AMPK and PGC-α following maximal and supramaximal exercise in men and women: a randomized cross-over study.

We tested the hypothesis that AMPK activation and peroxisome proliferator gamma coactivator 1 alpha (PGC-1α) expression are not augmented as exercise intensity (power output) increases from maximal to supramaximal intensities and conducted an exploratory analysis comparing AMPK activation and PGC-1α expression in males and females. Seventeen (n = 9 males; n = 8 females) recreationally active, healthy, young individuals volunteered to participate in the current study. Participants completed work matched interval exercise at 100% (Max) and 133% (Supra) of peak work rate (WRpeak). Intervals were 1 min in duration and participants were prescribed 6 and 8 intervals of Max and Supra, respectively, to equate external work across protocols. PGC-1α mRNA expression and activation of AMPK (p-ACC) were examined in muscle biopsy samples. Interval WR (watts; W), intensity (%WRpeak) and average HR (bpm), blood lactate (mmol/L) and rating of perceived exertion were all higher (all p < 0.05) in Supra. Fatigue was greater (p < 0.05) in Supra. PGC-1α mRNA expression significantly increased after exercise in Max (p < 0.01) and Supra (p < 0.01), but was not significantly different (p = 0.71) between intensities. A main effect of time (Pre - 0 h) (p < 0.01) was observed for p-ACC; however, no effect of intensity (p = 0.08) or interaction (p = 0.97) was observed. No significant effects of time (p = 0.05) intensity (p = 0.42), or interaction (p = 0.97) were observed for p-AMPK (Thr172). Exploratory sex analysis demonstrated a main effect of sex for p-ACC (greater p-ACC in males; p < 0.05) but not for p-AMPK or PGC-1α expression. Our results confirm that AMPK-PGC-1α signalling is not augmented following supramaximal exercise and provide novel data demonstrating a decrease in AMPK activation (p-ACC) in females compared to men. Trial registration: https://doi.org/10.17605/OSF.IO/U7PX9.

The charm-quark contribution to light-by-light scattering in the muon ( g - 2 ) from lattice QCD.

We compute the hadronic light-by-light scattering contribution to the muon g - 2 from the charm quark using lattice QCD. The calculation is performed on ensembles generated with dynamical (u, d, s) quarks at the SU(3) f symmetric point with degenerate pion and kaon masses of around 415 MeV. It includes the connected charm contribution, as well as the leading disconnected Wick contraction, involving the correlation between a charm and a light-quark loop. Cutoff effects turn out to be sizeable, which leads us to use lighter-than-physical charm masses, to employ a broad range of lattice spacings reaching down to 0.039 fm and to perform a combined charm-mass and continuum extrapolation. We use the η c meson to define the physical charm-mass point and obtain a final value of a µ HLbL , c = ( 2.8 ± 0.5 ) × 10 - 11 , whose uncertainty is dominated by the systematics of the extrapolation. Our result is consistent with the estimate based on a simple charm-quark loop, whilst being free of any perturbative scheme dependence on the charm mass. The mixed charm-light disconnected contraction contributes a small negative amount to the final value.

Quantification of calcium in infant formula using laser-induced breakdown spectroscopy (LIBS), Fourier transform mid-infrared (FT-IR) and Raman spectroscopy combined with chemometrics including data fusion.

Laser-induced breakdown spectroscopy (LIBS), Fourier transform mid-infrared (FT-IR) and Raman spectroscopy combined with chemometrics were investigated to quantify calcium (Ca) content in infant formula powder (INF). INF samples (n = 51) with calcium content levels (ca. 6.5-30 mg Ca/100 kJ) were prepared in accordance with the guidelines of Commission Directive 2006/125/EC. Atomic absorption spectroscopy (AAS) was used as the reference method for Ca content determination. To predict Ca content in INF samples, partial least squares regression (PLSR) models that developed based on LIBS, Raman and FT-IR spectral data, respectively. The model developed using LIBS data achieved the best performance for the quantification of Ca content in INF (R2 (cross-validation (CV))-0.99, RMSECV-0.29 mg/g; R2 (prediction (P))-1, RMSEP-0.63 mg/g). PLSR models that developed based on data fusion of Raman and FT-IR spectral features obtained the second best performance (R2CV-0.97, RMSECV-0.38 mg/g; R2P-0.97, RMSEP-0.36 mg/g). This study demonstrated the potential of LIBS, FT-IR and Raman spectroscopy to accurately quantify Ca content in INF.

