The elicitor VP2 from Verticillium dahliae triggers defence response in cotton.

Verticillium dahliae is a widespread and destructive soilborne vascular pathogenic fungus that causes serious diseases in dicot plants. Here, comparative transcriptome analysis showed that the number of genes upregulated in defoliating pathotype V991 was significantly higher than in the non-defoliating pathotype 1cd3-2 during the early response of cotton. Combined with analysis of the secretome during the V991-cotton interaction, an elicitor VP2 was identified, which was highly upregulated at the early stage of V991 invasion, but was barely expressed during the 1cd3-2-cotton interaction. Full-length VP2 could induce cell death in several plant species, and which was dependent on NbBAK1 but not on NbSOBIR1 in N. benthamiana. Knock-out of VP2 attenuated the pathogenicity of V991. Furthermore, overexpression of VP2 in cotton enhanced resistance to V. dahliae without causing abnormal plant growth and development. Several genes involved in JA, SA and lignin synthesis were significantly upregulated in VP2-overexpressing cotton. The contents of JA, SA, and lignin were also significantly higher than in the wild-type control. In summary, the identified elicitor VP2, recognized by the receptor in the plant membrane, triggers the cotton immune response and enhances disease resistance.

Food emulsifier polysorbate 80 promotes the intestinal absorption of mono-2-ethylhexyl phthalate by disturbing intestinal barrier.

Di-2-ethylhexyl phosphate (DEHP) and its main toxic metabolite mono-2-ethylhexyl phthalate (MEHP) are the typical endocrine disrupting chemicals (EDCs) and widely affect human health. Our previous research reported that synthetic nonionic dietary emulsifier polysorbate 80 (P80, E433) had the promotional effect on the oral absorption of DEHP in rats. The aim of this study was to explore its mechanism of promoting oral absorption, focusing on the mucus barrier and mucosal barrier of the small intestine. A small molecule fluorescent probe 5-aminofluorescein-MEHP (MEHP-AF) was used as a tracker of MEHP in vivo and in vitro. First of all, we verified that P80 promoted the bioavailability of MEHP-AF in the long-term and low-dose exposure of MEHP-AF with P80 as a result of increasing the intestinal absorption of MEHP-AF. Afterwards, experimental results from Western blot, qPCR, immunohistochemistry, and immunofluorescence showed that P80 decreased the expression of proteins (mucus protein mucin-2, tight junction proteins claudin-1 and occludin) related to mucus barrier and mucosal barrier in the intestine, changed the integrity of intestinal epithelial cell, and increased the permeability of intestinal epithelial mucosa. These results indicated that P80 promoted the oral absorption of MEHP-AF by altering the intestinal mucus barrier and mucosal barrier. These findings are of great importance for assessing the safety risks of some food emulsifiers and clarifying the absorption mechanism of chemical pollutants in food, especially for EDCs.

Mitochondria-targeting graphene oxide nanocomposites for fluorescence imaging-guided synergistic phototherapy of drug-resistant osteosarcoma.

BACKGROUND: Osteosarcoma (OS) is the most common primary malignant bone tumor occurring in children and young adults. Drug-resistant osteosarcoma often results in chemotherapy failure. Therefore, new treatments aimed at novel therapeutic targets are urgently needed for the treatment of drug-resistant osteosarcoma. Mitochondria-targeted phototherapy, i.e., synergistic photodynamic/photothermal therapy, has emerged as a highly promising strategy for treating drug-resistant tumors. This study proposed a new nano-drug delivery system based on near-infrared imaging and multifunctional graphene, which can target mitochondria and show synergistic phototherapy, with preferential accumulation in tumors. METHODS AND RESULTS: Based on our previous study, (4-carboxybutyl) triphenyl phosphonium bromide (TPP), a mitochondria-targeting ligand, was conjugated to indocyanine green (ICG)-loaded, polyethylenimine-modified PEGylated nanographene oxide sheets (TPP-PPG@ICG) to promote mitochondrial accumulation after cellular internalization. Thereafter, exposure to a single dose of near-infrared irradiation enabled synergistic photodynamic and photothermal therapy, which simultaneously inhibited adenosine triphosphate synthesis and mitochondrial function. Induction of intrinsic apoptosis assisted in surmounting drug resistance and caused tumor cell death. After fluorescence imaging-guided synergistic phototherapy, the mitochondria-targeting, multifunctional graphene-based, drug-delivery system showed highly selective anticancer efficiency in vitro and in vivo, resulting in marked inhibition of tumor progression without noticeable toxicity in mice bearing doxorubicin-resistant MG63 tumor cells. CONCLUSION: The mitochondria-targeting TPP-PPG@ICG nanocomposite constitutes a new class of nanomedicine for fluorescence imaging-guided synergistic phototherapy and shows promise for treating drug-resistant osteosarcoma.

