Metabolomics analysis in rats with thiamine deficiency identifies key metabolites in vulnerable brain regions and suggests neural stem progenitor cells play a role in ameliorating metabolic dysfunction

La documentation scientifique fait état de la présence, chez l’adulte, de cellules souches et progénitrices neurales (CSPN) endogènes dans les zones sous-ventriculaire et sous-granulaire du cerveau ainsi que dans le gyrus denté de l’hippocampe. De plus, un postulat selon lequel il serait également possible de retrouver ce type de cellules dans la moelle épinière et le néocortex des mammifères adultes a été énoncé. L’encéphalopathie de Wernicke, un trouble neurologique grave toutefois réversible qui entraîne un dysfonctionnement, voire une défaillance du cerveau, est causée principalement par une carence importante en thiamine (CT). Des observations récentes laissent envisager que les facteurs en cause dans la prolifération et la différenciation des CSPN pourraient également jouer un rôle important lors d’un épisode de CT. L’hypothèse, selon laquelle l’identification de nouveaux métabolites entrant dans le mécanisme ou la séquence de réactions se soldant en une CT pourraient en faciliter la compréhension, a été émise au moyen d'une démarche en cours permettant d’établir le profil des modifications métaboliques qui surviennent en de telles situations. Cette approche a été utilisée pour constater les changements métaboliques survenus au niveau du foyer cérébral dans un modèle de rats déficients en thiamine (rats DT), particulièrement au niveau du thalamus et du colliculus inférieur (CI). La greffe de CSPN a quant à elle été envisagée afin d’apporter de nouvelles informations sur la participation des CSPN lors d’un épisode de CT et de déterminer les bénéfices thérapeutiques potentiels offerts par cette intervention. Les sujets de l’étude étaient répartis en quatre groupes expérimentaux : un premier groupe constitué de rats dont la CT était induite par la pyrithiamine (rats DTiP), un deuxième groupe constitué de rats-contrôles nourris ensemble (« pair-fed control rats » ou rats PFC) ainsi que deux groupes de rats ayant subi une greffe de CSPN, soit un groupe de rats DTiP greffés et un dernier groupe constitué de rats-contrôles (rats PFC) greffés. Les échantillons de foyers cérébraux (thalamus et CI) des quatre groupes de rats ont été prélevés et soumis à des analyses métabolomiques non ciblées ainsi qu’à une analyse visuelle par microscopie à balayage électronique (SEM). Une variété de métabolites-clés a été observée chez les groupes de rats déficients en thiamine (rats DTiP) en plus de plusieurs métabolites dont la documentation ne faisait pas mention. On a notamment constaté la présence d’acides biliaires, d’acide cynurénique et d’acide 1,9— diméthylurique dans le thalamus, alors que la présence de taurine et de carnosine a été observée dans le colliculus inférieur. L’étude a de plus démontré une possible implication des CSPN endogènes dans les foyers cérébraux du thalamus et du colliculus inférieur en identifiant les métabolites-clés ciblant les CSPN. Enfin, les analyses par SEM ont montré une amélioration notable des tissus à la suite de la greffe de CSPN. Ces constatations suggèrent que l’utilisation de CSPN pourrait s’avérer une avenue thérapeutique intéressante pour soulager la dégénérescence symptomatique liée à une grave carence en thiamine chez l’humain.

Excess open solar magnetic flux from satellite data: 1. Analysis of the third perihelion Ulysses pass

We use the third perihelion pass by the Ulysses spacecraft to illustrate and investigate the “flux excess” effect, whereby open solar flux estimates from spacecraft increase with increasing heliocentric distance. We analyze the potential effects of small-scale structure in the heliospheric field (giving fluctuations in the radial component on timescales smaller than 1 h) and kinematic time-of-flight effects of longitudinal structure in the solar wind flow. We show that the flux excess is explained by neither very small-scale structure (timescales < 1 h) nor by the kinematic “bunching effect” on spacecraft sampling. The observed flux excesses is, however, well explained by the kinematic effect of larger-scale (>1 day) solar wind speed variations on the frozen-in heliospheric field. We show that averaging over an interval T (that is long enough to eliminate structure originating in the heliosphere yet small enough to avoid cancelling opposite polarity radial field that originates from genuine sector structure in the coronal source field) is only an approximately valid way of allowing for these effects and does not adequately explain or account for differences between the streamer belt and the polar coronal holes.