Predatory behavior of Polistes dominulus wasps in response to cardenolides and glucosinolates in Pieris napi caterpillars.

To examine how plant allelochemicals in prey affect foraging choices made by generalist predator paper wasps, Polistes dominulus (Vespidae), we compared predation on Pieris napi (Pieridae) caterpillars reared on host plants with different allelochemicals. In naturalistic behavioral choice experiments, free-flying wasps chose between living pierids reared on cabbage (Brassica oleracea), which lacks deterrent allelochemicals, or alternate host plants with potentially deterrent allelochemicals. The alternative host plants were: wormwood mustard, (Erysimum cheiranthoides: Brassicaceae), which contains cardenolides; nasturtium (Tropaeolum majus: Tropaeolaceae) with high concentrations of chlorogenic acid; and black mustard (Brassica nigra: Brassicaceae) with high concentrations of the aliphatic glucosinolate, sinigrin. Although wasps captured equal numbers of caterpillars reared on cabbage and each alternate host plant, they spent significantly longer handling prey from the alternate host plants as they selectively removed the caterpillar's gut, which contained the plant material. This was true even if the caterpillar did not sequester toxins in its tissues, as revealed by high performance liquid chromatography (HPLC) analysis of Erysimum-reared pierids. Because handling time is longer, predators that capture pierids containing non-sequestered allelochemicals experience an overall reduction in foraging rate that may translate into a fitness cost.

A feeding stimulant for Manduca sexta from Solanum surattenses.

The acceptance of Solanum surattenses as a host plant for the larvae of Manduca sexta was explained by the presence of feeding stimulants in foliage. Bioassay-guided fractionation of plant extracts resulted in the isolation of a highly active compound (1), which was identified as a furostan derivative {26-O-beta-D-glucopyranosyl-(25R)-furosta-5-ene-3-beta-yl-O-alpha-L-rhamnopyranosyl-(1''-2')-O-alpha-L-rhamnopyranosyl-(1'''-3'')-O-beta-D-glucopyranoside}. This compound has the same steroidal core substructure as that in a stimulant (indioside D) previously identified from potato foliage. However, the sugar substituents attached to the core are different.

Isothiocyanates stimulating oviposition by the diamondback moth, Plutella xylostella.

Recognition of cabbage as a host plant for the diamondback moth (DBM) has previously been shown to depend on compounds that are extracted by soaking intact foliage in chloroform. Analysis of such chloroform extracts by open column chromatography has now resulted in the isolation of highly active fractions that elicit oviposition on treated filter papers. Further separation of these fractions by high-performance liquid chromatography revealed the presence of two distinct groups of active compounds that may be classified as volatile and non-volatile. The two prominent volatile components were separated and identified by mass spectrometry as the isothiocyanates, iberin (3-methylsulfinylpropyl isothiocyanate) and sulforaphane (4-methylsulfinyl-3-butenyl isothiocyanate). Subsequent bioassays of a range of isothiocyanates showed that iberin and sulforaphane were the most active of those tested. Other isothiocyanates with sulfur in the side chain were also active, whereas alkyl and phenyl isothiocyanates had only limited activity. In electrophysiological experiments, electroantennograms (EAGs) indicated positive responses of moth antennae to the isothiocyanates that were most active in behavioral assays. Since sulforaphane has been identified as a major inducer of anticarcinogenic activity in mouse tissue, a synthetic analog (exo-2-acetyl-5-isothiocyanatonorbornane) that shows similar inducer activity was tested on DBM. This bicyclic analog was highly active in both behavioral and EAG assays, suggesting similarity in receptor sites for the two types of biological activity.

