How to Delegate Computations: The Power of No-Signaling Proofs

We construct a 1-round delegation scheme (i.e., argument-system) for every language computable in time t = t ( n ), where the running time of the prover is poly ( t ) and the running time of the verifier is n · polylog ( t ). In particular, for every language in P we obtain a delegation scheme with almost linear time verification. Our construction relies on the existence of a computational sub-exponentially secure private information retrieval ( PIR ) scheme. The proof exploits a curious connection between the problem of computation delegation and the model of multi-prover interactive proofs that are sound against no-signaling (cheating) strategies , a model that was studied in the context of multi-prover interactive proofs with provers that share quantum entanglement, and is motivated by the physical principle that information cannot travel faster than light. For any language computable in time t = t ( n ), we construct a multi-prover interactive proof ( MIP ), that is, sound against no-signaling strategies, where the running time of the provers is poly ( t ), the number of provers is polylog ( t ), and the running time of the verifier is n · polylog ( t ). In particular, this shows that the class of languages that have polynomial-time MIP s that are sound against no-signaling strategies, is exactly EXP . Previously, this class was only known to contain PSPACE . To convert our MIP into a 1-round delegation scheme, we use the method suggested by Aiello et al. (ICALP, 2000), which makes use of a PIR scheme. This method lacked a proof of security. We prove that this method is secure assuming the underlying MIP is secure against no-signaling provers.

Hydropersulfides (RSSH) and Nitric Oxide (NO) Signaling: Possible Effects on S-Nitrosothiols (RS-NO)

S-Nitrosothiol (RS-NO) formation in proteins and peptides have been implicated as factors in the etiology of many diseases and as possible regulators of thiol protein function. They have also been proposed as possible storage forms of nitric oxide (NO). However, despite their proposed functions/roles, there appears to be little consensus regarding the physiological mechanisms of RS-NO formation and degradation. Hydropersulfides (RSSH) have recently been discovered as endogenously generated species with unique reactivity. One important reaction of RSSH is with RS-NO, which leads to the degradation of RS-NO as well as the release of NO. Thus, it can be speculated that RSSH can be a factor in the regulation of steady-state RS-NO levels, and therefore may be important in RS-NO (patho)physiology. Moreover, RSSH-mediated NO release from RS-NO may be a possible mechanism allowing RS-NO to serve as a storage form of NO.

GSNOR regulates ganoderic acid content in Ganoderma lucidum under heat stress through S-nitrosylation of catalase

As a master regulator of the balance between NO signaling and protein S-nitrosylation, S-nitrosoglutathione (GSNO) reductase (GSNOR) is involved in various developmental processes and stress responses. However, the proteins and specific sites that can be S-nitrosylated, especially in microorganisms, and the physiological functions of S-nitrosylated proteins remain unclear. Herein, we show that the ganoderic acid (GA) content in GSNOR-silenced (GSNORi) strains is significantly lower (by 25%) than in wild type (WT) under heat stress (HS). Additionally, silencing GSNOR results in an 80% increase in catalase (CAT) activity, which consequently decreases GA accumulation via inhibition of ROS signaling. The mechanism of GSNOR-mediated control of CAT activity may be via protein S-nitrosylation. In support of this possibility, we show that CAT is S-nitrosylated (as shown via recombinant protein in vitro and via GSNORi strains in vivo). Additionally, Cys (cysteine) 401, Cys642 and Cys653 in CAT are S-nitrosylation sites (assayed via mass spectrometry analysis), and Cys401 may play a pivotal role in CAT activity. These findings indicate a mechanism by which GSNOR responds to stress and regulates secondary metabolite content through protein S-nitrosylation. Our results also define a new S-nitrosylation site and the function of an S-nitrosylated protein regulated by GSNOR in microorganisms.

