Effects of Flubeneteram on Inhibiting the Development of Puccinia striiformis f. sp. tritici in Wheat Leaves.

Stripe rust caused by Puccinia striiformis f. sp. tritici (Pst) is a serious threat to wheat production, and the application of fungicides is one of the most important means for controlling the disease. The purpose of this study is to determine the effects of a new succinate dehydrogenase inhibitor (SDHI) fungicide, flubeneteram, on reducing stripe rust. The baseline sensitivity of 173 Pst isolates from 13 provinces of China to flubeneteram was determined. Flubeneteram displayed significant effects on inhibiting SDH enzymes of Pst. Histological observations showed that after flubeneteram application, the formation and development of Pst hyphae and haustoria were significantly inhibited, and the structures were destroyed. Flubeneteram primed wheat for salicylic acid-induced defenses via upregulating pathogenesis-related genes (PR1 and PR2). Altogether, our study is the first to provide evidence that flubeneteram induces wheat defense against Pst infection. The findings indicate that flubeneteram could be an effective fungicide for managing stripe rust.

Sensitivity and Resistance Risk Assessment of Puccinia striiformis f. sp. tritici to Triadimefon in China.

Wheat stripe rust, caused by Puccinia striiformis f. sp. tritici (Pst), is a destructive disease of wheat that seriously threatens production safety in wheat-producing areas worldwide. In China, the disease has been largely controlled with the fungicide triadimefon. Although high levels of fungicide resistance in other fungal pathogens have been reported, failure to control Pst with any fungicides has seldomly been reported, and fungicide sensitivity of Pst has not been evaluated in China. The distribution of triadimefon-resistant Pst isolates was investigated in the present study. The baseline sensitivity of 446 Pst isolates across the country to triadimefon was determined, and the concentration for 50% of maximal effect showed a unimodal distribution curve, with a mean value of 0.19 µg ml-1. The results indicated a wide range of sensitivity to triadimefon, with more insensitive isolates collected from Pst winter-increasing areas and northwest oversummering areas, whereas more sensitive isolates were collected from southwest oversummering areas and epidemic areas of Xinjiang and Tibet. The majority of the tested Pst isolates were sensitive to triadimefon; only 6.79% had developed varying degrees of resistance. Characterization of parasitic fitness revealed that the triadimefon-resistant isolates exhibited strong adaptive traits in the urediniospore germination rate, latent period, sporulation intensity, and lesion expansion rate. Positive cross-resistance was observed between triadimefon and tebuconazole or hexaconazole, but not between pyraclostrobin or flubeneteram. The point mutation Y134F in the 14α-demethylase enzyme (CYP51) was detected in triadimefon-resistant isolates. A molecular method (kompetitive allele-specific PCR) was established for the rapid detection of Y134F mutants in the Pst population. Two genotypes with one point mutation Y134F conferred resistance to triadimefon in Pst. The risk of resistance to triadimefon in Pst may be low to moderate. This study provided important data for establishment of high throughput molecular detection methods, fungicide resistance risk management, and the development of new target fungicides.

De novo Assembly of the Benzenoid Ring as a Core Strategy for Synthesis of the Isoindolinone Natural Products Isohericerin, Erinacerin A, and Sterenin A.

Here we describe the use of the hexadehydro-Diels-Alder (HDDA) reaction for the de novo construction of the isoindolinone scaffold and its application to the synthesis of the title natural products. The key isoindolinone-forming HDDA reaction involved an unprecedented substrate motif in which an amide carbonyl group was conjugated to the 4π 1,3-diyne component. In addition, a dimethylsilyl (-SiMe2H) substituent was exploited to trigger a Fleming-Tamao-Kumada oxidation for the installation of an essential phenolic hydroxyl group.

Reactions of thermally generated benzynes with six-membered N-heteroaromatics: pathway and product diversity.

We report here various pathways by which six-membered N-heteroaromatic compounds react with benzynes that are generated by the HDDA reaction. The initially formed 1,3-zwitterionic species (a) can collapse intramolecularly to give novel 1 : 1 adducts of the heterocycle and benzyne; (b) can react with an externally added, electrophilic third-component to give functionalized heterocyclic products; or (c) can react with an external protic nucleophile to produce, following collapse of the ion pair resulting from protonation of the zwitterion, a variety of three-component assemblies. Mechanisms for formation of some of the 1 : 1 adducts are supported by DFT methods. The scope of the protic nucleophilic coupling was also expanded to a two-pot operation by using triflic acid as a protic "non-nucleophile", followed by the addition of a suitably reactive nucleophile.