Long-term survival data from a phase 3 study of Filgrastim as an adjunct to chemotherapy in adults with de novo acute myeloid leukemia.

We previously reported the results of a double-blind, placebo-controlled study of Filgrastim in patients with de novo AML undergoing induction and consolidation chemotherapy. The study demonstrated that Filgrastim was effective and well tolerated and had no impact on complete remission or survival. We now report follow-up data on these patients, assessing long-term effects with emphasis on prognostic indicators. After a median follow-up of 7 years, 434 (83%) patients were dead, 73 (14%) were alive, and 14 (3%) were lost to follow-up. The proportions of deaths were similar in the Filgrastim (83%) and placebo (84%) groups. No differences in median time to death (1.04 years Filgrastim, 1.13 years placebo; P = 0.97) or median disease-free survival (0.86 years Filgrastim, 0.79 years placebo; P = 0.52) were evident. Proportional hazard modeling identified age, performance status, and French-American-British subtype as independent predictors for survival (P < 0.001, P = 0.005, and P = 0.036, respectively), whereas cytogenetic status was not (P = 0.118). Filgrastim had no effect on overall survival in any of these subgroup analyses as none of the treatment comparisons were statistically significant. These findings indicate that Filgrastim can be effectively used to support patients with AML undergoing induction and consolidation chemotherapy without worsening long-term disease outcome.

XIAP-mediated neuroprotection in retinal ischemia.

Retinal ischemia results in the loss of vision in a number of ocular diseases including acute glaucoma, diabetic retinopathy, hypertensive retinopathy and retinal vascular occlusion. Recent studies have shown that most of the neuronal death that leads to loss of vision results from apoptosis. XIAP-mediated gene therapy has been shown to protect a number of neuronal types from apoptosis but has never been assessed in retinal neurons following ischemic-induced cell death. We injected an adeno-associated viral vector expressing XIAP or GFP into rat eyes and 6 weeks later, rendered them ischemic by raising intraocular pressure. Functional analysis revealed that XIAP-treated eyes retained larger b-wave amplitudes than GFP-treated eyes up to 4 weeks post-ischemia. The number of cells in the inner nuclear layer (INL) and the thickness of the inner retina were significantly preserved in XIAP-treated eyes compared to GFP-treated eyes. Similarly, there was no significant reduction in optic nerve axon numbers in XIAP-treated eyes. There were also significantly fewer TUNEL (TdT-dUTP terminal nick end labeling) positive cells in the INL of XIAP-treated retinas at 24 h post-ischemia. Thus, XIAP-mediated gene therapy imparts both functional and structural protection to the retina after a transient ischemic episode.

Behavioral and chemosensory responses to a host recognition cue by larvae of Pieris rapae.

Larvae of the cabbage white Pieris rapae are specialists on plants belonging to the family Brassicaceae (Cruciferae). Adult females have been shown to use the glucosinolate gluconasturtiin (phenylethylglucosinolate) as a recognition cue for cruciferous plants, so they can identify an appropriate host for oviposition (Huang and Renwick in J Chem Ecol 20:1025-1037, 1994). Here, we report our results from a study of the role of this glucosinolate in feeding preferences of P. rapae larvae. The larvae were allowed to choose between leaf disks from the non-host cowpea Vigna sinensis (Fabaceae) that were treated with pure gluconasturtiin in solvent, or solvent alone. Our results showed that gluconasturtiin is a feeding stimulant for P. rapae larvae. A series of chemosensory ablations revealed that this response is mediated by one set of taste sensilla, the sensilla styloconica. Electrophysiological tip recordings revealed two neurons in the lateral sensillum styloconicum that are sensitive to gluconasturtiin. These neurons show significantly higher firing frequencies with 4 mM gluconasturtiin added to the recording pipette than for recording solution alone. We propose that the sensitivity to gluconasturtiin shown by these two taste neurons is an important contributor to the animals' behavioral preference for this compound.

A saponin correlated with variable resistance of Barbarea vulgaris to the diamondback moth Plutella xylostella.

