Inorganic nitrate supplementation improves muscle oxygenation, O2 uptake kinetics and exercise tolerance at high but not low pedal rates

Copyright © 2014, Journal of Applied PhysiologyWe tested the hypothesis that inorganic nitrate (NO3-) supplementation would improve muscle oxygenation, pulmonary O2 uptake (VO2) kinetics and exercise tolerance (Tlim) to a greater extent when cycling at high compared low pedal rates. In a randomized, placebo-controlled, cross-over study, seven subjects (mean ± SD, age 21 ± 2 yr, body mass 86 ± 10 kg) completed severe-intensity step cycle tests at pedal cadences of 35 rpm and 115 rpm during separate 9 day supplementation periods with NO3--rich beetroot juice (BR; providing 8.4 mmol NO3-∙day-1) and placebo (PLA). Compared to PLA, plasma nitrite concentration increased 178% with BR (P0.05). However, when cycling at 115 rpm, muscle [O2Hb] was higher at baseline and throughout exercise, phase II VO2 kinetics was faster (47 ± 16 s vs. 61 ± 25 s; P<0.05) and Tlim was greater (362 ± 137 s vs. 297 ± 79 s; P<0.05) with BR compared to PLA. These results suggest that short-term BR supplementation can increase muscle oxygenation, expedite the adjustment of oxidative metabolism and enhance exercise tolerance when cycling at a high, but not a low, pedal cadence in healthy recreationally-active subjects. These findings support recent observations that NO3- supplementation may be particularly effective at improving physiological and functional responses in type II muscle fibers

Synergism/complementarity of recombinant adenoviral vectors and other vaccination platforms during induction of protective immunity against malaria

The lack of immunogenicity of most malaria antigens and the complex immune responses required for achieving protective immunity against this infectious disease have traditionally hampered the development of an efficient human malaria vaccine. The current boom in development of recombinant viral vectors and their use in prime-boost protocols that result in enhanced immune outcomes have increased the number of malaria vaccine candidates that access pre-clinical and clinical trials. In the frontline, adenoviruses and poxviruses seem to be giving the best immunization results in experimental animals and their mutual combination, or their combination with recombinant proteins (formulated in adjuvants and given in sequence or being given as protein/virus admixtures), has been shown to reach unprecedented levels of anti-malaria immunity that predictably will be somehow reproduced in the human setting. However, all this optimism was previously seen in the malaria vaccine development field without many real applicable results to date. We describe here the current state-of-the-art in the field of recombinant adenovirus research for malaria vaccine development, in particular referring to their use in combination with other immunogens in heterologous prime-boost protocols, while trying to simultaneously show our contributions and point of view on this subject

Generating and repairing genetically programmed DNA breaks during immunoglobulin class switch recombination

Adaptive immune responses require the generation of a diverse repertoire of immunoglobulins (Igs) that can recognize and neutralize a seemingly infinite number of antigens. V(D)J recombination creates the primary Ig repertoire, which subsequently is modified by somatic hypermutation (SHM) and class switch recombination (CSR). SHM promotes Ig affinity maturation whereas CSR alters the effector function of the Ig. Both SHM and CSR require activation-induced cytidine deaminase (AID) to produce dU:dG mismatches in the Ig locus that are transformed into untemplated mutations in variable coding segments during SHM or DNA double-strand breaks (DSBs) in switch regions during CSR. Within the Ig locus, DNA repair pathways are diverted from their canonical role in maintaining genomic integrity to permit AID-directed mutation and deletion of gene coding segments. Recently identified proteins, genes, and regulatory networks have provided new insights into the temporally and spatially coordinated molecular interactions that control the formation and repair of DSBs within the Ig locus. Unravelling the genetic program that allows B cells to selectively alter the Ig coding regions while protecting non-Ig genes from DNA damage advances our understanding of the molecular processes that maintain genomic integrity as well as humoral immunity