Non-sedated functional imaging based on deep synchronization of PROPELLER MRI and NIRS.

BACKGROUND AND OBJECTIVE: Periodically rotated overlapping parallel lines with enhanced reconstruction-echo planar imaging (PROPELLER-EPI) is a promising technique for non-sedated functional imaging due to its unique advantage of motion correction. However, its multiple-blades sampling blood-oxygen-level dependent (BOLD) signal leads to low sampling rate and aliasing of higher frequency physiological signal components such as the cardiac pulsation. METHODS: In this study, we use near infrared spectroscopy (NIRS) synchronized with pulse sequences of PROPELLER-EPI, utilizing the fact that the optical sensing speed is inherently high. NIRS measures changes of oxyhemoglobin and deoxyhemoglobin to identify the transient states of on-BOLD and off-BOLD, and then labels each blade by temporal co-registration. The labeled blades from multiple epochs of a functional experiment are then used for the k-space data combination and subsequent image reconstruction. An eigenfunction model is proposed for temporal co-registration and to quantify the temporal resolution of the hemodynamic response. RESULT: The experiment of NIRS labeled PROPELLER-EPI was carried out with the optical sampling rate of 10 Hz and the magnetic pulses repetition time of 1000 ms, and the temporal resolution is 20 times better than that of the state-of-the-art sliding-window PROPELLER-EPI. We compared the functional imaging results against the conventional magnetic resonance echo planar imaging-measured activity and achieved an accuracy of 0.9. CONCLUSIONS: Using the synchronization of NIRS, the proposed imaging scheme provides an effective way to implement PROPELLER-EPI, which features motion free, high SNR, and enhanced spatial-temporal resolution.

Divergent Reactivity during the Trapping of Benzynes by Glycidol Analogs: Ring Cleavage via Pinacol-Like Rearrangements vs Oxirane Fragmentations.

Hydroxy-containing cyclic ethers react with thermally generated benzynes to produce aryl ethers. Diverse reactivity was observed. Cleavage of the cyclic ether was involved in most of the pathways. The transformations are rationalized via initial formation of oxonium ion-containing 1,3-zwitterions arising from preferential nucleophilic attack on the benzyne by the ether oxygen. Pinacol-like rearrangements, including ring expansion, to yield aldehydes or ketones and oxirane fragmentations to generate aryl enol ethers were main competing events.

Atypical Mode of [3 + 2]-Cycloaddition: Pseudo-1,3-dipole Behavior in Reactions of Electron-Deficient Thioamides with Benzynes.

Thioamides bearing electron-withdrawing groups on the thiocarbonyl carbon atom react with benzynes [generated by the hexadehydro-Diels-Alder cycloisomerization] in an unprecedented fashion. Namely, the dihydrobenzothiazole products are consistent with a pathway involving initial formation of a stabilized ammonium ylide by a rare type of [3 + 2]-cycloaddition reaction. The fate of this species depends upon the nature of the R group(s) attached to the ylide nitrogen atom. The demonstration of new modes of reactivity represents the major advance arising from this study.

Antidepressive effects of ginsenoside Rg1 via regulation of HPA and HPG axis.

BACKGROUND: Hypothalamic-pituitary-adrenal (HPA) axis hyperactivity is a well-established pathological feature of major depression, accompanied by the persistent increase of glucocorticoid level and the dysfunction of hypothalamic-pituitary-gonadal (HPG) axis. Ginsenoside Rg1 (Rg1) is one of the most active ingredients of Panax ginseng, which has various biological activity. OBJECTIVE: This study aimed to investigate the antidepressive effects of Rg1 and elucidate its impact on neuroendocrine system. METHODS: The antidepressive effects of Rg1 were first analysed in mice, and was further identified in the chronic-unpredictable-mild-stress (CUMS) model and the gonadectomized (GDX) model. The effects of Rg1 on depression-like behaviour were analysed by the forced swimming test (FST), tail suspension test (TST), sucrose preference test, and measurement of pentobarbital-induced sleep. The serum corticosterone and testosterone levels were detected by ELISA. The protein levels of glucocorticoid receptor (GR) and androgen receptor (AR) were analysed by western blot and immunohistochemistry analysis. RESULTS: Rg1 significantly decreased the immobility time of mice in FST and TST. Furthermore, Rg1 alleviated anhedonia and hopelessness, decreased serum corticosterone level, and increased serum testosterone level, and the GR protein level in the PFC and hippocampus of the CUMS-treated rats. Moreover, Rg1 improved sleep disruption, down-regulated the serum corticosterone level, and increased AR protein level in the PFC of the GDX-treated mice. CONCLUSION: Together, these studies suggest that Rg1 displayed antidepressant activity through the modulation of the HPA and the HPG axis. These findings provide new mechanism involved in the antidepressive effects of Rg1 and propose theoretical clues for clinical therapies.