Two types of Barbarea vulgaris var. arcuata, the G-type and the P-type, differed in resistance to larvae of the diamondback moth (DBM) Platella xylostella. Rosette plants of the G-type were fully resistant to the DBM when grown in a greenhouse or collected in the summer season, but leaves collected during the late fall were less resistant, as previously found for flea beetle resistance. The P-type was always susceptible. Extracts of resistant leaflets inhibited larval growth in a bioassay, and a growth-inhibiting fraction was isolated by activity-guided fractionation. A triterpenoid saponin (1) was isolated from this fraction and identified as 3-O-beta-cellobiosyloleanolic acid from spectroscopic data and analysis of hydrolysis products. The decrease in resistance of the G-type in the fall was correlated with a decrease in the level of 1, from 0.6-0.9 to < 0.2 micromol/g dry wt. Compound 1 was not detected in the susceptible P-type. We conclude that 1 is correlated with the variable resistance of B. vulgaris foliage to the DBM.

A randomized double-blind multicenter phase III study of fixed-dose single-administration pegfilgrastim versus daily filgrastim in patients receiving myelosuppressive chemotherapy.

BACKGROUND: We evaluated the efficacy of a single fixed 6 mg dose of pegfilgrastim (a pegylated version of filgrastim) per cycle of chemotherapy, compared with daily administration of filgrastim, in the provision of neutrophil support. PATIENTS AND METHODS: Patients (n = 157) were randomized to receive either a single 6 mg subcutaneous (s.c.) injection of pegfilgrastim or daily 5 mg/kg s.c. injections of filgrastim, after doxorubicin and docetaxel chemotherapy (60 mg/m(2) and 75 mg/m(2), respectively). Duration of grade 4 neutropenia, depth of neutrophil nadir, incidence of febrile neutropenia, time to neutrophil recovery and safety information were recorded. RESULTS: A single 6 mg injection of pegfilgrastim was as effective as daily injections of filgrastim for all efficacy measures for all cycles. The mean duration of grade 4 neutropenia in cycle 1 was 1.8 and 1.6 days for the pegfilgrastim and filgrastim groups, respectively. Results for all efficacy end points in cycles 2-4 were consistent with the results from cycle 1. A trend towards a lower incidence of febrile neutropenia was noted across all cycles with pegfilgrastim compared with filgrastim (13% versus 20%, respectively). A single fixed dose of pegfilgrastim was as safe and well tolerated as standard daily filgrastim. CONCLUSIONS: A single fixed dose of pegfilgrastim administered once per cycle of chemotherapy was comparable to multiple daily injections of filgrastim in safely providing neutrophil support during myelosuppressive chemotherapy. Pegfilgrastim may have utility in other clinical settings of neutropenia.

Sequestration of glucosinolates by harlequin bug Murgantia histrionica.

Murgantia histrionica, the harlequin bug, is an aposematic pentatomid that feeds on toxic crucifer plants. By performing predator trials, we found that the bugs are distasteful to several species of bird predators. Given this, we tested the hypothesis that the bugs sequester toxins from the crucifer plants they feed on for use in defense against predation. We used high-pressure liquid chromatography for analyses and tested if M. histrionica sequesters toxic chemicals from its crucifer diet. We found that M. histrionica sequesters mustard oil glycosides, precursors to zootoxic mephitic nitriles, and that sequestration is characteristic of the plant species fed upon. Glucosinolate titers in M. histrionica bodies were 20-30 times higher than in their guts. We found that cabbage-fed M. histrionica had higher titers of cabbage glucosinolates than bugs that were fed on a cabbage diet and then switched to a diet of garden nasturtium. This indicates that M. histrionica immediately sequesters chemicals from whichever plant it feeds upon. The study shows that M. histrionica can sequester glucosinolates from its host plants for use in defense against predation and that the bugs can retain the glucosinolates for an extended period of time.

Mayolenes: labile defensive lipids from the glandular hairs of a caterpillar (Pieris rapae).

