Anosmin-1 modulates fibroblast growth factor receptor 1 signaling in human gonadotropin-releasing hormone olfactory neuroblasts through a heparan sulfate-dependent mechanism

Defects of either anosmin-1 or fibroblast growth factor receptor 1 (FGFR1) are known to underlie hereditary Kallmann's syndrome (KS), a human disorder of olfactory and gonadotropin-releasing hormone (GnRH) neuronal ontogeny. Here, we report a functional interaction between anosmin-1 and the FGFR1-FGF2-heparan sulfate complex, leading to amplified responses in the FGFR1 signaling pathway. In human embryonic GnRH olfactory neuroblasts, wild-type anosmin-1, but not proteins with loss-of-function KS mutations, induces neurite outgrowth and cytoskeletal rearrangements through FGFR1-dependent mechanisms involving p42/44 and p38 mitogen-activated protein kinases and Cdc42/Rac1 activation. Furthermore, anosmin-1 enhances FGF2 signaling specifically through FGFR1 IIIc in heterologous BaF3 lymphoid cells in a heparan sulfate-dependent manner. Our study provides compelling evidence for anosmin-1 as an isoform-specific co-ligand modulator of FGFR signaling that amplifies and specifies FGFR1 signaling responses during human nervous system development and defines a mechanism underlying the link between autosomal and X-linked KS.</p

Hypertension in autosomal dominant polycystic kidney disease: a meta-analysis

CONTEXT: Autosomal dominant polycystic kidney disease (ADPKD) is a common disorder that can cause hypertension during childhood, but the true prevalence of hypertension during childhood is not known. OBJECTIVE: We undertook a systematic review and meta-analysis to determine the prevalence of hypertension in children with ADPKD. DATA SOURCES: Systematic review of articles published between 1980 and 2015 in MEDLINE and EMBASE. STUDY SELECTION: Studies selected by two authors independently if reporting data on prevalence of hypertension in children and young persons aged 15 children. Articles were excluded if inadequate diagnostic criteria for hypertension were used. Studies with selection bias were included but analysed separately. DATA EXTRACTION: Data extracted on prevalence of hypertension, proteinuria and reduced renal function using standardised form. Meta-analysis was performed to calculate weighted mean prevalence. RESULTS: 903 articles were retrieved from our search; 14 studies met the inclusion criteria: 1 prospective randomised controlled trial; 8 prospective observational studies; and 5 retrospective cross-sectional studies. From 928 children with clinically confirmed ADPKD, 20% (95% CI 15% to 27%) were hypertensive. The estimated prevalence of proteinuria in children with ADPKD is 20% (8 studies; 95% CI 9% to 40%) while reduced renal function occurred in 8% (5 studies; 95% CI 2% to 26%). LIMITATIONS: Studies showed a high degree of methodological heterogeneity (I(2)=73.4%, τ(2)=0.3408, p<0.0001). Most studies did not use ambulatory blood pressure (BP) monitoring to diagnose hypertension. CONCLUSIONS: In this meta-analysis we estimate 20% of children with ADPKD have hypertension. In the population, many children with ADPKD are not under regular follow-up and remain undiagnosed. We recommend that all children at risk of ADPKD have regular BP measurement

Dietary nitrate accelerates postexercise muscle metabolic recovery and O2 delivery in hypoxia.

We tested the hypothesis that the time constants (τ) of postexercise T2* MRI signal intensity (an index of O2 delivery) and muscle [PCr] (an index of metabolic perturbation, measured by (31)P-MRS) in hypoxia would be accelerated after dietary nitrate (NO3 (-)) supplementation. In a double-blind crossover design, eight moderately trained subjects underwent 5 days of NO3 (-) (beetroot juice, BR; 8.2 mmol/day NO3 (-)) and placebo (PL; 0.003 mmol/day NO3 (-)) supplementation in four conditions: normoxic PL (N-PL), hypoxic PL (H-PL; 13% O2), normoxic NO3 (-) (N-BR), and hypoxic NO3 (-) (H-BR). The single-leg knee-extension protocol consisted of 10 min of steady-state exercise and 24 s of high-intensity exercise. The [PCr] recovery τ was greater in H-PL (30 ± 4 s) than H-BR (22 ± 4 s), N-PL (24 ± 4 s) and N-BR (22 ± 4 s) (P 0.05). These findings suggest that the NO3 (-)-NO2 (-)-NO pathway is a significant modulator of muscle energetics and O2 delivery during hypoxic exercise and subsequent recovery.J. Fulford's salary was supported via National Institute of Health Research Grant 50112