The Phenol-Ene Reaction: Biaryl Synthesis via Trapping Reactions between HDDA-Generated Benzynes and Phenolics.

Benzynes produced thermally by the cycloisomerization of triyne-containing precursors [i.e., by the hexadehydro-Diels-Alder (HDDA) reaction] react with phenols at the carbon ortho to the hydroxyl in an enelike fashion. Following tautomerization of the intermediate cyclohexadienones, this produces biaryl derivatives. DFT calculations of model reactions support this mechanistic interpretation. Substituted, unsymmetrical phenols and bis-phenols react in a fashion that can be explained by engagement of the most readily available (non-hydrogen-bonded) hydroxyl in the phenol-ene process.

Simultaneous quantification of ginsenoside Rg1 and its metabolites by HPLC-MS/MS: Rg1 excretion in rat bile, urine and feces.

Ginsenoside Rg1 (Rg1), the major effective component of ginseng, has been shown to have multiple bioactivities, but low oral bioavailability. The aim of this study was to develop a simple, sensitive and rapid high performance liquid chromatography-tandem mass spectrometry (LC-MS/MS) method, which could be used to validate and quantify the concentrations of Rg1 and its metabolites in Sprague-Dawley rat bile, urine, and feces after oral administration (25 mg/kg). Calibration curves offered satisfactory linearity (r>0.995) within the determined ranges. Both intra-day and inter-day variances were less than 15%, and the accuracy was within 80-120%. The excretion recoveries of Rg1, ginsenoside Rh1 (Rh1), and protopanaxatriol (Ppt) in bile, urine, and feces combined were all greater than 70%. The fecal excretion recoveries of Rg1, Rh1, and Ppt were 40.11%, 22.19%, and 22.88%, respectively, whereas 6.88% of Rg1 and 0.09% of Rh1 were excreted in bile. Urinary excretion accounted for only 0.04% of Rg1. In conclusion, the observed excretion profiles for Rg1 and its metabolites after oral administration are helpful for understanding the poor oral bioavailability of Rg1 and will aid further investigations of Rg1 as a pharmacologically active component.

Polyphenols: Potential source of drugs for the treatment of ischaemic heart disease.

Polyphenols, which are naturally present in plants, have been studied for their chemical and pharmacological properties. Polyphenols have been found to exhibit various bioactivities such as antioxidant, free radical scavenging and anti-inflammatory effects, in addition to regulating the intracellular free calcium levels. These bioactivities are related to the underlying mechanisms of ischaemic heart diseases. Pharmacological studies have proven polyphenols to be effective in treating cardiovascular diseases in various ways, particularly ischaemic heart diseases. Based on their mode of action, we propose that some polyphenols can be developed as drugs to treat ischaemic heart diseases. For this purpose, a strategy to evaluate the therapeutic value of drugs for ischaemic heart diseases is needed. Despite several advances in percutaneous coronary intervention (PCI), the incidence of myocardial infarction and deaths due to cardiovascular diseases has not decreased markedly in China. Due to their pleiotropic properties and structural diversity, polyphenols have been of great interest in pharmacology. In the present review, we summarize the pharmacological effects and mechanisms of polyphenols reported after 2000, and we analyse the benefits or druggability of these compounds for ischaemic heart diseases.

The anti-dementia drug candidate, (-)-clausenamide, improves memory impairment through its multi-target effect.