Larvae of the European cabbage butterfly, Pieris rapae (Pieridae), are beset with glandular hairs, bearing droplets of a clear oily secretion at their tip. The fluid consists primarily of a series of chemically labile, unsaturated lipids, the mayolenes, which are derived from 11-hydroxylinolenic acid. In bioassays with the ant Crematogaster lineolata, the secretion was shown to be potently deterrent, indicating that the fluid plays a defensive role in nature.

Variable diets and changing taste in plant-insect relationships.

The host ranges of phytophagous insects are determined to a large degree by plant chemistry. Specialist insects are often closely associated with plants that produce characteristic chemicals, which may act as attractants or stimulants to aid in finding or recognizing a host. Generalist insects are generally believed to rely on the presence of repellents or deterrents to ensure avoidance of unsuitable plants. However, the chemistry of any plant can be highly variable, as a result of growth characteristics, genetic variation, or environmental factors. Such variable chemistry may provide windows of opportunity for nonadapted insects to utilize a plant or for a plant to become resistant to a normally adapted herbivore. Differences in insect responses to plant constituents may also result from genetic variation or environmental factors. In particular, dietary experience has been found to influence the ability of insects to taste plant chemicals that may serve as signals of suitability or unsuitability. Certain dietary constituents appear to suppress the development of taste sensitivity to deterrents in an insect, whereas the presence of specific stimulants in the diet may result in the development of dependence on these compounds. These findings further emphasize the fact that the dynamics of plant biochemistry along with plasticity in the sensory system of insects might be expected to play a major role in the evolution of new plant-insect relationships.

Dual chemical barriers protect a plant against different larval stages of an insect.

The host plants of the native American butterfly, Pieris napi oleracea, include most wild mustards. However, garlic mustard, Alliaria petiolata, a highly invasive weed that was introduced from Europe, appears to be protected from this insect. Although adults will oviposit on the plant, most larvae of P. n. oleracea do not survive on garlic mustard. We used feeding bioassays with different larval stages of the insect to monitor the isolation and identification of two bioactive constituents that could explain the natural resistance of this plant. A novel cyanopropenyl glycoside (1), alliarinoside, strongly inhibits feeding by first instars, while a flavone glycoside (2), isovitexin-6"-D-beta-glucopyranoside, deters later instars from feeding. Interestingly, the first instars are insensitive to 2, and the late instars are little affected by 1. Furthermore, differential effects of dietary experience on insect responses suggest that 1 acts through a mechanism of post-ingestive inhibition, whereas 2 involves gustatory deterrence of feeding.

Seasonal and population variation in flavonoid and alliarinoside content of Alliaria petiolata.

Pieris napi oleracea, an indigenous butterfly in North America, lays eggs on Alliaria petiolata, an invasive weed that was introduced from Europe. However, larval development on plants from different sources varies considerably. A. petiolata is a compulsive biennial, and its foliage is rich in apigenin flavonoids. We compared the chemistry of different vegetative forms from different populations in the vicinity of Ithaca, NY throughout the year. Significant differences occurred in the number of apigenin derivatives in different populations and vegetative forms, and seasonal variations in the amounts of these compounds were found. We have previously isolated two major compounds, alliarinoside [(2Z)-4-(beta-D-glucopyranosyloxy)-2-butenenitrile] (1) and isovitexin-6-O"-beta-D-glucoside (3), which negatively affect development of P. napi oleracea larvae. Comparative analyses of these compounds in two populations throughout the year showed that their concentrations reached maxima twice annually. Foliage is almost devoid of flavonoids in June-July. Thus, variation in the chemistry of the plant may account for observed variation in development rates and survival of the larvae. Several apigenin compounds were isolated and identified by spectral studies.

Host recognition by the tobacco hornworm is mediated by a host plant compound.

