Antioxidant responses to an acute ultra-endurance exercise: Impact on DNA stability and indications for an increased need for nutritive antioxidants in the early recovery phase

Antioxidant requirements have neither been defined for endurance nor been defined for ultra-endurance athletes. To verify whether an acute bout of ultra-endurance exercise modifies the need for nutritive antioxidants, we aimed (1) to investigate the changes of endogenous and exogenous antioxidants in response to an Ironman triathlon; (2) to particularise the relevance of antioxidant responses to the indices of oxidatively damaged blood lipids, blood cell compounds and lymphocyte DNA and (3) to examine whether potential time-points of increased susceptibility to oxidative damage are associated with alterations in the antioxidant status. Blood that was collected from forty-two well-trained male athletes 2 d pre-race, immediately post-race, and 1, 5 and 19 d later was sampled. The key findings of the present study are as follows: (1) Immediately post-race, vitamin C, alpha-tocopherol, and levels of the Trolox equivalent antioxidant capacity, the ferric reducing ability of plasma and the oxygen radical absorbance capacity (ORAC) assays increased significantly. Exercise-induced changes in the plasma antioxidant capacity were associated with changes in uric acid, bilirubin and vitamin C. (2) Significant inverse correlations between ORAC levels and indices of oxidatively damaged DNA immediately and 1 d post-race suggest a protective role of the acute antioxidant responses in DNA stability. (3) Significant decreases in carotenoids and gamma-tocopherol 1 d post-race indicate that the antioxidant intake during the first 24 h of recovery following an acute ultra-endurance exercise requires specific attention. Furthermore, the present study illustrates the importance of a diversified and well-balanced diet to maintain a physiological antioxidant status in ultra-endurance athletes in reference to recommendations.

Decompression melting driving intraplate volcanism in Australia: Evidence from magnetotelluric sounding

A long-period magnetotelluric (MT) survey, with 39 sites covering an area of 270 by 150 km, has identified melt within the thinned lithosphere of Pleistocene-Holocene Newer Volcanics Province (NVP) in southeast Australia, which has been variously attributed to mantle plume activity or edge-driven mantle convection. Two-dimensional inversions from the MT array imaged a low-resistivity anomaly (10-30Ωm) beneath the NVP at ∼40-80 km depth, which is consistent with the presence of ∼1.5-4% partial melt in the lithosphere, but inconsistent with elevated iron content, metasomatism products or a hot spot. The conductive zone is located within thin juvenile oceanic mantle lithosphere, which was accreted onto thicker Proterozoic continental mantle lithosphere. We propose that the NVP owes its origin to decompression melting within the asthenosphere, promoted by lithospheric thickness variations in conjunction with rapid shear, where asthenospheric material is drawn by shear flow at a "step" at the base of the lithosphere.

Charge mediated semiconducting-to-metallic phase transition in molybdenum disulfide monolayer and hydrogen evolution reaction in new 1T′ phase

The phase transition of single layer molybdenum disulfide (MoS2) from semiconducting 2H to metallic 1T and then to 1T′ phases, and the effect of the phase transition on hydrogen evolution reaction (HER) are investigated within this work by density functional theory. Experimentally, 2H-MoS2 has been widely used as an excellent electrode for HER and can get charged easily. Here we find that the negative charge has a significant impact on the structural phase transition in a MoS2 monolayer. The thermodynamic stability of 1T-MoS2 increases with the negative charge state, comparing with the 2H-MoS2 structure before phase transition and the kinetic energy barrier for a phase transition from 2H to 1T decreases from 1.59 to 0.27 eV when 4e– are injected per MoS2 unit. Additionally, 1T phase is found to transform into the distorted structure (1T′ phase) spontaneously. On their activity toward hydrogen evolution reaction, 1T′-MoS2 structure shows comparable hydrogen evolution reaction activity to the 2H-MoS2 structure. If the charge transfer kinetics is taken into account, the catalytic activity of 1T′-MoS2 is superior to that of 2H-MoS2. Our finding provides a possible novel method for phase transition of MoS2 and enriches understanding of the catalytic properties of MoS2 for HER.