Digital pulse-shape discrimination of fast neutrons and gamma rays

Discrimination of the detection of fast neutrons and gamma rays in a liquid scintillator detector has been investigated using digital pulse-processing techniques. An experimental setup with a 252Cf source, a BC-501 liquid scintillator detector, and a BaF2 detector was used to collect waveforms with a 100 Ms/s, 14 bit sampling ADC. Three identical ADC's were combined to increase the sampling frequency to 300 Ms/s. Four different digital pulse-shape analysis algorithms were developed and compared to each other and to data obtained with an analogue neutron-gamma discrimination unit. Two of the digital algorithms were based on the charge comparison method, while the analogue unit and the other two digital algorithms were based on the zero-crossover method. Two different figure-of-merit parameters, which quantify the neutron-gamma discrimination properties, were evaluated for all four digital algorithms and for the analogue data set. All of the digital algorithms gave similar or better figure-of-merit values than what was obtained with the analogue setup. A detailed study of the discrimination properties as a function of sampling frequency and bit resolution of the ADC was performed. It was shown that a sampling ADC with a bit resolution of 12 bits and a sampling frequency of 100 Ms/s is adequate for achieving an optimal neutron-gamma discrimination for pulses having a dynamic range for deposited neutron energies of 0.3-12 MeV. An investigation of the influence of the sampling frequency on the time resolution was made. A FWHM of 1.7 ns was obtained at 100 Ms/s.Comment: 26 pages, 14 figures, submitted to Nuclear Instruments and Methods in Physics Research

L-citrulline supplementation improves O2 uptake kinetics and high-intensity exercise performance in humans

This is the author accepted manuscript. The final version is available from the American Physiological Society via the DOI in this record.The purpose of this study was to compare the effects of L-citrulline (CIT) and L-arginine (ARG) supplementation on nitric oxide (NO) biomarkers, pulmonary O2 uptake (VO2) kinetics and exercise performance. In a randomised, placebo-controlled, cross-over study, ten healthy adult males completed moderate- and severe-intensity cycling exercise on days 6 and 7 of a 7 day supplementation period with placebo (PLA), 6 g•day(-1) of ARG and 6 g•day(-1) of CIT. Compared to PLA, plasma [ARG] was increased by a similar magnitude with ARG and CIT supplementation, but plasma [CIT] was only increased (P0.05). In conclusion, these results suggest that short-term CIT, but not ARG, supplementation can improve blood pressure, VO2 kinetics and exercise performance in healthy adults

Dietary nitrate supplementation: effects on plasma nitrite and pulmonary O2 uptake dynamics during exercise in hypoxia and normoxia

