Metabolic responses to acute and prolonged hypoxic exposure

This thesis examined the metabolic effects of acute and intermediate hypoxic exposure in humans, specifically, physiological mechanisms associated with weight loss. Namely; increased metabolic rate, changes in substrate oxidation, altered lipid metabolism and changes in taste. Study one assessed the validity and reproducibility of an online gas analyser in normobaric hypoxia [Fraction of inspired oxygen: 0.12 (FiO2:0.12) equivalent to approximately 4,500m] (n=nine; two females, seven males). The MetaMax3x demonstrates good reproducibility between repeated trials. Differences exist between the system and the gold standard Douglas Bag method for measures of oxygen uptake (percent differences of V̇O2; 21%), carbon dioxide production (V̇CO2; 10%) and minute ventilation (V̇E; 5%). The second study investigated the free fatty acid (FFA) and triglyceride (TAG) response to an acute (45 minutes) hypoxic exposure (FiO2: 0.12) (n=10; five females, five males). A greater resting metabolic rate (RMR) (+28 ± 6 kcal.hr-1 ) was observed, through increased carbohydrate (CHO) and fat oxidation. Increased plasma FFA (+54%) and TAG (+26%) were observed, highlighting metabolic perturbations from acute exposure. Study three investigated the metabolic responses to an acute (60 minute) hypoxic exposure (FiO2: 0.12) at rest and a subsequent bout of moderate exercise in normoxia following a high fat meal (n=eight males). Experimental trials included a lipid ingestion prior to a rest period at hypoxia or normoxia followed by moderate intensity exercise (60% heart rate reserve). Control trials consisted of the same protocol without lipid ingestion. Acute, severe hypoxia increased energy expenditure (EE), (+22 ± 11 kcal.hr-1 ) CHO and fat oxidation following exposure. A prior acute bout of severe hypoxia did not alter EE and substrate use during subsequent moderate intensity exercise. An exercise bout, postlipid ingestion, resulted in lower triglyceride concentration. No changes in Meteorin-like were observed throughout trials. These findings suggest that an increase in RMR occurs following a single resting hypoxic exposure and independently to Meteorin-like protein. The fourth study observed reductions in body mass (-2.36 ± 1.41 kg) and increases in CHO oxidation during an altitude stay in Peru (18 days, 3400 m) (n=10; five females, five males). The reduction in body mass (-1.89 ± 1.31 kg) was sustained four weeks post-return to sea-level. Salt, sweet and bitter taste sensations were reduced at 3,400 m compared to sea-level. No changes in self-reported appetite were observed throughout the testing period. Furthermore no changes in circulating Meteorin-like protein were observed upon return to sea-level at one and four weeks post-altitude stay. Study five investigated the blood lipid response to a high lipid meal consumed one and four weeks post-return to sea-level following an altitude stay (18 days, 3400 m) (n=10; five females, five males). No lasting postprandial effects were observed. It is likely that a time dependent effect of hypoxia exists with regards to postprandial blood lipid responses. Taken together acute and intermediate exposure to hypoxic conditions alter substrate oxidation with the potential to induce losses in body mass, independently to changes in Meteorin-like protein and self-reported appetite. Specifically, prolonged stay at moderate altitude results in a greater dependency on CHO use. Increases in RMR were observed during an acute severe bout of hypoxia, although this was not a consistent effect throughout prolonged exposure and should be further investigated. Altered taste during an altitude stay may influence food preferences, energy intake and subsequent changes in body mass and should be considered an area of future investigation. Higher circulating levels of FFA and TAG, demonstrates a metabolic perturbation from a single, acute severe hypoxic exposure

Correlations between three ELISA protocols measurements of RTS,S/AS01-induced anti-CSP IgG antibodies