Time series analysis of lava flux

We have applied time series analytical techniques to the flux of lava from an extrusive eruption. Tilt data acting as a proxy for flux are used in a case study of the May–August 1997 period of the eruption at Soufrière Hills Volcano, Montserrat. We justify the use of such a proxy by simple calibratory arguments. Three techniques of time series analysis are employed: spectral, spectrogram and wavelet methods. In addition to the well-known ~9-hour periodicity shown by these data, a previously unknown periodic flux variability is revealed by the wavelet analysis as a 3-day cycle of frequency modulation during June–July 1997, though the physical mechanism responsible is not clear. Such time series analysis has potential for other lava flux proxies at other types of volcanoes.

Analysis of time-related metabolic fluctuations induced by ethionine in the rat

The time-course of metabolic events following response to a model hepatotoxin ethionine (800 mg/kg) was investigated over a 7 day period in rats using high-resolution (1)H NMR spectroscopic analysis of urine and multivariate statistics. Complementary information was obtained by multivariate analysis of (1)H MAS NMR spectra of intact liver and by conventional histopathology and clinical chemistry of blood plasma. (1)H MAS NMR spectra of liver showed toxin-induced lipidosis 24 h postdose consistent with the steatosis observed by histopathology, while hypertaurinuria was suggestive of liver injury. Early biochemical changes in urine included elevation of guanidinoacetate, suggesting impaired methylation reactions. Urinary increases in 5-oxoproline and glycine suggested disruption of the gamma-glutamyl cycle. Signs of ATP depletion together with impairment of the energy metabolism were given from the decreased levels in tricarboxylic acid cycle intermediates, the appearance of ketone bodies in urine, the depletion of hepatic glucose and glycogen, and also hypoglycemia. The observed increase in nicotinuric acid in urine could be an indication of an increase in NAD catabolism, a possible consequence of ATP depletion. Effects on the gut microbiota were suggested by the observed urinary reductions in the microbial metabolites 3-/4-hydroxyphenyl propionic acid, dimethylamine, and tryptamine. At later stages of toxicity, there was evidence of kidney damage, as indicated by the tubular damage observed by histopathology, supported by increased urinary excretion of lactic acid, amino acids, and glucose. These studies have given new insights into mechanisms of ethionine-induced toxicity and show the value of multisystem level data integration in the understanding of experimental models of toxicity or disease.

Integrated cytokine and metabolic analysis of pathological responses to parasite exposure in rodents

Parasitic infections cause a myriad of responses in their mammalian hosts, on immune as well as on metabolic level. A multiplex panel of cytokines and metabolites derived from four parasite-rodent models, namely, Plasmodium berghei-mouse, Trypanosoma brucei brucei-mouse, Schistosoma mansoni-mouse, and Fasciola hepatica-rat were statistically coanalyzed. 1H NMR spectroscopy and multivariate statistical analysis were used to characterize the urine and plasma metabolite profiles in infected and noninfected animals. Each parasite generated a unique metabolic signature in the host. Plasma cytokine concentrations were obtained using the ‘Meso Scale Discovery’ multi cytokine assay platform. Multivariate data integration methods were subsequently used to elucidate the component of the metabolic signature which is associated with inflammation and to determine specific metabolic correlates with parasite-induced changes in plasma cytokine levels. For example, the relative levels of acetyl glycoproteins extracted from the plasma metabolite profile in the P. berghei-infected mice were statistically correlated with IFN-γ, whereas the same cytokine was anticorrelated with glucose levels. Both the metabolic and the cytokine data showed a similar spatial distribution in principal component analysis scores plots constructed for the combined murine data, with samples from all infected animals clustering according to the parasite species and whereby the protozoan infections (P. berghei and T. b. brucei) grouped separately from the helminth infection (S. mansoni). For S. mansoni, the main infection-responsive cytokines were IL-4 and IL-5, which covaried with lactate, choline, and D-3-hydroxybutyrate. This study demonstrates that the inherently differential immune response to single and multicellular parasites not only manifests in the cytokine expression, but also consequently imprints on the metabolic signature, and calls for in-depth analysis to further explore direct links between immune features and biochemical pathways.