Genetic variation in IL28B predicts hepatitis C treatment-induced viral clearance.

Chronic infection with hepatitis C virus (HCV) affects 170 million people worldwide and is the leading cause of cirrhosis in North America. Although the recommended treatment for chronic infection involves a 48-week course of peginterferon-alpha-2b (PegIFN-alpha-2b) or -alpha-2a (PegIFN-alpha-2a) combined with ribavirin (RBV), it is well known that many patients will not be cured by treatment, and that patients of European ancestry have a significantly higher probability of being cured than patients of African ancestry. In addition to limited efficacy, treatment is often poorly tolerated because of side effects that prevent some patients from completing therapy. For these reasons, identification of the determinants of response to treatment is a high priority. Here we report that a genetic polymorphism near the IL28B gene, encoding interferon-lambda-3 (IFN-lambda-3), is associated with an approximately twofold change in response to treatment, both among patients of European ancestry (P = 1.06 x 10(-25)) and African-Americans (P = 2.06 x 10(-3)). Because the genotype leading to better response is in substantially greater frequency in European than African populations, this genetic polymorphism also explains approximately half of the difference in response rates between African-Americans and patients of European ancestry.

[Optimization and characterization of curcumin-piperine dual drug loaded self-microemulsifying drug delivery system by simplex lattice design].

The objective of the study was to prepare and evaluate the quality of curcumin-piperinedual drug loaded self-microemulsifying drug delivery system(Cur-PIP-SMEDDS). Simplex lattice design was constructed using optimal oil phase, surfactant and co-surfactant concentration as independent variables, and the curcumin and piperine were used as model drugs to optimize Cur-PIP-SMEDDS formulation. In the present study, the drug loadings of curcumin and piperine, mean particle size of Cur-PIP-SMEDDS were made as indicators, and the experiment design, model building and response surface analysis were established using Design Expert 8. 06 software to optimize and verify the composition of SMEDDS formulation. The quality of Cur-PIP-SMEDDS was evaluated by observing the appearance status, transmission electron microscope micrographs and determining particle diameter, electric potential, drug entrapment efficiency and drug loading of it. As a result, the optimal formulation of SMEDDS was CapryoL 90-Cremophor RH40-TranscutoL HP (10:60:30). The appearance of Cur-PIP-SMEDDS remained clarified and transparent, and the microemulsion droplets appeared spherical without aggregation with uniform particle size distribution. The mean size of microemulsion droplet formed from Cur-PIP-SMEDDS was 15.33 nm, the drug loading of SMEDDS for Cur and PIP were 40.90 mg · g(-1) and 0.97 mg · g(-1), respectively, the drug entrapment efficiency were 94.98% and 90.96%, respectively. The results show that Cur-PIP-SMEDDS can increase the solubility and stability of curcumin significantly, in the expectation of enhancing the bioavailability of it. Taken together, these findings can provide the reference to a preferable choice of the Cur formulation and contribute to therapeutic application in clinical research.

Novel luminescent hybrids by incorporating rare earth ß-diketonates into polymers through ion pairing with an imidazolium counter ion.