Background RTS,S/AS01 induced anti-circumsporozoite protein (CSP) IgG antibodies are associated with the vaccine efficacy. There is currently no international standardisation of the assays used in the measurement of anti-CSP IgG antibody concentrations for use in evaluations of the vaccine’s immunogenicity and/or efficacy. Here, we compared the levels of RTS,S/AS01 induced anti-CSP IgG antibodies measured using three different enzyme-Linked ImmunoSorbent Assays (ELISA). Methods 196 plasma samples were randomly selected from the 447 samples collected during the RTS,S/AS01 phase IIb trial in 2007 from Kenyan children aged between 5–17 months. The vaccine-induced anti-CSP IgG antibodies were then measured using two independently developed ELISA protocols (‘Kilifi-RTS,S’ and ‘Oxford-R21’) and compared to the results from the reference ‘Ghent-RTS,S’ protocol for the same participants. For each pair of protocols, a deming regression model was fitted. Linear equations were then derived to aid in conversions into equivalent ELISA units. The agreement was assessed using Bland and Altman method. Findings The anti-CSP IgG antibodies measured from the three ELISA protocols were in agreement, and were positively and linearly correlated; ‘Oxford’ and ‘Kilifi’ r = 0.93 (95% CI 0.91–0.95), ‘Oxford’ and ‘Ghent’ r = 0.94 (95% CI: 0.92–0.96), and ‘Kilifi’ and ‘Ghent’ r = 0.97 (95% CI: 0.96–0.98), p<0.0001 for all correlations. Conclusions With the linearity, agreement and correlations established between the assays, conversion equations can be applied to convert results into equivalent units, enabling comparisons of immunogenicities across different vaccines of the same CSP antigens. This study highlights the need for the international harmonisation of anti-CSP antibody measurements

Tactile thresholds are preserved yet complex sensory function is impaired over the lumbar spine of chronic non-specific low back pain patients. A preliminary investigation

Objectives: To investigate impairments in sensory function in chronic non-specific low back pain patients and the relationship between any impairment and the clinical features of the condition. Design: A cross-sectional case-control study. Setting: Laboratory based study. Participants: Nineteen chronic non-specific low back pain patients and nineteen healthy controls. Main Outcome measures: Tactile threshold, two point discrimination distance and accuracy at a task involving recognizing letters drawn over the skin of the lower back (graphaesthesia) were assessed over the lumbar spine in both groups. Pain duration, pain intensity, physical function, anxiety and depression were assessed by questionnaire in the back pain group Results: We found no difference in tactile threshold between the two groups (median difference 0.00 95% CI -0.04 – 0.04). There was a significant difference between controls and back pain patients for two point discrimination (mean difference 17.85 95% CI 5.93 – 29.77) and graphaesthesia accuracy (mean difference 6.13 95% CI 1.27-10.99). Low back pain patients had a larger lumbar two point discrimination distance threshold and a greater letter recognition error rate. In the patient group, we found no relationship between clinical profile and sensory function and no relationship between the sensory tests. Conclusions: These data support existing findings of perceptual abnormalities in chronic non-specific low back pain patients and are suggestive of cortical rather than peripheral sensory dysfunction. Amelioration of these abnormalities may present a target for therapeutic intervention

Pervasive Rise of Small-scale Deforestation in Amazonia

Understanding forest loss patterns in Amazonia, the Earth’s largest rainforest region, is critical for effective forest conservation and management. Following the most detailed analysis to date, spanning the entire Amazon and extending over a 14-year period (2001–2014), we reveal significant shifts in deforestation dynamics of Amazonian forests. Firstly, hotspots of Amazonian forest loss are moving away from the southern Brazilian Amazon to Peru and Bolivia. Secondly, while the number of new large forest clearings (>50 ha) has declined significantly over time (46%), the number of new small clearings (<1 ha) increased by 34% between 2001–2007 and 2008–2014. Thirdly, we find that small-scale low-density forest loss expanded markedly in geographical extent during 2008–2014. This shift presents an important and alarming new challenge for forest conservation, despite reductions in overall deforestation rates

Independent or Simultaneous Lowering of Core and Skin Temperature Has no Impact on Self‑paced Intermittent Running Performance in Hot Conditions