H-NOX proteins in the virulence of pathogenic bacteria

Nitric oxide (NO) is a toxic gas encountered by bacteria as a product of their own metabolism or as a result of a host immune response. Non-toxic concentrations of NO have been shown to initiate changes in bacterial behaviors such as the transition between planktonic and biofilm-associated lifestyles. The heme nitric oxide/oxygen binding proteins (H-NOX) are a widespread family of bacterial heme-based NO sensors that regulate biofilm formation in response to NO. The presence of H-NOX in several human pathogens combined with the importance of planktonic-biofilm transitions to virulence suggests that H-NOX sensing may be an important virulence factor in these organisms. Here we review the recent data on H-NOX NO signaling pathways with an emphasis on H-NOX homologues from pathogens and commensal organisms. The current state of the field is somewhat ambiguous regarding the role of H-NOX in pathogenesis. However, it is clear that H-NOX regulates biofilm in response to environmental factors and may promote persistence in the environments that serve as reservoirs for these pathogens. Finally, the evidence that large subgroups of H-NOX proteins may sense environmental signals besides NO is discussed within the context of a phylogenetic analysis of this large and diverse family.

Identification of Partner Proteins of the Algae Klebsormidium nitens NO Synthases: Toward a Better Understanding of NO Signaling in Eukaryotic Photosynthetic Organisms

In animals, NO is synthesized from L-arginine by three isoforms of nitric oxide synthase (NOS) enzyme. NO production and effects have also been reported in plants but the identification of its sources, especially the enzymatic ones, remains one of the critical issues in the field. NOS-like activities have been reported, although there are no homologs of mammalian NOS in the land plant genomes sequenced so far. However, several NOS homologs have been found in algal genomes and transcriptomes. A first study has characterized a functional NOS in the chlorophyte Ostreococcus tauri and the presence of NOS homologs was later confirmed in a dozen algae. These results raise the questions of the significance of the presence of NOS and their molecular diversity in algae. We hypothesize that comparisons among protein structures of the two KnNOS, together with the identification of their interacting partner proteins, might allow a better understanding of the molecular diversification and functioning of NOS in different physiological contexts and, more generally, new insights into NO signaling in photosynthetic organisms. We recently identified two NOS homologs sequences in the genome of the streptophyte Klebsormidium nitens, a model alga in the study of plant adaptation to terrestrial life. The first sequence, named KnNOS1, contains canonical NOS signatures while the second, named KnNOS2, presents a large C-ter extension including a globin domain. In order to identify putative candidates for KnNOSs partner proteins, we draw the protein–protein interaction networks of the three human NOS using the BioGRID database and hypothesized on the biological role of K. nitens orthologs. Some of these conserved partners are known to be involved in mammalian NOSs regulation and functioning. In parallel, our methodological strategy for the identification of partner proteins of KnNOS1 and KnNOS2 by in vitro pull-down assay is presented.

GPR87 Promotes Metastasis through the AKT-eNOS-NO Axis in Lung Adenocarcinoma

Lung adenocarcinoma is one of the leading causes of cancer-related deaths. Despite the availability of advanced anticancer drugs for lung cancer treatment, the prognosis of patients still remains poor. There is a need to explore novel oncogenic mechanisms to overcome these therapeutic limitations. The functional experiments in vitro and in vivo were performed to evaluate the role of GPR87 expression on lung adenocarcinoma metastasis. The public lung adenocarcinoma TCGA dataset was used to determine the clinical relevance of GPR87 expression in patients with lung adenocarcinoma. GPR87 is upregulated in various cancer; however, the biological function of GPR87 has not yet been established in lung adenocarcinoma. In this study, we found that GPR87 expression is upregulated in lung adenocarcinoma and is associated with poor patient prognosis. Additionally, we showed that GPR87 overexpression promotes invasiveness and metastasis of lung adenocarcinoma cells. Furthermore, we demonstrated that AKT-eNOS-NO signaling is a novel downstream pathway of GPR87 in lung adenocarcinoma. Conversely, we confirmed that silencing of GPR87 expression suppressed these phenotypes. Our results reveal the oncogenic function of GPR87 in cancer progression and metastasis through the activation of eNOS as a key mediator. Therefore, we propose that targeting eNOS could be a novel therapeutic strategy to improve the clinical treatment of lung adenocarcinoma.