A series of luminescent polymers are synthesized by incorporating rare earth complex units into polymer matrices. Firstly, we functionalize the selected polymer matrices with the imidazolium moieties, and then introduce the rare earth tetrakis(ß-diketonate) complexes into polymer matrices through a mild anion exchange method. The resulting materials are characterized by FTIR, XRD, EDAX, SEM, thermogravimetric analysis, luminescence excitation spectra and emission spectra, luminescence lifetime measurements and diffuse reflectance UV-Vis spectra. The photoluminescence measurements indicate that all these rare earth complex functionalized polymers exhibit a characteristic luminescence emission originating from the corresponding rare earth ions. Among the hybrids, the europium tetrakis(TTA) complex functionalized polymers show remarkable luminescence quantum yields and relatively long (5)D0 lifetimes at room temperature.

Nitric oxide releasing polyvinyl alcohol and sodium alginate hydrogels as antibacterial and conductive strain sensors.

Conductive hydrogels have promising applications in flexible electronic devices and artificial intelligence, which have attracted much attention in recent years. However, most conductive hydrogels have no antimicrobial activity, inevitably leading to microbial infections during utilization. In this work, a series of antibacterial and conductive polyvinyl alcohol and sodium alginate (PVA-SA) hydrogels were successfully developed with the incorporation of S-nitroso-N-acetyl-penicillamine (SNAP) and MXene through a freeze-thaw approach. Due to the reversibility of hydrogen bonding and electrostatic interactions, the resulting hydrogels had excellent mechanical properties. Specifically, the presence of MXene readily interrupted the crosslinked hydrogel network, but the best stretching can reach up to >300 %. Moreover, the impregnation of SNAP achieved the release of nitric oxide (NO) over several days under physiological conditions. Due to the release of NO, these composited hydrogels demonstrated high antibacterial activities (> 99 %) against both Gram-positive and negative S. aureus and E. coli bacteria. Notably, the excellent conductivity of MXene endowed the hydrogel with a sensitive, fast, and stable strain-sensing ability, to accurately monitor and distinguish subtle physiological activities of the human body including finger bending and pulse beating. These novel composited hydrogels are likely to have potential as strain-sensing materials in the field of biomedical flexible electronics.

Effect of phenol formaldehyde-associated microplastics on soil microbial community, assembly, and functioning.

Increasing investigations explore the effects of plastic pollutants on bacterial communities, diversity, and functioning in various ecosystems. However, the impact of microplastics (MPs) on the eukaryotic community, microbial assemblages, and interactions is still limited. Here, we investigated bacterial and micro-eukaryotic communities and functioning in soils with different concentrations of phenol formaldehyde-associated MPs (PF-MPs), and revealed the factors, such as soil properties, microbial community assembly, and interactions between microbes, influencing them. Our results showed that a high concentration (1%) of PF-MPs decreased the microbial interactions and the contribution of deterministic processes to the community assembly of microbes, and consequently changed the communities of bacteria, but not eukaryotes. A significant and negative relationship was determined between N2O emission rate and functional genes related to nitrification, indicating that the competitive interactions between functional microbes would affect the nitrogen cycling of soil ecosystem. We further found that vegetable biomass weakly decreased in treatments with a higher concentration of PF-MPs and positively related to the diversity of micro-eukaryotic communities and functional diversity of bacterial communities. These results suggest that a high concentration of the PF-MPs would influence crop growth by changing microbial communities, interactions, and eukaryotic and functional diversity. Our findings provide important evidence for agriculture management of phenol formaldehyde and suggest that we must consider their threats to microbial community compositions, diversity, and assemblage in soils due to the accumulation of PF-MPs widely used in the field.

Polyethyleneimine-coated MXene quantum dots improve cotton tolerance to Verticillium dahliae by maintaining ROS homeostasis.