Purpose To investigate the effects of lowering core (Tgi) and mean skin temperature (Tsk) concomitantly and independently on self-paced intermittent running in the heat. Methods 10 males (30.5 ± 5.8 years, 73.2 ± 14.5 kg, 176.9 ± 8.0 cm, 56.2 ± 6.6 ml/kg/min) completed four randomised 46-min self-paced intermittent protocols on a non-motorised treadmill in 34.4 ± 1.4 °C, 36.3 ± 4.6% relative humidity. 30-min prior to exercise, participants were cooled via either ice slurry ingestion (INT); a cooling garment (EXT); mixed-cooling (ice slurry and cooling garment concurrently) (MIX); or no-cooling (CON). Results At the end of pre-cooling and the start of exercise Tgi were lower during MIX (36.11 ± 1.3 °C) compared to CON (37.6 ± 0.5 °C) and EXT (36.9 ± 0.5 °C, p 0.05). Peak sprint speeds were also similar between conditions (CON: 25.6 ± 4.48 km/h, INT: 25.4 ± 3.6 km/h, EXT: 26.0 ± 4.94 km/h, MIX: 25.6 ± 3.58 km/h) (p > 0.05). Blood lactate, heart rate and RPE were similar between conditions (p > 0.05). Conclusion Lowering Tgi and Tsk prior to self-paced intermittent exercise did not improve sprint, or submaximal running performance

Correlations between three ELISA protocols measurements of RTS,S/AS01-induced anti-CSP IgG antibodies

Background RTS,S/AS01 induced anti-circumsporozoite protein (CSP) IgG antibodies are associated with the vaccine efficacy. There is currently no international standardisation of the assays used in the measurement of anti-CSP IgG antibody concentrations for use in evaluations of the vaccine’s immunogenicity and/or efficacy. Here, we compared the levels of RTS,S/AS01 induced anti-CSP IgG antibodies measured using three different enzyme-Linked ImmunoSorbent Assays (ELISA). Methods 196 plasma samples were randomly selected from the 447 samples collected during the RTS,S/AS01 phase IIb trial in 2007 from Kenyan children aged between 5–17 months. The vaccine-induced anti-CSP IgG antibodies were then measured using two independently developed ELISA protocols (‘Kilifi-RTS,S’ and ‘Oxford-R21’) and compared to the results from the reference ‘Ghent-RTS,S’ protocol for the same participants. For each pair of protocols, a deming regression model was fitted. Linear equations were then derived to aid in conversions into equivalent ELISA units. The agreement was assessed using Bland and Altman method. Findings The anti-CSP IgG antibodies measured from the three ELISA protocols were in agreement, and were positively and linearly correlated; ‘Oxford’ and ‘Kilifi’ r = 0.93 (95% CI 0.91–0.95), ‘Oxford’ and ‘Ghent’ r = 0.94 (95% CI: 0.92–0.96), and ‘Kilifi’ and ‘Ghent’ r = 0.97 (95% CI: 0.96–0.98), p<0.0001 for all correlations. Conclusions With the linearity, agreement and correlations established between the assays, conversion equations can be applied to convert results into equivalent units, enabling comparisons of immunogenicities across different vaccines of the same CSP antigens. This study highlights the need for the international harmonisation of anti-CSP antibody measurements

Modeling the resonant planetary system GJ876

The two planets about the star GJ 876 appear to have undergone extensive migration from their point of origin in the protoplanetary disk -- both because of their close proximity to the star (30 and 60 day orbital periods) and because of their occupying three stable orbital resonances at the 2:1 mean-motion commensurability. The resonances were most likely established by converging differential migration of the planets leading to capture into the resonances. A problem with this scenario is that continued migration of the system while it is trapped in the resonances leads to orbital eccentricities that rapidly exceed the observational upper limits of e_1 = 0.31 and e_2 = 0.05. As seen in forced 3-body simulations, lower eccentricities would persist during migration only for an applied eccentricity damping. Here we explore the evolution of the GJ 876 system using two-dimensional hydrodynamical simulations that include viscous heating and radiative effects. We find that a hydrodynamic evolution within the resonance, where only the outer planet interacts with the disk, always rapidly leads to large values of eccentricities that exceed those observed. Only if mass is removed from the disk on a time scale of the order of the migration time scale (before there has been extensive migration after capture), as might occur for photoevaporation in the late phases of planet formation, can we end up with eccentricities that are consistent with the observations.Comment: Paper accepted by A&A, 17 Pages, 17 Figure

GRACES: Gemini remote access to CFHT ESPaDOnS Spectrograph through the longest astronomical fiber ever made (Experimental phase completed.)