Sensitivity analysis of an ocean carbon cycle model in the North Atlantic: an investigation of parameters affecting the air-sea CO2 flux, primary production and export of detritus

The sensitivity of the biological parameters in a nutrient-phytoplankton-zooplankton-detritus (NPZD) model in the calculation of the air-sea CO2 flux, primary production and detrital export is analysed. We explore the effect on these outputs of variation in the values of the twenty parameters that control ocean ecosystem growth in a 1-D formulation of the UK Met Office HadOCC NPZD model used in GCMs. We use and compare the results from one-at-a-time and all-at-a-time perturbations performed at three sites in the EuroSITES European Ocean Observatory Network: the Central Irminger Sea (60° N 40° W), the Porcupine Abyssal Plain (49° N 16° W) and the European Station for Time series in the Ocean Canary Islands (29° N 15° W). Reasonable changes to the values of key parameters are shown to have a large effect on the calculation of the air-sea CO2 flux, primary production, and export of biological detritus to the deep ocean. Changes in the values of key parameters have a greater effect in more productive regions than in less productive areas. The most sensitive parameters are generally found to be those controlling well-established ocean ecosystem parameterisations widely used in many NPZD-type models. The air-sea CO2 flux is most influenced by variation in the parameters that control phytoplankton growth, detrital sinking and carbonate production by phytoplankton (the rain ratio). Primary production is most sensitive to the parameters that define the shape of the photosynthesis-irradiance curve. Export production is most sensitive to the parameters that control the rate of detrital sinking and the remineralisation of detritus.

The relationship between diet quality and basal metabolic rate in endotherms: Insights from intraspecific analysis

In this article, we review intraspecific studies of basal metabolic rate (BMR) that address the correlation between diet quality and BMR. The food-habit hypothesis stands as one of the most striking and often-mentioned interspecific patterns to emerge from studies of endothermic energetics. Our main emphasis is the explicit empirical comparison of predictions derived from interspecific studies with data gathered from within-species studies in order to explore the mechanisms and functional significance of the putative adaptive responses encapsulated by the food-habit hypothesis. We suggest that, in addition to concentrating on the relationship among diet quality, internal morphology, and BMR, new studies should also attempt to unravel alternative mechanisms that shape the interaction between diet and BMR, such as enzymatic plasticity, and the use of energy-saving mechanisms, such as torpor. Another avenue for future study is the measurement of the effects of diet quality on other components of the energy budget, such as maximum thermogenic and sustainable metabolic rates. It is possible that the effects of diet quality operate on such components rather than directly on BMR, which might then push or pull along changes in these traits. Results from intraspecific studies suggest that the factors responsible for the association between diet and BMR at an ecological timescale might not be the same as those that promoted the evolution of this correlation. Further analyses should consider how much of a role the proximate and ultimate processes have played in the evolution of BMR.

Extensive impact of saturated fatty acids on metabolic and cardiovascular profile in rats with diet-induced obesity: A canonical analysis

Background: Although hypercaloric interventions are associated with nutritional, endocrine, metabolic, and cardiovascular disorders in obesity experiments, a rational distinction between the effects of excess adiposity and the individual roles of dietary macronutrients in relation to these disturbances has not previously been studied. This investigation analyzed the correlation between ingested macronutrients (including sucrose and saturated and unsaturated fatty acids) plus body adiposity and metabolic, hormonal, and cardiovascular effects in rats with diet-induced obesity. Methods: Normotensive Wistar-Kyoto rats were submitted to Control (CD; 3.2 Kcal/g) and Hypercaloric (HD; 4.6 Kcal/g) diets for 20 weeks followed by nutritional evaluation involving body weight and adiposity measurement. Metabolic and hormonal parameters included glycemia, insulin, insulin resistance, and leptin. Cardiovascular analysis included systolic blood pressure profile, echocardiography, morphometric study of myocardial morphology, and myosin heavy chain (MHC) protein expression. Canonical correlation analysis was used to evaluate the relationships between dietary macronutrients plus adiposity and metabolic, hormonal, and cardiovascular parameters. Results: Although final group body weights did not differ, HD presented higher adiposity than CD. Diet induced hyperglycemia while insulin and leptin levels remained unchanged. In a cardiovascular context, systolic blood pressure increased with time only in HD. Additionally, in vivo echocardiography revealed cardiac hypertrophy and improved systolic performance in HD compared to CD; and while cardiomyocyte size was unchanged by diet, nuclear volume and collagen interstitial fraction both increased in HD. Also HD exhibited higher relative β-MHC content and β/α-MHC ratio than their Control counterparts. Importantly, body adiposity was weakly associated with cardiovascular effects, as saturated fatty acid intake was directly associated with most cardiac remodeling measurements while unsaturated lipid consumption was inversely correlated with these effects. Conclusion: Hypercaloric diet was associated with glycemic metabolism and systolic blood pressure disorders and cardiac remodeling. These effects directly and inversely correlated with saturated and unsaturated lipid consumption, respectively. © 2013 Oliveira Junior et al.; licensee BioMed Central Ltd.