Clinical TrialThis is the author accepted manuscript. The final version is available from the American Physiological Society via the DOI in this record.We investigated the effects of dietary nitrate (NO3 (-)) supplementation on the concentration of plasma nitrite ([NO2 (-)]), oxygen uptake (V̇o2) kinetics, and exercise tolerance in normoxia (N) and hypoxia (H). In a double-blind, crossover study, 12 healthy subjects completed cycle exercise tests, twice in N (20.9% O2) and twice in H (13.1% O2). Subjects ingested either 140 ml/day of NO3 (-)-rich beetroot juice (8.4 mmol NO3; BR) or NO3 (-)-depleted beetroot juice (PL) for 3 days prior to moderate-intensity and severe-intensity exercise tests in H and N. Preexercise plasma [NO2 (-)] was significantly elevated in H-BR and N-BR compared with H-PL (P < 0.01) and N-PL (P < 0.01). The rate of decline in plasma [NO2 (-)] was greater during severe-intensity exercise in H-BR [-30 ± 22 nM/min, 95% confidence interval (CI); -44, -16] compared with H-PL (-7 ± 10 nM/min, 95% CI; -13, -1; P < 0.01) and in N-BR (-26 ± 19 nM/min, 95% CI; -38, -14) compared with N-PL (-1 ± 6 nM/min, 95% CI; -5, 2; P < 0.01). During moderate-intensity exercise, steady-state pulmonary V̇o2 was lower in H-BR (1.91 ± 0.28 l/min, 95% CI; 1.77, 2.13) compared with H-PL (2.05 ± 0.25 l/min, 95% CI; 1.93, 2.26; P = 0.02), and V̇o2 kinetics was faster in H-BR (τ: 24 ± 13 s, 95% CI; 15, 32) compared with H-PL (31 ± 11 s, 95% CI; 23, 38; P = 0.04). NO3 (-) supplementation had no significant effect on V̇o2 kinetics during severe-intensity exercise in hypoxia, or during moderate-intensity or severe-intensity exercise in normoxia. Tolerance to severe-intensity exercise was improved by NO3 (-) in hypoxia (H-PL: 197 ± 28; 95% CI; 173, 220 vs. H-BR: 214 ± 43 s, 95% CI; 177, 249; P = 0.04) but not normoxia. The metabolism of NO2 (-) during exercise is altered by NO3 (-) supplementation, exercise, and to a lesser extent, hypoxia. In hypoxia, NO3 (-) supplementation enhances V̇o2 kinetics during moderate-intensity exercise and improves severe-intensity exercise tolerance. These findings may have important implications for individuals exercising at altitude

Dietary nitrate modulates cerebral blood flow parameters and cognitive performance in humans: A double-blind, placebo-controlled, crossover investigation.

This is the author accepted manuscript. The final version is available from the publisher via the DOI in this record.Nitrate derived from vegetables is consumed as part of a normal diet and is reduced endogenously via nitrite to nitric oxide. It has been shown to improve endothelial function, reduce blood pressure and the oxygen cost of sub-maximal exercise, and increase regional perfusion in the brain. The current study assessed the effects of dietary nitrate on cognitive performance and prefrontal cortex cerebral blood-flow (CBF) parameters in healthy adults. In this randomised, double-blind, placebo-controlled, parallel-groups study, 40 healthy adults received either placebo or 450 ml beetroot juice (~5.5 mmol nitrate). Following a 90 minute drink/absorption period, participants performed a selection of cognitive tasks that activate the frontal cortex for 54 min. Near-Infrared Spectroscopy (NIRS) was used to monitor CBF and hemodynamics, as indexed by concentration changes in oxygenated and deoxygenated-haemoglobin, in the frontal cortex throughout. The bioconversion of nitrate to nitrite was confirmed in plasma by ozone-based chemi-luminescence. Dietary nitrate modulated the hemodynamic response to task performance, with an initial increase in CBF at the start of the task period, followed by consistent reductions during the least demanding of the three tasks utilised. Cognitive performance was improved on the serial 3s subtraction task. These results show that single doses of dietary nitrate can modulate the CBF response to task performance and potentially improve cognitive performance, and suggest one possible mechanism by which vegetable consumption may have beneficial effects on brain function

Nudged elastic bands and lightly bound skyrmions

It has become clear in recent years that the configuration space of the nuclear Skyrme model has, in each topological class, many almost degenerate local energy minima and that the number of such minima grows with the degree (or baryon number) $B$. Rigid body quantization, in which one quantizes motion on the spin-isospin orbit of just one minimum, is thus an ill-justified approximation. Instead, one should identify a (finite dimensional) moduli space of configurations containing all local minima (for a given $B$) as well as fields interpolating smoothly between them. This paper proposes a systematic computational scheme for generating such a moduli space: one constructs an energy minimizing path between each pair of local minima, then defines the moduli space to be the union of spin-isospin orbits of points on the union of these curves, a principal bundle over a graph. The energy minimizing curves may be constructed in practice using the nudged elastic band method, a standard tool in mathematical chemistry for analyzing reaction paths and computing activation energies. To illustrate, we apply this scheme to the lightly bound Skyrme model in the point particle approximation, constructing the graphs for $5\leq B\leq 10$. We go on to complete the quantization for $B=7$, in which the graph has two vertices and a single edge. The low-lying quantum states with isospin $1/2$ do not strongly localize around either of the local energy minima (the vertices). Their energies rise monotonically with spin, conflicting with experimental data for Lithium-7.Comment: 31 pages, 4 figure