Verticillium dahliae is a soil-borne hemibiotrophic fungal pathogen that threatens cotton production worldwide. In this study, we assemble the genomes of two V. dahliae isolates: the more virulence and defoliating isolate V991 and nondefoliating isolate 1cd3-2. Transcriptome and comparative genomics analyses show that genes associated with pathogen virulence are mostly induced at the late stage of infection (Stage II), accompanied by a burst of reactive oxygen species (ROS), with upregulation of more genes involved in defense response in cotton. We identify the V991-specific virulence gene SP3 that is highly expressed during the infection Stage II. V. dahliae SP3 knock-out strain shows attenuated virulence and triggers less ROS production in cotton plants. To control the disease, we employ polyethyleneimine-coated MXene quantum dots (PEI-MQDs) that possess the ability to remove ROS. Cotton seedlings treated with PEI-MQDs are capable of maintaining ROS homeostasis with enhanced peroxidase, catalase, and glutathione peroxidase activities and exhibit improved tolerance to V. dahliae. These results suggest that V. dahliae trigger ROS production to promote infection and scavenging ROS is an effective way to manage this disease. This study reveals a virulence mechanism of V. dahliae and provides a means for V. dahliae resistance that benefits cotton production.

Transcriptome analysis of flower bud identified genes associated with pistil abortions between long branches and spur twigs in apricots (Prunus armeniaca L.).

Pistil abortions of flower buds occur frequently in many apricot cultivars, especially in long branches. However, the molecular mechanism underlying pistil abortion in apricots remains unclear. To better understand the molecular mechanism of pistil abortions between long branches and spur twigs, paraffin sections and high-throughput sequencing technology were employed to analyze the expression patterns of genes associated with pistil abortions during later flower bud development stage in 'Shajinhong' apricot. The result of stage III (separation of bud scales) was the critical stage of pistil abortion in apricots. A total of 163 differentially expressed genes were identified as candidate genes related to pistil abortion in long branches. These genes are implicated in programmed cell death, hormone signaling, cell wall degeneration, and the carbohydrate metabolism pathway. The results showed that the up-regulation of gene expression of Xyloglucan endotransglucosylase/hydrolase and ß-glucosidase in flower buds might be the direct cause of cell wall breakdown and pistil necrosis in long branches. We hypothesize that there is a molecular relationship between pistil abortion before blooming and cellulose degradation, and then carbohydrate transport in the case of carbon deficiency in long branches. Our work provides new insights into cellulose degradation in abortion pistils and valuable information on flower development in apricots, and also provides a useful reference for cultivation regulation in apricot or other fruit crops.

Near-Infrared Light-Controllable Multifunction Mesoporous Polydopamine Nanocomposites for Promoting Infected Wound Healing.

The successful treatment of infected wounds requires strategies with effective antimicrobial, anti-inflammatory, and healing-promoting properties. Accordingly, the use of Cu2+ and tetracycline (TC), which can promote angiogenesis, re-epithelialization, and collagen deposition, also antibacterial activity, at the wound site, has shown application prospects in promoting infected wound repair. However, realizing controllable release to prolong action time and avoid potential toxicities is critical. Moreover, near-infrared light (NIR)-activated mesoporous polydopamine nanoparticles (MPDA NPs) reportedly exert anti-inflammatory effects by eliminating the reactive oxygen species generated during inflammatory responses. In this study, we assess whether Cu2+ and TC loaded in MPDA NPs can accelerate infected wound healing in mice. In particular, Cu2+ is chelated and immobilized on the surface of MPDA NPs, while a thermosensitive phase-change material (PCM; melting point: 39-40 °C), combined with antibiotics, was loaded into the MPDA NPs as a gatekeeper (PPMD@Cu/TC). Results show that PPMD@Cu/TC exhibits significant great photothermal properties with NIR irradiation, which induces the release of Cu2+, while inducing PCM melting and, subsequent, TC release. In combination with anti-inflammatory therapy, NIR-triggered Cu2+ and TC release enables the nanocomposite to eradicate bacterial wound infections and accelerate healing. Importantly, negligible damage to primary organs and satisfactory biocompatibility were observed in the murine model. Collectively, these findings highlight the therapeutic potential of this MPDA-based platform for controlling bacterial infection and accelerating wound healing.

Deep-skin multiphoton microscopy in vivo excited at 1600 nm: A comparative investigation with silicone oil and deuterium dioxide immersion.