SRS supplemental safety system injection (gas pressurizer) test

An evaluation and validation of an existing version of the RELAP5 thermal hydraulics computer code was undertaken for the purpose of certification for use in the new production reactor - heavy water reactor (NPR-HWR) program. This version of the code was RELAP5/MOD3 Version 5q, designated for the purposes of the NPR-HWR program as RELAP5/NPR Version 0. As part of the evaluation and assessment, test data from theSRS Supplemental Safety System Injection (Gas Pressurizer) was used to verify and assess the ability of RELAP5/NPR Version 0 to perform thermal-hydraulic model analysis using the test data. Specifically, the assessment determines RELAP5/NPR Version 0 capability in modeling sudden depressurization phenomena. Two RELAP5/NPR Version 0 components (pipe and accumulator) were used to compare calculated pressure and temperature against test data. The code deficiencies are a temperature clamp in the accumulator component prevents the gas temperature from going below [minus]9[degrees]F, and RELAP5 accumulator and pipe components wall-to-fluid heat transfer correlation and interfacial vapor heat transfer correlation need substantial improvement. Only the code pipe component calculated pressures and temperatures within the specified 10 percent accuracy

Influence of Prior Exercise on VO2 Kinetics Subsequent Exhaustive Rowing Performance

Prior exercise has the potential to enhance subsequent performance by accelerating the oxygen uptake (VO(2)) kinetics. The present study investigated the effects of two different intensities of prior exercise on pulmonary VO(2) kinetics and exercise time during subsequent exhaustive rowing exercise. It was hypothesized that in prior heavy, but not prior moderate exercise condition, overall VO(2) kinetics would be faster and the VO(2) primary amplitude would be higher, leading to longer exercise time at VO(2max). Six subjects (mean ± SD; age: 22.9±4.5 yr; height: 181.2±7.1 cm and body mass: 75.5±3.4 kg) completed square-wave transitions to 100% of VO(2max) from three different conditions: without prior exercise, with prior moderate and heavy exercise. VO(2) was measured using a telemetric portable gas analyser (K4b(2), Cosmed, Rome, Italy) and the data were modelled using either mono or double exponential fittings. The use of prior moderate exercise resulted in a faster VO(2) pulmonary kinetics response (τ(1) = 13.41±3.96 s), an improved performance in the time to exhaustion (238.8±50.2 s) and similar blood lactate concentrations ([La(−)]) values (11.8±1.7 mmol.L(−1)) compared to the condition without prior exercise (16.0±5.56 s, 215.3±60.1 s and 10.7±1.2 mmol.L(−1), for τ(1), time sustained at VO(2max) and [La(−)], respectively). Performance of prior heavy exercise, although useful in accelerating the VO(2) pulmonary kinetics response during a subsequent time to exhaustion exercise (τ(1) = 9.18±1.60 s), resulted in a shorter time sustained at VO(2max) (155.5±46.0 s), while [La(−)] was similar (13.5±1.7 mmol.L(−1)) compared to the other two conditions. Although both prior moderate and heavy exercise resulted in a faster pulmonary VO(2) kinetics response, only prior moderate exercise lead to improved rowing performance

Influenza Virus Specific CD8+ T Cells Exacerbate Infection Following High Dose Influenza Challenge of Aged Mice

Influenza viruses cause severe illnesses and death, mainly in the aged population. Protection afforded by licensed vaccines through subtype-specific neutralizing antibodies is incomplete, especially when the vaccine antigens fail to closely match those of the circulating viral strains. Efforts are underway to generate a so-called universal influenza vaccine expressing conserved viral sequences that induce broad protection to multiple strains of influenza virus through the induction of CD8+ T cells. Here we assess the effect of a potent antiviral CD8+ T cell response on influenza virus infection of young and aged mice. Our results show that CD8+ T cell-inducing vaccines can provide some protection to young mice, but they exacerbate influenza virus-associated disease in aged mice, causing extensive lung pathology and death