Ageing modifies the effects of beetroot juice supplementation on 24-hour blood pressure variability: an individual participant meta-analysis

Copyright © 2015 Elsevier. NOTICE: this is the author’s version of a work that was accepted for publication in Nitric Oxide: Biology and Chemistry. Changes resulting from the publishing process, such as peer review, editing, corrections, structural formatting, and other quality control mechanisms may not be reflected in this document. Changes may have been made to this work since it was submitted for publication. A definitive version was subsequently published in Nitric Oxide: Biology and Chemistry (2015), DOI: 10.1016/j.niox.2015.04.007OBJECTIVES: Abnormal circadian oscillations of blood pressure (BP) and nocturnal-diurnal BP differences (i.e., dipping) increase cardiovascular risk. Whether inorganic nitrate supplementation influences 24-hr BP variability is currently unknown. We studied the effects of high-nitrate beetroot juice supplementation on BP variability measured by 24-hr ambulatory BP monitoring (24-hr ABPM) in older subjects. METHODS: Data from four independent randomised clinical trials were collated. Eighty-five older participants (age range: 55-76 years) were included in the final database. Two trials had an open-label, parallel design and two trials had a cross-over, double-blind design. Participants were randomised to either beetroot juice or placebo. Changes in 24-hr ABPM (daily, diurnal, nocturnal), variability (weighted-SDs), night-dipping, morning surge for systolic and diastolic BP were measured. Meta-analysis was conducted to obtain pooled estimates of the effect size for each BP outcome. Sub-group analyses were conducted to evaluate the influence of age, BMI, gender, BP status and changes in nitrite concentrations on the effect size. RESULTS: The pooled effect of beetroot juice on all BP outcomes was not significant. Beetroot juice ingestion determined a significant decrease in nocturnal systolic BP variability in subjects aged less than 65y (2.8mmHg, -4.5 -1.0, p=0.002) compared to the older group (≥65y; 1.0mmHg, -2.2 4.2, p=0.54). A greater change in NO2(-) concentrations after beetroot supplementation was associated with significant differences for nocturnal mean (-3.4mmHg, -0.6 -2.4, p=0.02) and variability (-0.8mmHg, -1.5 -0.06, p=0.03) of systolic BP. CONCLUSIONS: The vascular responsiveness to inorganic nitrate may be modified by mechanisms of vascular ageing influencing the reducing capacity to convert inorganic nitrate into nitrite and tissue-specific responses to dietary nitrate supplementation.NIHR Exeter Clinical Research Facilit

Clinical relevance of biomarkers of oxidative stress

SIGNIFICANCE Oxidative stress is considered to be an important component of various diseases. A vast number of methods have been developed and used in virtually all diseases to measure the extent and nature of oxidative stress, ranging from oxidation of DNA to proteins, lipids, and free amino acids. Recent Advances: An increased understanding of the biology behind diseases and redox biology has led to more specific and sensitive tools to measure oxidative stress markers, which are very diverse and sometimes very low in abundance. CRITICAL ISSUES The literature is very heterogeneous. It is often difficult to draw general conclusions on the significance of oxidative stress biomarkers, as only in a limited proportion of diseases have a range of different biomarkers been used, and different biomarkers have been used to study different diseases. In addition, biomarkers are often measured using nonspecific methods, while specific methodologies are often too sophisticated or laborious for routine clinical use. FUTURE DIRECTIONS Several markers of oxidative stress still represent a viable biomarker opportunity for clinical use. However, positive findings with currently used biomarkers still need to be validated in larger sample sizes and compared with current clinical standards to establish them as clinical diagnostics. It is important to realize that oxidative stress is a nuanced phenomenon that is difficult to characterize, and one biomarker is not necessarily better than others. The vast diversity in oxidative stress between diseases and conditions has to be taken into account when selecting the most appropriate biomarker. Antioxid. Redox Signal. 00, 000-000