Multiphoton microscopy (MPM) excited at the 1700-nm window has enabled deep-tissue penetration in biological tissue, especially brain. MPM of skin may also benefit from this deep-penetration capability. Skin is a layered structure with varying refractive index (from 1.34 to 1.5). Consequently, proper immersion medium should be selected when imaging with high numerical aperture objective lens. To provide guidelines for immersion medium selection for skin MPM, here we demonstrate comparative experimental investigation of deep-skin MPM excited at 1600 nm in vivo, using both silicone oil and deuterium dioxide (D2 O) immersion. We specifically characterize imaging depths, signal levels and spatial resolution. Our results show that both immersion media give similar performance in imaging depth and spatial resolution, while signal levels are slightly better with silicone oil immersion. We also demonstrate that local injection of fluorescent beads into the skin is a viable technique for spatial resolution characterization in vivo.

Biomimetic tubular scaffold with heparin conjugation for rapid degradation in in situ regeneration of a small diameter neoartery.

To address the clinical need for readily available small diameter vascular grafts, biomimetic tubular scaffolds were developed for rapid in situ blood vessel regeneration. The tubular scaffolds were designed to have an inner layer that is porous, interconnected, and with a nanofibrous architecture, which provided an excellent microenvironment for host cell invasion and proliferation. Through the synthesis of poly(spirolactic-co-lactic acid) (PSLA), a highly functional polymer with a norbornene substituting a methyl group in poly(l-lactic acid) (PLLA), we were able to covalently attach biomolecules onto the polymer backbone via thiol-ene click chemistry to impart desirable functionalities to the tubular scaffolds. Specifically, heparin was conjugated on the scaffolds in order to prevent thrombosis when implanted in situ. By controlling the amount of covalently attached heparin we were able to modulate the physical properties of the tubular scaffold, resulting in tunable wettability and degradation rate while retaining the porous and nanofibrous morphology. The scaffolds were successfully tested as rat abdominal aortic replacements. Patency and viability were confirmed through dynamic ultrasound and histological analysis of the regenerated tissue. The harvested tissue showed excellent vascular cellular infiltration, proliferation, and migration with laminar cellular arrangement. Furthermore, we achieved both complete reendothelialization of the vessel lumen and native-like media extracellular matrix. No signs of aneurysm or hyperplasia were observed after 3 months of vessel replacement. Taken together, we have developed an effective vascular graft able to generate small diameter blood vessels that can function in a rat model.

Binary blended co-delivery nanoparticles with the characteristics of precise pH-responsive acting on tumor microenvironment.

Although combined chemotherapy had achieved the ideal efficacy in clinical anti-cancer therapeutic, the issues that need to be addressed are non-targeting and toxic-side effects of small molecule chemical drug (SMCD). In this study, we designed and prepared a novel binary blended co-delivered nanoparticles (BBCD NPs) with pH-responsive feature on tumor microenvironment. The BBCD NPs consists of two kind of drug-loaded NPs, in one of which carboxymethyl chitosan (CMC) and Poly (lactic-co-glycolic acid) (PLGA) were chosen as delivery carrier to load anti-cancer drug vincristine (VCR), named CMC-PLGA-VCR NPs (or CPNPVCR); and in the other of which methoxy poly(ethylene glycol)-poly(ß-amino ester) (mPEG-PAE) were chosen as delivery carrier to load anti-fibrotic drug pirfenidone (PFD), named mPEG-PAE-PFD NPs (or PPNPPFD). Then, the two types of NPs (CPNPVCR and PPNPPFD) were physically mixed in mass ratios to form BBCD NPs, which was named CPNPVCR&PPNPPFD. CPNPVCR&PPNPPFD had good encapsulation efficiency and loading capacity, and the particle size distribution was uniform. In cytotoxicity experiments and non-contact co-culture studies in vitro, the model drugs loaded in CPNPVCR&PPNPPFD could respectively target cancer cell and cancer associated fibroblast (CAF) owing to the precise pH-sensitive drug release in the pharmacological targets and show stronger synergism than that of the combined treatment of two free drugs. As a modularity and assemble ability feature in design, BBCD NPs would have the advantages on the terms of concise on preparation process, controllable on quality standard, stable in natural environment storage. The research results can provide scientific evidence for the further development of a novel drug co-delivery system with multi-type cell targets.

