Redox regulation of plant S-nitrosylation

Nitric oxide (NO), a diffusible gas molecule, is a major signal molecule in both plants and animals and regulates a plethora of biological processes. S-nitrosylation, a post-translation modification, is conducted by NO, which covalently attaches protein cysteine thiols and forms an S-nitroso thiol. S-nitrosylation plays an important role in plant development and plant immune systems. In Arabidopsis thaliana, S-nitrosoglutathione (GSNO) is the major NO donor for S-nitrosylation, and GSNO reductase (GSNOR) indirectly controls the S-nitrosylation level by turning over the GSNO. An A. thaliana T-DNA insertion mutant gsnor1-3 shows the loss of GSNOR activity and increases the S-nitrosylation level, resulting in loss of apical dominance, reduction of SA accumulation, increased hypersensitive response (HR) cell death and reduced disease resistance against virulence, avirulence and non-host pathogens. Interestingly, loss of GSNOR in Drosophila melanogaster, an animal model system, reduces the resistance against gram-positive and fungal pathogens. Catalase is an antioxidant enzyme and regulates the redox environment through scavenging the hydrogen peroxide (H2O2) to oxygen and water. Previous work in our lab had discovered two gsnor1-3 suppressor mutants, gsnor1-3 spl7 and gsnor1-3 spl8, which restore the loss of apical dominance and partially restore disease resistance. These two suppressor mutants were then identified as the point mutation in CAT3. CAT3, one of the three CAT genes in Arabidopsis, expresses catalase specifically in vascular tissues. To further extend the suppression of cat3 in gsnor1-3, the mutations in CAT3 and its paralogs CAT2 and CAT1, as well as other redox-related genes in gsnor1-3 background, were generated. In the developmental phenotype, only the gsnor1-3 cat3 showed significant changes compared with gsnor1-3. The disease susceptibility and HR cell death in gsnor1-3 cat3 were less than gsnor1- 3 and similar to wild-type. Moreover, the redox-related genes and CAT3 paralog mutations in gsnor1-3 background showed no significant changes in disease resistance against virulence pathogen compared with gsnor1-3 plant. Meanwhile, an SA-dependent (salicylic acid) defence-related gene (PR1, pathogenesis-related gene 1) showed the early expression in gsnor1-3 cat3 plant compared with gsnor1-3 plant. Results of developmental and disease-related phenotypes suggest the suppression effects which turn-over the malfunction in gsnor1- 3 are highly specific to CAT3. The previous report demonstrates that the hydroxyl radical, a reactive oxygen species by-product from H2O2, decomposes GSNO to oxidised glutathione in vitro. The interaction of GSNO and hydroxyl radical may be the possible mechanism of how cat3 suppresses gsnor1- 3. Therefore, we speculated less amount of GSNO in gsnor1-3 cat3 plant than in gsnor1-3 plant and lower level of hydroxyl radicals in gsnor1-3 cat3 plant than in cat3 plant. To evaluate our hypothesis, the content hydroxyl and GSNO were analysed in wild-type, gsnor1-3, cat3 and gsnor1-3 cat3 plants. The total S-nitrosylated protein, which indicates the GSNO content in vivo, was less in gsnor1-3 cat3 than in gsnor1-3. Furthermore, the level of hydroxyl radical in gsnor1-3 cat3 was lower than cat3. Accordingly, the reduction of hydroxyl radical in gsnor1- 3 cat3 may occur due to the reaction with GSNO and vice versa. Similar to what has been found in Arabidopsis, D. melanogaster also reported partial restoration of the immunodeficiency phenotypes of gsnor knock-out flies with an additional mutation in CAT gene. Interestingly, the content of hydroxyl radical in gsnor-/- cat-/- line was less than cat+/-. Collectively, our results suggest an interaction of hydroxyl radical and GSNO may happen both in Arabidopsis and Drosophila. Further research is needed to clarify the interaction between hydroxyl radical and GSNO in Arabidopsis as well as in Drosophila

Synthesis of new 2′-deoxy-2′-fluoro-4′-azido nucleoside analogues as potent anti-HIV agents