Expression GWAS of PGIP1 Identifies STOP1-Dependent and STOP1-Independent Regulation of PGIP1 in Aluminum Stress Signaling in Arabidopsis

To elucidate the unknown regulatory mechanisms involved in aluminum (Al)-induced expression of POLYGALACTURONASE-INHIBITING PROTEIN 1 (PGIP1), which is one of the downstream genes of SENSITIVE TO PROTON RHIZOTOXICITY 1 (STOP1) regulating Al-tolerance genes, we conducted a genome-wide association analysis of gene expression levels (eGWAS) of PGIP1 in the shoots under Al stress using 83 Arabidopsis thaliana accessions. The eGWAS, conducted through a mixed linear model, revealed 17 suggestive SNPs across the genome having the association with the expression level variation in PGIP1. The GWAS-detected SNPs were directly located inside transcription factors and other genes involved in stress signaling, which were expressed in response to Al. These candidate genes carried different expression level and amino acid polymorphisms. Among them, three genes encoding NAC domain-containing protein 27 (NAC027), TRX superfamily protein, and R-R-type MYB protein were associated with the suppression of PGIP1 expression in their mutants, and accordingly, the system affected Al tolerance. We also found the involvement of Al-induced endogenous nitric oxide (NO) signaling, which induces NAC027 and R-R-type MYB genes to regulate PGIP1 expression. In this study, we provide genetic evidence that STOP1-independent NO signaling pathway and STOP1-dependent regulation in phosphoinositide (PI) signaling pathway are involved in the regulation of PGIP1 expression under Al stress.

The role of nitric oxide in the regulation of the electrical activity of the trigeminal nerve in the rat

Nitric oxide (NO) is a gaseous signaling molecule that regulates a number of physiological functions, including its role in the formation of migraine has been established. NO is endogenously produced in the body from L-arginine by NO synthase. The NO donor, nitroglycerin, is a trigger of migraine in humans and is widely used in the modeling of this disease in animals, which suggests the involvement of components of the NO signaling cascade in the pathogenesis of migraine. Based on the results obtained, it was found that an increase in the concentration of both the substrate for the synthesis of NO, L-arginine, and the NO donor, sodium nitroprusside, has a pro-nociceptive effect in the afferents of the trigeminal nerve. In this case, the effect of sodium nitroprusside is associated with the activation of intracellular soluble guanylate cyclase. Key words: nitric oxide, migraine, trigeminal nerve, L-arginine, guanylate cyclase, sodium nitroprusside, nociception.

Salicylic Acid and Nitric Oxide: Insight Into the Transcriptional Regulation of Their Metabolism and Regulatory Functions in Plants

Salicylic acid (SA) and nitric oxide (NO) are key signaling molecules required to activate the plant's innate immunity against abiotic stresses and biotrophic attackers. Stress-induced signaling and accumulation of SA and NO triggers extensive transcriptional reprogramming of defense-related genes, induced biosynthesis of secondary metabolites and anti-microbial compounds, thereby protecting/steering plant growth and immunity. Transcriptional regulation of SA and NO signaling are crucial for fine-tuning important cellular and metabolic functions, thus making plant defense impervious against many pathogens. The development of an impenetrable immune response is often associated with an unavoidable trade-off in the form of active suppression of plant growth and reproduction. Therefore, we highlighted recent advancements and research to unravel transcriptional regulation of SA and NO signaling essential for fulfilling their role as defense signaling molecules. We also emphasized comprehensive knowledge related to transcriptional reprogramming of SA and NO signaling important in strengthening plant growth-immunity trade-off. We also highlighted the progress on SA and NO signaling playing an indispensable role in stimulating plant-microbe interaction to modulate crucial plant functions.