Low δ18O zircons from the Bruneau-­Jarbidge eruptive center: A key to crustal anatexis along the track of the Yellowstone hotspot

The Bruneau-Jarbidge eruptive center (BJEC) in the central Snake River Plain, Idaho, USA consists of the Cougar Point Tuff (CPT), a series of ten, high-temperature (900-1000°C) voluminous ignimbrites produced over the explosive phase of volcanism (12.8-10.5 Ma) and more than a dozen equally high-temperature rhyolite lava flows produced during the effusive phase (10.5-8 Ma). Spot analyses by ion microprobe of oxygen isotope ratios in 210 zircons demonstrate that all of the eruptive units of the BJEC are characterized by zircon δ¹⁸O values ≤ 2.5‰, thus documenting the largest low δ¹⁸O silicic volcanic province known on Earth (>10⁴ km³). There is no evidence for voluminous normal δ¹⁸O magmatism at the BJEC that precedes generation of low δ¹⁸O magmas as there is at other volcanic centers that generate low δ¹⁸O magmas such as Heise and Yellowstone. At these younger volcanic centers of the hotspot track, such low δ¹⁸O magmas represent ~45 % and ~20% respectively of total eruptive volumes. Zircons in all BJEC tuffs and lavas studied (23 units) document strong δ¹⁸O depletion (median CPT δ¹⁸OZrc = 1.0‰, post-CPT lavas = 1.5‰) with the third member of the CPT recording an excursion to minimum δ¹⁸O values (δ¹⁸OZrc= -1.8‰) in a supereruption > 2‰ lower than other voluminous low δ¹⁸O rhyolites known worldwide (δ¹⁸OWR ≤0.9 vs. 3.4‰). Subsequent units of the CPT and lavas record a progressive recovery in δ¹⁸OZrc to ~2.5‰ over a ~ 4 m.y. interval (12 to 8 Ma). We present detailed evidence of unit-to-unit systematic patterns in O isotopic zoning in zircons (i.e. direction and magnitude of Δcore-rim), spectrum of δ¹⁸O in individual units, and zircon inheritance patterns established by re-analysis of spots for U-Th-Pb isotopes by LA-ICPMS and SHRIMP. In conjunction with mineral thermometry and magma compositions, these patterns are difficult to reconcile with the well-established model for "cannibalistic" low δ¹⁸O magma genesis at Heise and Yellowstone. We present an alternative model for the central Snake River Plain using the modeling results of Leeman et al. (2008) for ¹⁸O depletion as a function of depth in a mid-upper crustal protolith that was hydrothermally altered by infiltrating meteoric waters prior to the onset of silicic magmatism. The model proposes that BJEC silicic magmas were generated in response to the propagation of a melting front, driven by the incremental growth of a vast underlying mafic sill complex, over a ~5 m.y. interval through a crustal volume in which a vertically asymmetric δ¹⁸OWR gradient had previously developed that was sharply inflected from ~ -1 to 10‰ at mid-upper crustal depths. Within the context of the model, data from BJEC zircons are consistent with incremental melting and mixing events in roof zones of magma reservoirs that accompany surfaceward advance of the coupled mafic-silicic magmatic system.

Phase-selective hydrothermal synthesis of Cu2ZnSnS4nanocrystals: The effect of the sulphur precursor

High quality Cu2ZnSnS4 (CZTS) films with uniform thickness and smooth surface were prepared using nanocrystals synthesized by a one-step hydrothermal method. It is found that the nature of the sulphur precursor used in the hydrothermal reaction influences both the compositional purity and the crystal structure of the synthesized hydrothermal product significantly. The CZTS material consisting of both wurtzite and kesterite crystal structures was obtained when using an organic sulfur precursor such as thioacetamide and thiourea in the precursor solution of the hydrothermal reaction while the pure kesterite phase CZTS nanocrystals were made when Na2S was employed as the sulphur precursor. CZTS thin films deposited on a Mo–soda lime glass substrate with uniform thickness (1.7 μm) were made by a simple doctor-blading method. The investigation of the effect of thermal treatment on the film has indicated that the wurtzite CZTS material was completely transformed to the kesterite phase when the material was annealed at 550 °C. Large grains (around 2 μm in size) were found on the surface of the CZTS film which was annealed at 600 °C. The evaluation of the photoresponse of the CZTS thin films has showed that a higher and very stable photocurrent was generated by the film annealed at 600 °C compared to the film annealed at 550 °C.

