27 research outputs found

    Doubly Efficient Interactive Proofs for General Arithmetic Circuits with Linear Prover Time

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    We propose a new doubly efficient interactive proof protocol for general arithmetic circuits. The protocol generalizes the doubly efficient interactive proof for layered circuits proposed by Goldwasser, Kalai and Rothblum to arbitrary circuits while preserving the optimal prover complexity that is strictly linear to the size of the circuits. The proof size remains succinct for low depth circuits and the verifier time is sublinear for structured circuits. We then construct a new zero knowledge argument scheme for general arithmetic circuits using our new interactive proof protocol together with polynomial commitments. Not only does our new protocol achieve optimal prover complexity asymptotically, but it is also efficient in practice. Our experiments show that it only takes 1 second to generate the proof for a circuit with 600,000 gates, which is 7 times faster than the original interactive proof protocol on the corresponding layered circuit. The proof size is 229 kilobytes and the verifier time is 0.56 second. Our implementation can take general arithmetic circuits generated by existing tools directly, without transforming them to layered circuits with high overhead on the size of the circuits

    Ambient temperature regulates root circumnutation in rice through the ethylene pathway: transcriptome analysis reveals key genes involved

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    Plant roots are constantly prepared to adjust their growth trajectories to avoid unfavorable environments, and their ability to reorient is particularly crucial for survival. Under laboratory conditions, this continuous reorientation of the root tip is manifested as coiling or waving, which we refer to as root circumnutation. However, the effect of ambient temperature (AT) on root circumnutation remains unexplored. In this study, rice seedlings were employed to assess the impact of varying ATs on root circumnutation. The role of ethylene in mediating root circumnutation under elevated AT was examined using the ethylene biosynthesis inhibitor aminooxyacetic acid (AOA) and the ethylene perception antagonist silver thiosulfate (STS). Furthermore, transcriptome sequencing, weighted gene co-expression network analysis, and real-time quantitative PCR were utilized to analyze gene expressions in rice root tips under four distinct treatments: 25°C, 35°C, 35°C+STS, and 35°C+AOA. As a result, genes associated with ethylene synthesis and signaling (OsACOs and OsERFs), auxin synthesis and transport (OsYUCCA6, OsABCB15, and OsNPFs), cell elongation (OsEXPAs, OsXTHs, OsEGL1, and OsEXORDIUMs), as well as the inhibition of root curling (OsRMC) were identified. Notably, the expression levels of these genes increased with rising temperatures above 25°C. This study is the first to demonstrate that elevated AT can induce root circumnutation in rice via the ethylene pathway and proposes a potential molecular model through the identification of key genes. These findings offer valuable insights into the growth regulation mechanism of plant roots under elevated AT conditions

    Reaction hijacking inhibition of Plasmodium falciparum asparagine tRNA synthetase

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    Malaria poses an enormous threat to human health. With ever increasing resistance to currently deployed drugs, breakthrough compounds with novel mechanisms of action are urgently needed. Here, we explore pyrimidine-based sulfonamides as a new low molecular weight inhibitor class with drug-like physical parameters and a synthetically accessible scaffold. We show that the exemplar, OSM-S-106, has potent activity against parasite cultures, low mammalian cell toxicity and low propensity for resistance development. In vitro evolution of resistance using a slow ramp-up approach pointed to the Plasmodium falciparum cytoplasmic asparaginyl-tRNA synthetase (PfAsnRS) as the target, consistent with our finding that OSM-S-106 inhibits protein translation and activates the amino acid starvation response. Targeted mass spectrometry confirms that OSM-S-106 is a pro-inhibitor and that inhibition of PfAsnRS occurs via enzyme-mediated production of an Asn-OSM-S-106 adduct. Human AsnRS is much less susceptible to this reaction hijacking mechanism. X-ray crystallographic studies of human AsnRS in complex with inhibitor adducts and docking of pro-inhibitors into a model of Asn-tRNA-bound PfAsnRS provide insights into the structure-activity relationship and the selectivity mechanism