Multi-target drugs, such as the cocktail therapy used for treating AIDS, often show stronger efficacy than single-target drugs in treating complicated diseases. This review will focus on clausenamide (clau), a small molecule compound originally isolated from the traditional Chinese herbal medicine, Clausenalansium. The finding of four chiral centers in clau molecules predicted the presence of 16 clau enantiomers, including (-)-clau and (+)-clau. All of the predicted enantiomers have been successfully synthesized via innovative chemical approaches, and pharmacological studies have demonstrated (-)-clau as a eutomer and (+)-clau as a distomer in improving cognitive function in both normal physiological and pathological conditions. Mechanistically, the nootropic effect of (-)-clau is mediated by its multi-target actions, which include mild elevation of intracellular Ca(2+) concentrations, modulation of the cholinergic system, regulation of synaptic plasticity, and activation of cellular and molecular signaling pathways involved in learning and memory. Furthermore, (-)-clau suppresses the pathogenesis of Alzheimer's disease by inhibiting multiple etiological processes: (1) beta amyloid protein-induced intracellular Ca(2+) overload and apoptosis and (2) tau hyperphosphorylation and neurodegeneration. In conclusion, the nature of the multi-target actions of (-)-clau substantiates it as a promising chiral drug candidate for enhancing human cognition in normal conditions and treating memory impairment in neurodegenerative diseases.

Post-trial anatomical frame alignment procedure for comparison of 3D joint angle measurement from magnetic/inertial measurement units and camera-based systems.

Magnetic and inertial measurement units (MIMUs) have been widely used as an alternative to traditional camera-based motion capture systems for 3D joint kinematics measurement. Since these sensors do not directly measure position, a pre-trial anatomical calibration, either with the assistance of a special protocol/apparatus or with another motion capture system is required to establish the transformation matrices between the local sensor frame and the anatomical frame (AF) of each body segment on which the sensors are attached. Because the axes of AFs are often used as the rotational axes in the joint angle calculation, any difference in the AF determination will cause discrepancies in the calculated joint angles. Therefore, a direct comparison of joint angles between MIMU systems and camera-based systems is less meaningful because the calculated joint angles contain a systemic error due to the differences in the AF determination. To solve this problem a new post-trial AF alignment procedure is proposed. By correcting the AF misalignments, the joint angle differences caused by the difference in AF determination are eliminated and the remaining discrepancies are mainly from the measurement accuracy of the systems themselves. Lower limb joint angles from 30 walking trials were used to validate the effectiveness of the proposed AF alignment procedure. This technique could serve as a new means for calibrating magnetic/inertial sensor-based motion capture systems and correcting for AF misalignment in scenarios where joint angles are compared directly.

Recent advances in the study of (-)clausenamide: chemistry, biological activities and mechanism of action.

Clausenamide (clau) is one of seven novel compounds isolated from Clausena lansium (Lour) skeels. Clau is unusual in that it contains 4 chiral centers yielding 8 pairs of enantiomers. After identification of the configuration of these enantiomers, the synthesis of 16 enantiomers, including optically active clau and (+) and (-)clau was carried out. During this study, many stereochemical and synthetic difficulties were solved and the Baldwin principle was updated. Production scale is now sufficient to meet the needs of clinical practice. In a pharmacological study numerous models and indicators showed that (-)clau is the active enantiomer, while (+)clau is inactive and elicits greater toxicity than (-)clau. The principal pharmacological effects of (-)clau are to increase cognition, demonstrated in ten models of memory impairment, as well as to inhibit ß-amyloid (Aß) toxicity, blocking neurofibrillary tangle formation by inhibiting the phosphorylation of tau protein. This anti-dementia effect is characterized by increased synaptic plasticity both in efficacy and in structure and provides new support for the theory that synaptic loss is the main cause of dementia. (-)Clau is considered to be a promising drug candidate for treatment of Alzheimer׳s disease and other neurodegenerative disorders.

Development of an energy harvesting backpack and performance evaluation.

A biomechanical energy harvesting backpack that generates electrical energy during human walking is presented. This device differs from previous designs because it integrates motion from both lower limbs into a single mechanical drive train. The energy harvesting backpack produced an average of 15 W of electricity during walking at a speed of 1.2m/s. It was found that approximately one quarter of the total mechanical work harvested was from the negative work performed during walking. This technology could potentially be used to power portable biomedical devices.

Investigation of a passive inter-limb device on step-to-step transition of human walking.