We prepared 1-(4′-azido-2′-deoxy-2′-fluoro-β -D-arabinofuranosyl)cytosine (10) and its hydrochloride salt (11) as potential antiviral agents based on the favorable antiviral profiles of 4′-substituted nucleosides. Compounds 10 and 11 were synthesized from 1,3,5-O-tribenzoyl-2-deoxy-2-fluoro-D-arabinofuranoside in multiple steps, and their structures were unequivocally established by IR, 1H NMR, 13C NMR, and 19F NMR spectroscopy, HRMS, and X-ray crystallography. Compounds 10 and 11 exhibited potent anti-HIV-1 activity (EC50: 0.3 and 0.13 nM, respectively) without significant cytotoxicity in concentrations up to 100 μM. Compound 11 exhibited extremely potent anti-HIV activity against NL4-3 (wild-type), NL4-3 (K101E), and RTMDR viral strains, with EC50 values of 0.086, 0.15, and 0.11 nM, respectively. Due to the high potency of 11, it was also screened against an NIH Reagent Program NRTI-resistant virus panel containing eleven mutated viral strains and for cytotoxicity against six different human cell lines. The results of this screening indicated that 11 is a novel NRTI that could be developed as an anti-AIDS clinical trial candidate to overcome drug-resistance issues

A Novel LMP1 Antibody Synergizes with Mitomycin C to Inhibit Nasopharyngeal Carcinoma Growth in Vivo Through Inducing Apoptosis and Downregulating Vascular Endothelial Growth Factor

Combined therapy emerges as an attractive strategy for cancer treatment. The aim of this study was to investigate the inhibitory effects of mitomycin C (MMC) combined with a novel antibody fragment (Fab) targeting latent membrane protein 1 (LMP1) on nasopharyngeal carcinoma (NPC) xenograft nude mice. The inhibitory rates of MMC (2 mg/kg), Fab (4 mg/kg), MMC (2 mg/kg) + Fab (4 mg/kg), and MMC (1 mg/kg) + Fab (4 mg/kg) were 20.1%, 7.3%, 42.5% and 40.5%, respectively. Flow cytometry analysis showed that the apoptotic rate of xenograft tumor cells in the MMC and Fab combination group was 28 ± 4.12%, significantly higher than the MMC (2 mg/kg) group (P < 0.01). Immunohistochemical staining showed that VEGF expression in NPC xenografts was significantly inhibited in the combination group compared to the Fab (4 mg/kg) group (P < 0.05). In conclusion, both MMC and Fab could inhibit NPC xenograft tumor growth in vivo and combination therapy showed apparent synergistic anti-tumor effects, which may be due to the induction of tumor cell apoptosis and the downregulation of VEGF expression. These results suggest that the novel combined therapy utilizing traditional chemotherapeutics and antibody-targeted therapy could be a promising strategy for the treatment of NPC

Ruptured appendiceal cystadenoma presenting as right inguinal hernia in a patient with left colon cancer: A case report and review of literature

BACKGROUND: Mucoceles resulting from cystadenomas of the appendix are uncommon. Although rare, rupture of the mucoceles can occur with or without causing any abdominal complaint. There are several reports associating colonic malignancy with cystadenomas of the appendix. Herein, we report an unusual and interesting case of right inguinal hernia associated with left colon cancer. CASE PRESENTATION: A case of ruptured mucocele resulting from cystadenoma of the appendix was presented as right inguinal hernia in a 70-year-old male. The patient underwent colonoscopy, x-ray, ultrasound and computed tomography. Localized pseudomyxoma peritonei associated with adenocarcinoma of the descending colon was diagnosed. The patient underwent segmental resection of the colon, appendectomy, debridement of pseudomyxoma and closure of the internal ring of right inguinal canal. He is free of symptoms in one year follow-up. CONCLUSION: Synchronous colon cancer may occur in patients with appendiceal mucoceles. In such patients, the colon should be investigated and colonoscopy can be performed meticulously in cases of ruptured mucoceles and localized pseudomyxoma peritonei. Surgical intervention is the current choice of management