    Reaction hijacking inhibition of Plasmodium falciparum asparagine tRNA synthetase

    Get PDF
    Malaria poses an enormous threat to human health. With ever increasing resistance to currently deployed drugs, breakthrough compounds with novel mechanisms of action are urgently needed. Here, we explore pyrimidine-based sulfonamides as a new low molecular weight inhibitor class with drug-like physical parameters and a synthetically accessible scaffold. We show that the exemplar, OSM-S-106, has potent activity against parasite cultures, low mammalian cell toxicity and low propensity for resistance development. In vitro evolution of resistance using a slow ramp-up approach pointed to the Plasmodium falciparum cytoplasmic asparaginyl-tRNA synthetase (PfAsnRS) as the target, consistent with our finding that OSM-S-106 inhibits protein translation and activates the amino acid starvation response. Targeted mass spectrometry confirms that OSM-S-106 is a pro-inhibitor and that inhibition of PfAsnRS occurs via enzyme-mediated production of an Asn-OSM-S-106 adduct. Human AsnRS is much less susceptible to this reaction hijacking mechanism. X-ray crystallographic studies of human AsnRS in complex with inhibitor adducts and docking of pro-inhibitors into a model of Asn-tRNA-bound PfAsnRS provide insights into the structure-activity relationship and the selectivity mechanism.</p

    Reaction hijacking inhibition of Plasmodium falciparum asparagine tRNA synthetase

    Get PDF
    Malaria poses an enormous threat to human health. With ever increasing resistance to currently deployed drugs, breakthrough compounds with novel mechanisms of action are urgently needed. Here, we explore pyrimidine-based sulfonamides as a new low molecular weight inhibitor class with drug-like physical parameters and a synthetically accessible scaffold. We show that the exemplar, OSM-S-106, has potent activity against parasite cultures, low mammalian cell toxicity and low propensity for resistance development. In vitro evolution of resistance using a slow ramp-up approach pointed to the Plasmodium falciparum cytoplasmic asparaginyl-tRNA synthetase (PfAsnRS) as the target, consistent with our finding that OSM-S-106 inhibits protein translation and activates the amino acid starvation response. Targeted mass spectrometry confirms that OSM-S-106 is a pro-inhibitor and that inhibition of PfAsnRS occurs via enzyme-mediated production of an Asn-OSM-S-106 adduct. Human AsnRS is much less susceptible to this reaction hijacking mechanism. X-ray crystallographic studies of human AsnRS in complex with inhibitor adducts and docking of pro-inhibitors into a model of Asn-tRNA-bound PfAsnRS provide insights into the structure-activity relationship and the selectivity mechanism

    Reaction hijacking inhibition of Plasmodium falciparum asparagine tRNA synthetase

    Get PDF
    Malaria poses an enormous threat to human health. With ever increasing resistance to currently deployed drugs, breakthrough compounds with novel mechanisms of action are urgently needed. Here, we explore pyrimidine-based sulfonamides as a new low molecular weight inhibitor class with drug-like physical parameters and a synthetically accessible scaffold. We show that the exemplar, OSM-S-106, has potent activity against parasite cultures, low mammalian cell toxicity and low propensity for resistance development. In vitro evolution of resistance using a slow ramp-up approach pointed to the Plasmodium falciparum cytoplasmic asparaginyl-tRNA synthetase (PfAsnRS) as the target, consistent with our finding that OSM-S-106 inhibits protein translation and activates the amino acid starvation response. Targeted mass spectrometry confirms that OSM-S-106 is a pro-inhibitor and that inhibition of PfAsnRS occurs via enzyme-mediated production of an Asn-OSM-S-106 adduct. Human AsnRS is much less susceptible to this reaction hijacking mechanism. X-ray crystallographic studies of human AsnRS in complex with inhibitor adducts and docking of pro-inhibitors into a model of Asn-tRNA-bound PfAsnRS provide insights into the structure-activity relationship and the selectivity mechanism