In walking like an inverted pendulum, the step-to-step transition period requires a substantial amount of simultaneous positive and negative mechanical work to redirect the center of mass between steps and it was considered as a major determinant of gait in terms of metabolic expenditure. In the current study, we developed a passive inter-limb device that transfers energy between the legs during the step-to-step transition period. By effectively transferring the energy dissipated at heel-strike from the leading leg to the trailing leg which is performing push-off, we hypothesize that the mechanical cost of transport (COT) will be reduced. Consequently, the lower limb muscles are required to do less positive and negative work, resulting in a reduced metabolic COT. Data from five subjects walking at 1.2m/s on an instrumented treadmill with the device active and passive was collected. It was found that the mechanical COT during the step-to-step transition period was reduced when walking with the device active. However, contrary to our hypothesis the metabolic COT increased when walking with the device active.

Concurrent validation of Xsens MVN measurement of lower limb joint angular kinematics.

This study aims to validate a commercially available inertial sensor based motion capture system, Xsens MVN BIOMECH using its native protocols, against a camera-based motion capture system for the measurement of joint angular kinematics. Performance was evaluated by comparing waveform similarity using range of motion, mean error and a new formulation of the coefficient of multiple correlation (CMC). Three dimensional joint angles of the lower limbs were determined for ten healthy subjects while they performed three daily activities: level walking, stair ascent, and stair descent. Under all three walking conditions, the Xsens system most accurately determined the flexion/extension joint angle (CMC > 0.96) for all joints. The joint angle measurements associated with the other two joint axes had lower correlation including complex CMC values. The poor correlation in the other two joint axes is most likely due to differences in the anatomical frame definition of limb segments used by the Xsens and Optotrak systems. Implementation of a protocol to align these two systems is necessary when comparing joint angle waveforms measured by the Xsens and other motion capture systems.

Stereoselective excretion and first-pass metabolism of clausenamide enantiomers.

Stereoselective differences in pharmacokinetics between clausenamide (CLA) enantiomers have been found after intravenous and oral administration of each enantiomer to rats. The differences could be associated with excretion and first-pass metabolism of two enantiomers. The data from this study demonstrated that (-)CLA was mainly excreted in feces with 13.9% of dose, whereas (+)CLA in bile with 17.2%. A large portion of CLA enantiomers could be transformed into hydroxyl metabolites. In the in vitro metabolic system using rat liver microsomes, it was found that (-)CLA was cleared more than its antipode with peak height ratios [(+)/(-)] from 1.0 to 1.8 at the corresponding substrate concentrations from 0.25 to 2mM. Further study in rabbits showed that two enantiomers underwent an intermediate degree of first-pass metabolism. (-)CLA had lower concentrations and AUC0-8h in the portal vein and heart than those of (+)CLA with rates of hepatic extraction 64.7% for (-)-isomer and 50.8% for (+)-isomer, and intrinsic metabolic clearances of (-) and (+)CLA being 186.3 and 107.2 (l/h), respectively. The first-pass metabolism was involved in CYP3A enzymes in the gut and liver, and different levels of CYP3A1 expression induced by (-)CLA or (+)CLA. Immunohistochemical analyses revealed that (-)-isomer significantly increased the expression of CYP3A1, while (+)-isomer had no obvious effects on it. Taken together, the results provided new evidence that stereoselective pharmacokinetics of CLA enantiomers could be resulted from their stereoselective excretion, first-pass metabolism and induction to metabolizing enzymes, which might be important in understanding the clinic pharmacology of active eutomer, (-)CLA, for treatment of Alzheimer's disease.

Estimation of spatio-temporal parameters for post-stroke hemiparetic gait using inertial sensors.

This paper represents the first step in developing an inertial sensor system that is capable of assessing post-stroke gait in terms of walking speed and temporal gait symmetry. Two inertial sensors were attached at the midpoint of each shank to measure the accelerations and angular velocity during walking. Despite the abnormalities in hemiparetic gait, the angular velocity of most of the testing subjects (12 out of 13) exhibited similar characteristics as those from a healthy population, enabling walking speed estimation and gait event detection based on the pendulum walking model. The results from a standardized 10-meter walk test demonstrated that the IMU-based method has an excellent agreement with the clinically used stopwatch method. The gait symmetry results were comparable with previous studies. The gait segmentation failed when the angular velocity deviates significantly from the healthy groups' profile. With further development and concurrent validations, the inertial sensor-based system may eventually become a useful tool for continually monitoring spatio-temporal gait parameters post stroke in a natural environment.