=0.040). Furthermore, stratified analysis revealed that the association between the rs873601 AA genotype and leiomyoma risk was more evident among subjects younger than 40 years old (adjusted OR = 1.58, 95% CI = 1.06-2.35, P=0.023) and patients who had more than three myomas (adjusted OR = 2.05, 95% CI = 1.24-3.41, P=0.006). Yet, no significant association between the other four polymorphisms and leiomyoma risk was observed. To sum up, the present study reported on the association between XPG gene polymorphisms and myoma risk. The observed data indicated that SNP rs873601 G>A contributes to uterine leiomyoma susceptibility in a Southern Chinese population.

Perioperative plasma mitochondrial DNA dynamics and correlation with inflammation during infantile cardiopulmonary bypass.

OBJECTIVE: Numerous studies in animals and humans have demonstrated that inflammatory mediators such as tumor necrosis factor (TNF)-α, interleukin (IL)-6, and IL-8 play a role in cardiopulmonary bypass (CPB), which might affect surgical outcomes. Plasma mitochondrial DNA (mtDNA), a recently discovered pro-inflammatory agent, is released by cells upon insult. This study aimed to detect changes in plasma mtDNA levels at different time points after infantile CPB and explore its potential association with inflammatory mediators. METHODS: In the present study, we analyzed the perioperative plasma mtDNA and inflammatory cytokine levels of 48 infants undergoing ventricular septal defect closure. Blood samples were collected before aortic cross-clamping (T1), at the end of CPB (T2), and 6h (T3), 12h (T4), and 24h (T5) post-CPB. Reverse transcription-polymerase chain reaction and specific enzyme-linked immunosorbent assay were used to quantify the plasma mtDNA and inflammatory cytokines, respectively. Bivariate correlation analysis was used to determine the correlations between plasma mtDNA and inflammatory cytokines. RESULTS: Plasma mtDNA levels increased at T2 and peaked at T3. Significant positive correlations were found between peak plasma mtDNA (at T3) and several inflammatory biomarkers, including IL-6 (at T3) (r=0.62, P<0.001), IL-8 (at T2) (r=0.53, P<0.001), and TNF-α (at T3) (r=0.61, P<0.001). CONCLUSION: Here we report that mtDNA may participate in a systemic inflammatory response to CPB.

Pathogen development and host responses to Plasmopara viticola in resistant and susceptible grapevines: an ultrastructural study.

The downy mildew disease in grapevines is caused by Plasmopara viticola. This disease poses a serious threat wherever viticulture is practiced. Wild Vitis species showing resistance to P. viticola offer a promising pathway to develop new grapevine cultivars resistant to P. viticola which will allow reduced use of environmentally unfriendly fungicides. Here, transmission and scanning microscopy was used to compare the resistance responses to downy mildew of three resistant genotypes of V. davidii var. cyanocarpa, V. piasesezkii and V. pseudoreticulata and the suceptible V. vinifera cultivar 'Pinot Noir'. Following inoculation with sporangia of P. viticola isolate 'YL' on V. vinifera cv. 'Pinot Noir', the infection was characterized by a rapid spread of intercellular hyphae, a high frequency of haustorium formation within the host's mesophyll cells, the production of sporangia and by the absence of host-cell necrosis. In contrast zoospores were collapsed in the resistant V. pseudoreticulata 'Baihe-35-1', or secretions appeared arround stomata at the beginning of the infection period in V. davidii var. cyanocarpa 'Langao-5' and V. piasezkii 'Liuba-8'. The main characteristics of the resistance responses were the rapid depositions of callose and the appearance of empty hyphae and the plasmolysis of penetrated tissue. Moreover, collapsed haustoria were observed in V. davidii var. cyanocarpa 'Langao-5' at 5 days post inoculation (dpi) and in V. piasezkii 'Liuba-8' at 7 dpi. Lastly, necrosis extended beyond the zone of restricted colonization in all three resistant genotypes. Sporangia were absent in V. piasezkii 'Liuba-8' and greatly decreased in V. davidii var. cyanocarpa 'Langao-5' and in V. pseudoreticulata 'Baihe-35-1' compared with in V. vinifera cv. 'Pinot Noir'. Overall, these results provide insights into the cellular biological basis of the incompatible interactions between the pathogen and the host. They indicate a number of several resistant Chinese wild species that could be used in developing new cultivars having good levels of downy mildew resistance.

Association study between SMPD1 p.L302P and sporadic Parkinson's disease in ethnic Chinese population.

PURPOSE: The protein encoded by sphingomyelin phosphodiesterase 1, acid lysosomal (SMPD1) is a lysosomal acid sphingomyelinase. While there are increasing evidences to suggest that lysosomal enzyme defects and Parkinson's disease (PD) have strong associations, and recently, SMPD1 p.L302P (c.T911C, NM_000543) was found to be a risk factor for PD in Ashkenazi Jewish ancestry population, we try to investigate the possible association between SMPD1 p.L302P and sporadic PD in ethnic Chinese population. METHODS: 455 sporadic PD and 476 health controls were included in our study. SMPD1 p.L302P (c.T911C) was genotyped by matrix-assisted laser desorption/ionization-time-of-flight mass spectrometry (MALDI-TOF MS) and the results were confirmed by Sanger sequencing. RESULTS: Our results showed that none of 455 sporadic PD and 476 health controls carried p.L302P. All of the 931 subjects' genotypes were wild type TT. Our data indicated that in an ethnic Chinese population, p.L302P did not appear to be enriched in sporadic PD, and p.L302P may not be a risk factor for Chinese sporadic PD. And combine our data with the results from previous studies, we found that all of the 2,268 participants of Chinese population carrying no p.L302P. CONCLUSIONS: We could make a conclusion that p.L302P may not be common events for Chinese population. Sequencing of SMPD1 gene to find additional novel rare variants in the SMPD1 gene in diverse populations is needed.

Transcriptome of Erysiphe necator-infected Vitis pseudoreticulata leaves provides insight into grapevine resistance to powdery mildew.

Powdery mildew (PM), which is caused by the pathogen Erysiphe necator (Schw.) Burr., is the single most damaging disease of cultivated grapes (Vitis vinifera) worldwide. However, little is known about the transcriptional response of grapes to infection with PM. RNA-seq analysis was used for deep sequencing of the leaf transcriptome to study PM resistance in Chinese wild grapes (V. pseudoreticulata Baihe 35-1) to better understand the interaction between host and pathogen. Greater than 100 million (M) 90-nt cDNA reads were sequenced from a cDNA library derived from PM-infected leaves. Among the sequences obtained, 6541 genes were differentially expressed (DEG) and were annotated with Gene Ontology terms and by pathway enrichment. The significant categories that were identified included the following: defense, salicylic acid (SA) and jasmonic acid (JA) responses; systemic acquired resistance (SAR); hypersensitive response; plant-pathogen interaction; flavonoid biosynthesis; and plant hormone signal transduction. Various putative secretory proteins were identified, indicating potential defense responses to PM infection. In all, 318 putative R-genes and 183 putative secreted proteins were identified, including the defense-related R-genes BAK1, MRH1 and MLO3 and the defense-related secreted proteins GLP and PR5. The expression patterns of 16 genes were further illuminated by RT-qPCR. The present study identified several candidate genes and pathways that may contribute to PM resistance in grapes and illustrated that RNA-seq is a powerful tool for studying gene expression. The RT-qPCR results reveal that effective resistance responses of grapes to PM include enhancement of JA and SAR responses and accumulation of phytoalexins.