EVERSUN: A phase 2 trial of alternating sunitinib and everolimus as first-line therapy for advanced renal cell carcinoma

Background We hypothesised that alternating inhibitors of the vascular endothelial growth factor receptor (VEGFR) and mammalian target of rapamycin pathways would delay the development of resistance in advanced renal cell carcinoma (aRCC). Patients and methods A single-arm, two-stage, multicentre, phase 2 trial to determine the activity, feasibility, and safety of 12-week cycles of sunitinib 50 mg daily 4 weeks on / 2 weeks off, alternating with everolimus 10 mg daily for 5 weeks on / 1 week off, until disease progression or prohibitive toxicity in favourable or intermediate-risk aRCC. The primary end point was proportion alive and progression-free at 6 months (PFS6m). The secondary end points were feasibility, tumour response, overall survival (OS), and adverse events (AEs). The correlative objective was to assess biomarkers and correlate with clinical outcome. Results We recruited 55 eligible participants from September 2010 to August 2012. Demographics: mean age 61, 71% male, favourable risk 16%, intermediate risk 84%. Cycle 2 commenced within 14 weeks for 80% of participants; 64% received ≥22 weeks of alternating therapy; 78% received ≥22 weeks of any treatment. PFS6m was 29/55 (53%; 95% confidence interval [CI] 40% to 66%). Tumour response rate was 7/55 (13%; 95% CI 4% to 22%, all partial responses). After median follow-up of 20 months, 47 of 55 (86%) had progressed with a median progression-free survival of 8 months (95% CI 5–10), and 30 of 55 (55%) had died with a median OS of 17 months (95% CI 12–undefined). AEs were consistent with those expected for each single agent. No convincing prognostic biomarkers were identified. Conclusions The EVERSUN regimen was feasible and safe, but its activity did not meet pre-specified values to warrant further research. This supports the current approach of continuing anti-VEGF therapy until progression or prohibitive toxicity before changing treatment.

Reliability control of GNSS carrier-phase integer ambiguity resolution

This research investigates how to obtain accurate and reliable positioning results with global navigation satellite systems (GNSS). The work provides a theoretical framework for reliability control in GNSS carrier phase ambiguity resolution, which is the key technique for precise GNSS positioning in centimetre levels. The proposed approach includes identification and exclusion procedures of unreliable solutions and hypothesis tests, allowing the reliability of solutions to be controlled in the aspects of mathematical models, integer estimation and ambiguity acceptance tests. Extensive experimental results with both simulation and observed data sets effectively demonstrate the reliability performance characteristics based on the proposed theoretical framework and procedures.

A new single-phase frequency adaptive Phase-Locked Loop (PLL) for harmonic measurement

The paper presents an improved Phase-Locked Loop (PLL) for measuring the fundamental frequency and selective harmonic content of a distorted signal. This information can be used by grid interfaced devices and harmonic compensators. The single-phase structure is based on the Synchronous Reference Frame (SRF) PLL. The proposed PLL needs only a limited number of harmonic stages by incorporating Moving Average Filters (MAF) for eliminating the undesired harmonic content at each stage. The frequency dependency of MAF in effective filtering of undesired harmonics is also dealt with by a proposed method for adaptation to frequency variations of input signal. The method is suitable for high sampling rates and a wide frequency measurement range. Furthermore, an extended model of this structure is proposed which includes the response to both the frequency and phase angle variations. The proposed algorithm is simulated and verified using Hardware-in-the-Loop (HIL) testing.

Increasing functional variability in the preparatory phase of the takeoff improves elite springboard diving performance

PURPOSE: Previous research demonstrating that specific performance outcome goals can be achieved in different ways is functionally significant for springboard divers whose performance environment can vary extensively. This body of work raises questions about the traditional approach of balking (terminating the takeoff) by elite divers aiming to perform only identical, invariant movement patterns during practice. METHOD: A 12-week training program (2 times per day; 6.5 hr per day) was implemented with 4 elite female springboard divers to encourage them to adapt movement patterns under variable takeoff conditions and complete intended dives, rather than balk. RESULTS: Intraindividual analyses revealed small increases in variability in the board-work component of each diver's pretraining and posttraining program reverse-dive takeoffs. No topological differences were observed between movement patterns of dives completed pretraining and posttraining. Differences were noted in the amount of movement variability under different training conditions (evidenced by higher normalized root mean square error indexes posttraining). An increase in the number of completed dives (from 78.91%-86.84% to 95.59%-99.29%) and a decrease in the frequency of balked takeoffs (from 13.16%-19.41% to 0.63%-4.41%) showed that the elite athletes were able to adapt their behaviors during the training program. These findings coincided with greater consistency in the divers' performance during practice as scored by qualified judges. CONCLUSION: Results suggested that on completion of training, athletes were capable of successfully adapting their movement patterns under more varied takeoff conditions to achieve greater consistency and stability of performance outcomes.