Deep-brain three-photon microscopy excited at 1600 nm with silicone oil immersion.

Three-photon microscopy excited at the 1700-nm window (roughly covering 1600-1840 nm) is especially suitable for deep-brain imaging in living animals. To match the brain refractive index, D2 O has been exclusively used as the immersion medium. However, the hygroscopic property of D2 O leads to a decrease of transmittance of the excitation light and as a result a decrease in three-photon signals over time. Solutions such as replacing D2 O from time to time, wrapping both the objective lens and the immersion D2 O, and sealing D2 O with paraffin liquid have all been demonstrated, which add to the system complexity. Based on our recent characterization of immersion oils, we propose using silicone oil as a potential alternative to D2 O for deep-brain imaging. Excited at 1600 nm, our comparative deep-brain imaging using both D2 O and silicone oil immersion show that silicone oil immersion yields 17% higher three-photon signal in third-harmonic generation imaging within the white matter. Besides, silicone oil immersion also enables three-photon fluorescence imaging of vasculature up to 1460 µm (mechanical depth) into the mouse brain in vivo acquired at 2 seconds/frame. Together with the nonhygroscopic physical property, silicone oil is promising for long-span three-photon brain imaging excited at the 1700-nm window.

Analysis of HCV resistance mutations during combination therapy with protease inhibitor boceprevir and PEG-IFN alpha-2b using TaqMan mismatch amplification mutation assay.

TaqMan Mismatch Amplification Mutation Assay (TaqMAMA) is a highly sensitive allelic discrimination method. The mismatch amplification mutation assay (MAMA) is based on preferential amplification of mutant allele by the 'MAMA' primer, which is designed to have two mismatches with the wild-type allele and only one mismatch with the mutant allele. In this report, the TaqMAMA method was adapted for the detection and quantitation of minor HCV variants resistant to the protease inhibitor boceprevir (SCH 503034) from clinical samples. A good correlation of mutant frequency was observed between TaqMAMA and the results of clonal sequencing. TaqMAMA detected consistently minor variants at a level as low as 0.1%. Using TaqMAMA, it was demonstrated that resistant variants existed in the viral population before boceprevir treatment. The frequency of two resistant mutants (T54A and V170A) increased significantly during treatment with boceprevir, but was suppressed by combination treatment of PEG-IFN alpha-2b and boceprevir. The prevalence of both mutants decreased at the end of the two-week follow-up period. These results show that TaqMAMA can be used to detect minor resistant variants in pretreatment samples and to study in detail the evolution of mutant viruses during targeted antiviral therapy.

An efficiently sustainable dextran-based flocculant: Synthesis, characterization and flocculation.

Polysaccharide-modified flocculant is a notable material in the field of wastewater treatment. Synthesis of biopolysaccharide derivatives as eco-friendly flocculants is remarkably desired for environmental protection. This work presents an efficient flocculant synthesized through copolymerization of acrylamide, sodium acrylate (AS), and dextran. Physicochemical properties of the flocculant were evaluated. Process parameters of coal-washing wastewater flocculation were tested using Response Surface Method. The application of graft polymers exhibited efficient flocculation performance at low level of flocculant dosage in alkalescent environment. The improved dextran contributes to handle industrial effluent and sanitary sewage.

Organization of the mitochondrial genome of Odontobutis sinensis (Perciformes: Odontobutidae): rearrangement of tRNAs and additional non-coding regions.