The Gemini Remote Access to CFHT ESPaDONS Spectrograph has achieved first light of its experimental phase in May 2014. It successfully collected light from the Gemini North telescope and sent it through two 270 m optical fibers to the the ESPaDOnS spectrograph at CFHT to deliver high-resolution spectroscopy across the optical region. The fibers gave an average focal ratio degradation of 14% on sky, and a maximum transmittance of 85% at 800nm. GRACES achieved delivering spectra with a resolution power of R = 40,000 and R = 66,000 between 400 and 1,000 nm. It has a ~8% throughput and is sensitive to target fainter than 21st mag in 1 hour. The average acquisition time of a target is around 10 min. This project is a great example of a productive collaboration between two observatories on Maunakea that was successful due to the reciprocal involvement of the Gemini, CFHT, and NRC Herzberg teams, and all the staff involved closely or indirectly.Comment: Presented at SPIE Astronomical Telescopes + Instrumentation 201

Chromosome-specific KASP markers for detecting Amblyopyrum muticum segments in wheat introgression lines

Many wild-relative species are being used in prebreeding programs to increase the genetic diversity of wheat (Triticum aestivum L.). Genotyping tools such as single nucleotide polymorphism (SNP)-based arrays and molecular markers have been widely used to characterize wheat–wild relative introgression lines. However, due to the polyploid nature of the recipient wheat genome, it is difficult to develop SNP-based Kompetitive allele-specific polymerase chain reaction (KASP) markers that are codominant to track the introgressions from the wild species. Previous attempts to develop KASP markers have involved both exome- and polymerase chain reaction (PCR)-amplicon-based sequencing of the wild species. But chromosome-specific KASP assays have been hindered by homoeologous SNPs within the wheat genome. This study involved whole genome sequencing of the diploid wheat wild relative Amblyopyrum muticum (Boiss.) Eig and development of a de novo SNP discovery pipeline that generated ∼38,000 SNPs in unique wheat genome sequences. New assays were designed to increase the density of Am. muticum polymorphic KASP markers. With a goal of one marker per 60 Mbp, 335 new KASP assays were validated as diagnostic for Am. muticum in a wheat background. Together with assays validated in previous studies, 498 well distributed chromosome-specific markers were used to recharacterize previously genotyped wheat–Am. muticum doubled haploid (DH) introgression lines. The chromosome-specific nature of the KASP markers allowed clarification of which wheat chromosomes were involved with recombination events or substituted with Am. muticum chromosomes and the higher density of markers allowed detection of new small introgressions in these DH lines

Neuroinflammation predicts disease progression in progressive supranuclear palsy

Introduction: In addition to tau pathology and neuronal loss, neuroinflammation occurs in progressive supranuclear palsy (PSP). However, the prognostic value of the in vivo imaging markers for these processes in PSP remains unclear. We test the primary hypothesis that baseline in vivo imaging assessment of neuroinflammation in subcortical regions predicts clinical progression in patients with PSP. Methods: Seventeen patients with PSP–Richardson’s syndrome underwent a baseline multimodal imaging assessment, including [11C]PK11195 positron emission tomography (PET) to index microglial activation, [18F]AV-1451 PET for tau pathology and structural MRI. Disease severity was measured at baseline and serially up to 4 years with the Progressive Supranuclear Palsy Rating Scale (PSPRS) (average interval of 5 months). Regional grey-matter volumes and PET ligand binding potentials were summarised by three principal component analyses (PCAs). A linear mixed-effects model was applied to the longitudinal PSPRS scores. Single-modality imaging predictors were regressed against the individuals’ estimated rate of progression to identify the prognostic value of baseline imaging markers. Results: PCA components reflecting neuroinflammation and tau burden in the brainstem and cerebellum correlated with the subsequent annual rate of change in the PSPRS. PCA-derived PET markers of neuroinflammation and tau pathology correlated with regional brain volume in the same regions. However, MRI volumes alone did not predict the rate of clinical progression. Conclusions: Molecular imaging with PET for microglial activation and tau pathology can predict clinical progression in PSP. These data encourage the evaluation of immunomodulatory approaches to disease-modifying therapies in PSP and the potential for PET to stratify patients in early phase clinical trials