Proteogenomics of selective susceptibility to endotoxin using circulating acute phase biomarkers and bioassay development in sheep: a review

Scientists have injected endotoxin into animals to investigate and understand various pathologies and novel therapies for several decades. Recent observations have shown that there is selective susceptibility to Escherichia coli lipopolysaccharide (LPS) endotoxin in sheep, despite having similar breed characteristics. The reason behind this difference is unknown, and has prompted studies aiming to explain the variation by proteogenomic characterisation of circulating acute phase biomarkers. It is hypothesised that genetic trait, biochemical, immunological and inflammation marker patterns contribute in defining and predicting mammalian response to LPS. This review discusses the effects of endotoxin and host responses, genetic basis of innate defences, activation of the acute phase response (APR) following experimental LPS challenge, and the current approaches employed in detecting novel biomarkers including acute phase proteins (APP) and micro-ribonucleic acids (miRNAs) in serum or plasma. miRNAs are novel targets for elucidating molecular mechanisms of disease because of their differential expression during pathological, and in healthy states. Changes in miRNA profiles during a disease challenge may be reflected in plasma. Studies show that gel-based two-dimensional electrophoresis (2-DE) coupled with either matrix-assisted laser desorption/ionisation time-of-flight mass spectrometry (MALDI-TOF MS) or liquid chromatography-mass spectrometry (LC-MS/MS) are currently the most used methods for proteome characterisation. Further evidence suggests that proteomic investigations are preferentially shifting from 2-DE to non-gel based LC-MS/MS coupled with data extraction by sequential window acquisition of all theoretical fragment-ion spectra (SWATH) approaches that are able to identify a wider range of proteins. Enzyme-linked immunosorbent assay (ELISA), quantitative real-time polymerase chain reaction (qRT-PCR), and most recently proteomic methods have been used to quantify low abundance proteins such as cytokines. qRT-PCR and next generation sequencing (NGS) are used for the characterisation of miRNA. Proteogenomic approaches for detecting APP and novel miRNA profiling are essential in understanding the selective resistance to endotoxin in sheep. The results of these methods could help in understanding similar pathology in humans. It might also be helpful in the development of physiological and diagnostic screening assays for determining experimental inclusion and endpoints, and in clinical trials in future

A phase 1b study of placenta-derived mesenchymal stromal cells in patients with idiopathic pulmonary fibrosis

BACKGROUND AND OBJECTIVE: Idiopathic pulmonary fibrosis (IPF) is a degenerative disease characterized by fibrosis following failed epithelial repair. Mesenchymal stromal cells (MSC), a key component of the stem cell niche in bone marrow and possibly other organs including lung, have been shown to enhance epithelial repair and are effective in preclinical models of inflammation-induced pulmonary fibrosis, but may be profibrotic in some circumstances. METHODS: In this single centre, non-randomized, dose escalation phase 1b trial, patients with moderately severe IPF (diffusing capacity for carbon monoxide (DLCO ) ≥ 25% and forced vital capacity (FVC) ≥ 50%) received either 1 × 10(6) (n = 4) or 2 × 10(6) (n = 4) unrelated-donor, placenta-derived MSC/kg via a peripheral vein and were followed for 6 months with lung function (FVC and DLCO ), 6-min walk distance (6MWD) and computed tomography (CT) chest. RESULTS: Eight patients (4 female, aged 63.5 (57-75) years) with median (interquartile range) FVC 60 (52.5-74.5)% and DLCO 34.5 (29.5-40)% predicted were treated. Both dose schedules were well tolerated with only minor and transient acute adverse effects. MSC infusion was associated with a transient (1% (0-2%)) fall in SaO2 after 15 min, but no changes in haemodynamics. At 6 months FVC, DLCO , 6MWD and CT fibrosis score were unchanged compared with baseline. There was no evidence of worsening fibrosis. CONCLUSIONS: Intravenous MSC administration is feasible and has a good short-term safety profile in patients with moderately severe IPF.