In this study, we cloned and sequenced the complete mitochondrial genome of Odontobutis sinensis. The genome was found to be 17,441 bp in size with a mostly conserved structural organization when compared with that of other teleost fish. It contained 37 genes (13 protein-coding genes, 22 transfer RNA genes and two ribosomal RNA genes) and two main non-coding regions (the control region and the origin of the light strand replication). Rearrangements of tRNAs (tRNA-Ser, tRNA-Leu, tRNA-His) and three additional longer non-coding regions (51 bp, 622 bp and 66 bp, respectively) were present between the ND4 and ND5 genes. Within the control region, one 322 bp long tandem repeat area (7*46 bp) and some typical conserved domains were identified. The molecular data here we presented could play a useful role to study the evolutionary relationships and population genetics of the Odontobutidae.

Scorpion peptide LqhIT2 activates phenylpropanoid pathways via jasmonate to increase rice resistance to rice leafrollers.

LqhIT2 is an insect-specific toxin peptide identified in Leiurus quinquestriatus hebraeus that can be toxic to lepidoptera pests. However, whether LqhIT2 induces insect resistance in rice, and how the LqhIT2 influences the biochemical metabolism of rice plants remains unknown. Here, purified LqhIT2-GST fusion protein had toxicity to rice leafrollers. Meanwhile, in vitro and field trials showed that LqhIT2 transgenic rice plants were less damaged by rice leafrollers compared to the wild type plants. Introducing LqhIT2 primed the elevated expression of lipoxygenase, a key component of the jasmonic acid biosynthetic pathway, together with enhanced linolenic acid, cis-(+)-12-oxophytodienoic acid, jasmonic acid, and jasmonic acid-isoleucine levels. In addition, phenylalanine ammonia-lyase, a key gene of the phenylpropanoid pathway, was up-regulated. Correspondingly, the contents of downstream products of the phenylpropanoid pathway such as flavonoids and lignins, were also increased in LqhIT2 transgenic plants. These changes were paralleled by decreased starch, glucose, and glucose-6-phosphate accumulation, the key metabolites of glycolysis pathway that supplies the raw material and intermediate carbon products for phenylpropanoids biosyntheses. These findings suggest that, in addition to its own toxicity against pests, LqhIT2 activate the phenylpropanoid pathway via jasmonate-mediated priming, which subsequently increases flavonoid and lignin content and improves insect resistance in rice.

Resistance-associated amino acid variants associated with boceprevir plus pegylated interferon-α2b and ribavirin in patients with chronic hepatitis C in the SPRINT-1 trial.

BACKGROUND: Resistance to direct-acting antivirals represents a new challenge in the treatment of chronic hepatitis C. METHODS: SPRINT-1 was a randomized study of treatment-naive patients with genotype (G) 1 hepatitis C infection (n=595) that evaluated the safety and efficacy of boceprevir (BOC) when added to pegylated interferon-α2b plus ribavirin (PR). Plasma samples collected at protocol-specified visits were analysed by population sequencing for detection of BOC-associated resistance-associated variants (RAVs). RESULTS: A total of 17/24 (71%) patients randomized to BOC with baseline RAVs achieved sustained virological response (SVR). V55A/I (n=14), Q41H (n=11) and T54S (n=9) were the most frequently detected polymorphisms at baseline. Seven non-SVR patients with baseline RAVs had V55A (relapse, n=3; breakthrough, n=1; and non-response, n=1) and/or R155K (non-response, n=2). In total, 63/144 (44%) patients with sequenced post-baseline samples (2 SVR, 61 non-SVR) had detectable RAVs after BOC treatment (G1a: R155K [39/49; 80%], V36M [37/49; 76%] and T54S [24/49; 49%]; G1b: T54S [3/11; 27%], T54A [4/11; 35%], A156S [2/11; 18%] and V170A [2/11; 18%]). RAV frequency varied according to the virological response: 90%, 67%, 27% and 37% of breakthrough, incomplete virological response, relapse and non-responder patients, respectively, had post-baseline RAVs present. Similar RAVs were identified in both the PR lead-in and no-lead-in arms and the frequency of post-baseline RAVs was highest in the low-dose ribavirin arm. CONCLUSIONS: SVR rates were not compromised among patients with RAVs at baseline; however, a lower starting mg/kg dose of ribavirin was associated with a higher frequency of post-baseline RAVs.