It is generally believed that animals make decisions about the selection of mates, kin or food on the basis of pre-constructed recognition templates. These templates can be innate or acquired through experience. An example of an acquired template is the feeding preference exhibited by larvae of the moth, Manduca sexta. Naive hatchlings will feed and grow successfully on many different plants or artificial diets, but once they have fed on a natural host they become specialist feeders. Here we show that the induced feeding preference of M. sexta involves the formation of a template to a steroidal glycoside, indioside D, that is present in solanaceous foliage. This compound is both necessary and sufficient to maintain the induced feeding preference. The induction of host plant specificity is at least partly due to a tuning of taste receptors to indioside D. The taste receptors of larvae fed on host plants show an enhanced response to indioside D as compared with other plant compounds tested.

A cyanoallyl glucoside from Alliaria petiolata, as a feeding deterrent for larvae of Pieris napi oleracea.

Alliarinoside, a feeding inhibitor against early instar larvae of Pieris napi oleracea, was isolated from the foliage of Alliaria petiolata and characterized as (2Z)-4-(beta-D-glucopyranosyloxy)-2-butenenitrile (1) by spectroscopic methods. The structural assignment was confirmed by synthesis of peracetylated alliarinoside (2) and its 2E isomer (3). A sample of synthetic 1 was isolated by preparative HPLC from the hydrolysis of the 2Z acetate. Feeding inhibition assays showed comparable activity for the synthetic and natural glycosides.

A new sinapoyl derivative of isovitexin 6'' -O-beta-D-glucopyranoside from Alliaria petiolata.

The new compound 6'''-O-sinapoylisovitexin 6'' -O-beta-D-glucopyranoside (1) was isolated from the foliage of Alliaria petiolata, and identified by spectral studies.

A randomised, blinded, placebo-controlled, dose escalation study of the tolerability and efficacy of filgrastim for haemopoietic stem cell mobilisation in patients with severe active rheumatoid arthritis.

Autologous haemopoietic stem cell transplantation (HSCT) represents a potential therapy for severe rheumatoid arthritis (RA). As a prelude to clinical trails, the safety and efficacy of haemopoietic stem cell (HSC) mobilisation required investigation as colony-stimulating factors (CSFs) have been reported to flare RA. A double-blind, randomised placebo-controlled dose escalation study was performed. Two cohorts of eight patients fulfilling strict eligibility criteria for severe active RA (age median 40 years, range 24-60 years; median disease duration 10.5 years, range 2-18 years) received filgrastim (r-Hu-methionyl granulocyte(G)-CSF) at 5 and 10 microg/kg/day, randomised in a 5:3 ratio with placebo. Patients were unblinded on the fifth day of treatment and those randomised to filgrastim underwent cell harvesting (leukapheresis) daily until 2 x 10(6)/kg CD34+ cells (haemopoietic stem and progenitor cells) were obtained. Patients were assessed by clinical and laboratory parameters before, during and after filgrastim administration. RA flare was defined as an increase of 30% or more in two of the following parameters: tender joint count, swollen joint count or pain score. Efficacy was assessed by quantitation of CD34+ cells and CFU-GM. One patient in the 5 microg/kg/day group and two patients in the 10 microg/kg/day group fulfilled criteria for RA flare, although this did not preclude successful stem cell collection. Median changes in swollen and tender joint counts were not supportive of filgrastim consistently causing exacerbation of disease, but administration of filgrastim at 10 microg/kg/day was associated with rises in median C-reactive protein and median rheumatoid factor compared with placebo. Other adverse events were well recognised for filgrastim and included bone pain (80%) and increases in alkaline phosphatase (four-fold) and lactate dehydrogenase (two-fold). With respect to efficacy, filgrastim at 10 microg/kg/day was more efficient with all patients (n = 5) achieving target CD34+ cell counts with a single leukapheresis (median = 2.8, range = 2.3-4.8 x 10(6)/kg, median CFU-GM = 22.1, range = 4.2-102.9 x 10(4)/kg), whereas 1-3 leukaphereses were necessary to achieve the target yield using 5 microg/kg/day. We conclude that filgrastim may be administered to patients with severe active RA for effective stem cell mobilisation. Flare of RA occurs in a minority of patients and is more likely with 10 than 5 microg/kg/day. However, on balance, 10 microg/kg/day remains the dose of choice in view of more efficient CD34+ cell mobilisation.