    Antiosteoporosis effect and possible mechanisms of the ingredients of Radix Achyranthis Bidentatae in animal models of osteoporosis: systematic review and meta-analysis of in vivo studies

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    Abstract Background The effect and mechanisms of the ingredients (IRAB) of Radix Achyranthis Bidentatae (RAB) on treating osteoporosis (OP) remains debated. We aimed to summary the evidence to evaluate the efficacy of IRAB for animal model OP and elucidate the potential mechanism of IRAB in the treatment of OP. Methods In this review and meta-analysis, we searched PubMed, EMBASE, Web of Science, Cochrane Library, Chinese National Knowledge Infrastructure, Wanfang, Chinese Biomedical Literature Database, as well as Chinese VIP databases for targeting articles published from inception to March 2023 in English or Chinese. All randomized controlled animal trials that assessed the efficacy and safety of IRAB for OP were included. We excluded trials according to exclusion criteria. The CAMARADES 10-item quality checklist was utilized to test the risk of potential bias for each including study and modifications were performed accordingly. The primary outcome measures were bone mineral density of the femoral neck (F-BMD), serum calcium (Ca), serum phosphorus (P), serum alkaline phosphatase (ALP), bone gla protein (BGP), bone maximum stress (M-STRESS). The secondary outcome measure was the antiosteoporosis mechanisms of IRAB. Results Data from nine articles were included in the systematic review and meta-analysis, which focused on 196 animals. Egger’s test revealed the presence of publication bias in various studies regarding the primary outcome. Administration of IRAB or RAB could significantly increases the F-BMD (SMD = 2.09; 95% CI = 1.29 to 2.89; P < 0.001, I 2 = 76%), Ca (SMD = 0.86; 95% CI = 0.39to1.34; P = 0.07, I 2 = 49%); P (SMD = 1.01; 95% CI = 0.45–4.57; P = 0.08, I 2 = 50%), BGP (SMD = 2.13; 95% CI = 1.48 to 2.78; I 2 = 46%, P = 0.10), while the ALP (SMD = − 0.85; 95% CI =  − 1.38 to − 0.31; I 2 = 46%, P = 0.10) was remarkably decreased in OP model animals. Moreover, the bone biomechanical indicator M-STRESS (SMD = 2.39; 95% CI = 1.74–3.04; I 2 = 32%, P = 0.21) was significantly improved. Conclusion Collectively, the findings suggest that the RAB or IRAB could be an effective drug or an ingredient in diet for the clinical treatment of OP in future

    Occurrence characteristics, source analysis and ecological risk of PFASs in different cultivated soil at an urban scale in Yangtze River Basin

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    Per- and polyfluorinated substances (PFASs) contaminates the arable soil through multiple paths, and poses a threat to both farmland ecosystems and human health. In this study, the potential sources and distribution characteristics of 12 legacy PFASs in the soil and rivers for irrigation purposes were investigated in farmland systems, and the risks posed by PFASs to earthworm and aquatic organisms were also assessed. Based on field investigations in Yangtze River Basin, we found long-chain perfluoroalkyl carboxylic acids (PFCAs) were the major contaminants in arable soil and rivers for irrigation purposes, with PFOA (Perfluorooctanoic acid) being the most dominant monomer. Concentration levels of PFASs in arable soil were strongly related to land use types, the average concentration of PFASs (341.18 ± 600.19 ng/g) in the paddy fields was 100-fold higher than that of dry fields (3.79 ± 4.11 ng/g). Source apportionment revealed that PFASs detected in paddy fields were mainly associated with industrial effluents, domestic sewage, and irrigation water. In rivers for irrigation purposes, higher PFASs contamination were primarily distributed in industrial areas, such as plastic processing, paper, textile and electronics factories. The PFASs in the irrigation river water posed a low-medium risk to daphnia and fish, while the PFASs (PFOA and perfluorododecanoic acid (PFDoDA)) in soil posed a medium-high risk to earthworms. These results provided insights that sewage irrigation caused serious pollution of PFASs in the agricultural environment, should be paid more attention
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