Manufacturing and use of human placenta-derived mesenchymal stromal cells for phase I clinical trials: Establishment and evaluation of a protocol

Background/Aim. Mesenchymal stromal cells (MSCs) have been utilised in many clinical trials as an experimental treatment in numerous clinical settings. Bone marrow remains the traditional source tissue for MSCs but is relatively hard to access in large volumes. Alternatively, MSCs may be derived from other tissues including the placenta and adipose tissue. In an initial study no obvious differences in parameters such as cell surface phenotype, chemokine receptor display, mesodermal differentiation capacity or immunosuppressive ability, were detected when we compared human marrow derived- MSCs to human placenta-derived MSCs. The aim of this study was to establish and evaluate a protocol and related processes for preparation placenta-derived MSCs for early phase clinical trials. Methods. A full-term placenta was taken after delivery of the baby as a source of MSCs. Isolation, seeding, incubation, cryopreservation of human placentaderived MSCs and used production release criteria were in accordance with the complex regulatory requirements applicable to Code of Good Manufacturing Practice manufacturing of ex vivo expanded cells. Results. We established and evaluated instructions for MSCs preparation protocol and gave an overview of the three clinical areas application. In the first trial, MSCs were co-transplanted iv to patient receiving an allogeneic cord blood transplant as therapy for treatmentrefractory acute myeloid leukemia. In the second trial, MSCs were administered iv in the treatment of idiopathic pulmonary fibrosis and without serious adverse effects. In the third trial, MSCs were injected directly into the site of tendon damage using ultrasound guidance in the treatment of chronic refractory tendinopathy. Conclusion. Clinical trials using both allogeneic and autologous cells demonstrated MSCs to be safe. A described protocol for human placenta-derived MSCs is appropriate for use in a clinical setting, relatively inexpensive and can be relatively easily adjusted to a different set of regulatory requirements, as applicable to early phase clinical trials.

Determination of tricyclazole in water using solid phase extraction and liquid chromatography

A method for determination of tricyclazole in water using solid phase extraction and high performance liquid chromatography (HPLC) with UV detection at 230nm and a mobile phase of acetonitrile:water (20:80, v/v) was developed. A performance comparison between two types of solid phase sorbents, the C18 sorbent of Supelclean ENVI-18 cartridge and the styrene-divinyl benzene copolymer sorbent of Sep-Pak PS2-Plus cartridge was conducted. The Sep-Pak PS2-Plus cartridges were found more suitable for extracting tricyclazole from water samples than the Supelclean ENVI-18 cartridges. For this cartridge, both methanol and ethyl acetate produced good results. The method was validated with good linearity and with a limit of detection of 0.008gL-1 for a 500-fold concentration through the SPE procedure. The recoveries of the method were stable at 80% and the precision was from 1.1-6.0% within the range of fortified concentrations. The validated method was also applied to measure the concentrations of tricyclazole in real paddy water.

Designs for phase I clinical trials with multiple courses of subjects at different doses

The goal of this article is to provide a new design framework and its corresponding estimation for phase I trials. Existing phase I designs assign each subject to one dose level based on responses from previous subjects. Yet it is possible that subjects with neither toxicity nor efficacy responses can be treated at higher dose levels, and their subsequent responses to higher doses will provide more information. In addition, for some trials, it might be possible to obtain multiple responses (repeated measures) from a subject at different dose levels. In this article, a nonparametric estimation method is developed for such studies. We also explore how the designs of multiple doses per subject can be implemented to improve design efficiency. The gain of efficiency from "single dose per subject" to "multiple doses per subject" is evaluated for several scenarios. Our numerical study shows that using "multiple doses per subject" and the proposed estimation method together increases the efficiency substantially.

A Bayesian decision approach for sample size determination in phase II trials

Stallard (1998, Biometrics 54, 279-294) recently used Bayesian decision theory for sample-size determination in phase II trials. His design maximizes the expected financial gains in the development of a new treatment. However, it results in a very high probability (0.65) of recommending an ineffective treatment for phase III testing. On the other hand, the expected gain using his design is more than 10 times that of a design that tightly controls the false positive error (Thall and Simon, 1994, Biometrics 50, 337-349). Stallard's design maximizes the expected gain per phase II trial, but it does not maximize the rate of gain or total gain for a fixed length of time because the rate of gain depends on the proportion: of treatments forwarding to the phase III study. We suggest maximizing the rate of gain, and the resulting optimal one-stage design becomes twice as efficient as Stallard's one-stage design. Furthermore, the new design has a probability of only 0.12 of passing an ineffective treatment to phase III study.