Safety Issues of Long-Term Glucose Load in Patients on Peritoneal Dialysis—A 7-Year Cohort Study

BACKGROUND: Effects of long-term glucose load on peritoneal dialysis (PD) patient safety and outcomes have seldom been reported. This study demonstrates the influence of long-term glucose load on patient and technique survival. METHODS: We surveyed 173 incident PD patients. Long-term glucose load was evaluated by calculating the average dialysate glucose concentration since initiation of PD. Risk factors were assessed by fitting Cox's models with repeatedly measured time-dependent covariates. RESULTS: We noted that older age, higher glucose concentration, and lower residual renal function (RRF) were significantly associated with a worse patient survival. We found that female gender, absence of diabetes, lower glucose concentration, use of icodextrin, higher serum high density lipoprotein cholesterol, and higher RRF were significantly associated with a better technique survival. CONCLUSIONS: Long-term glucose load predicted mortality and technique failure in chronic PD patients. These findings emphasize the importance of minimizing glucose load in PD patients

The Fourteenth Data Release of the Sloan Digital Sky Survey: First Spectroscopic Data from the extended Baryon Oscillation Spectroscopic Survey and from the second phase of the Apache Point Observatory Galactic Evolution Experiment

The fourth generation of the Sloan Digital Sky Survey (SDSS-IV) has been in operation since July 2014. This paper describes the second data release from this phase, and the fourteenth from SDSS overall (making this, Data Release Fourteen or DR14). This release makes public data taken by SDSS-IV in its first two years of operation (July 2014-2016). Like all previous SDSS releases, DR14 is cumulative, including the most recent reductions and calibrations of all data taken by SDSS since the first phase began operations in 2000. New in DR14 is the first public release of data from the extended Baryon Oscillation Spectroscopic Survey (eBOSS); the first data from the second phase of the Apache Point Observatory (APO) Galactic Evolution Experiment (APOGEE-2), including stellar parameter estimates from an innovative data driven machine learning algorithm known as "The Cannon"; and almost twice as many data cubes from the Mapping Nearby Galaxies at APO (MaNGA) survey as were in the previous release (N = 2812 in total). This paper describes the location and format of the publicly available data from SDSS-IV surveys. We provide references to the important technical papers describing how these data have been taken (both targeting and observation details) and processed for scientific use. The SDSS website (www.sdss.org) has been updated for this release, and provides links to data downloads, as well as tutorials and examples of data use. SDSS-IV is planning to continue to collect astronomical data until 2020, and will be followed by SDSS-V.Comment: SDSS-IV collaboration alphabetical author data release paper. DR14 happened on 31st July 2017. 19 pages, 5 figures. Accepted by ApJS on 28th Nov 2017 (this is the "post-print" and "post-proofs" version; minor corrections only from v1, and most of errors found in proofs corrected

Pan-Cancer Analysis of lncRNA Regulation Supports Their Targeting of Cancer Genes in Each Tumor Context

Long noncoding RNAs (lncRNAs) are commonly dys-regulated in tumors, but only a handful are known toplay pathophysiological roles in cancer. We inferredlncRNAs that dysregulate cancer pathways, onco-genes, and tumor suppressors (cancer genes) bymodeling their effects on the activity of transcriptionfactors, RNA-binding proteins, and microRNAs in5,185 TCGA tumors and 1,019 ENCODE assays.Our predictions included hundreds of candidateonco- and tumor-suppressor lncRNAs (cancerlncRNAs) whose somatic alterations account for thedysregulation of dozens of cancer genes and path-ways in each of 14 tumor contexts. To demonstrateproof of concept, we showed that perturbations tar-geting OIP5-AS1 (an inferred tumor suppressor) andTUG1 and WT1-AS (inferred onco-lncRNAs) dysre-gulated cancer genes and altered proliferation ofbreast and gynecologic cancer cells. Our analysis in-dicates that, although most lncRNAs are dysregu-lated in a tumor-specific manner, some, includingOIP5-AS1, TUG1, NEAT1, MEG3, and TSIX, synergis-tically dysregulate cancer pathways in multiple tumorcontexts