Impact of diabetes mellitus and metabolic control on bone healing around osseointegrated implants: Removal torque and histomorphometric analysis in rats

Objectives: To evaluate bone healing around dental implants with established osseointegration in experimental diabetes mellitus (DM) and insulin therapy by histomorphometric and removal torque analysis in a rat model. Materials and methods: A total of 80 male Wistar rats received a titanium implant in the tibiae proximal methaphysis. After a healing period of 60 days, the rats were divided into four groups of 20 animals each: a 2-month control group, sacrificed at time (group A), a diabetic group (group D), an insulin group (group I), and a 4-month control group (group C), subdivided half for removal torque and half for histomorphometric analysis. In the D and I groups the DM was induced by a single injection of 40 mg/kg body weight streptozotocin (STZ). Two days after DM induction, group I received subcutaneous doses of insulin twice a day, during 2 months. Groups C and D received only saline. Two months after induction of DM, the animals of groups D, C and I were sacrificed. The plasmatic levels of glucose (GPL) were monitored throughout the experiment. Evaluation of the percentages of bone-to-implant contact and bone area within the limits of the implant threads was done by histomorphometric and mechanical torque analysis. Data were analyzed by anova at significant level of 5%. Results: The GPL were within normal range for groups A, C and I and higher for group D. The means and standard deviations (SD) for histomorphometric bone area showed significant difference between group D (69.34 ± 5.00%) and groups C (78.20 ± 4.88%) and I (79.63 ± 4.97%). Related to bone-to-implant contact there were no significant difference between the groups D (60.81 + 6.83%), C (63.37 + 5.88%) and I (66.97 + 4.13%). The means and SD for removal torque showed that group D (12.91 ± 2.51 Ncm) was statistically lower than group I (17.10 ± 3.06 Ncm) and C (16.95 ± 5.39 Ncm). Conclusions: Diabetes mellitus impaired the bone healing around dental implants with established osseointegration because the results presented a lower percentage of bone area in group D in relation to groups C and I resulting in a lowest torque values for implant removal. Moreover, insulin therapy prevents the occurrence of bone abnormalities found in diabetic animals and osseointegration was not compromised. © 2012 John Wiley & Sons A/S.

Analysis of cardiopulmonary and metabolic variables measured during laboratory and sport-specific incremental tests for table tennis performance prediction

Purpose. - The purposes of this study were: i) to compare the physiological responses measured during a specific table tennis incremental test with the physiological responses measured during cycling, arm cranking, and treadmill running tests; and ii) to verify the accuracy of table tennis performance prediction based on the physiological responses from these tests.Methods. - Eleven national level male table tennis players participated in the study and undertook incremental tests using ergometers. Table tennis performance was defined as the ranking obtained during a simulated tournament between the participants.Results. - In general, peak values for physiological variables (e.g., (V) over dotO(2PEAK) and [La]PEAK) were significantly lower (P < 0.05) in the specific test (e.g., (V) over dotO(2PEAK) = 39.9 +/- 1.5 ml.kg(-1) per minute and [La]PEAK = 6.4 +/- 0.5 mmol.L-1) than during cycling (e.g., (V) over dotO(2PEAK) = 41.3 +/- 1.4 ml.kg(-1) per minute and [La]PEAK = 10.2 +/- 0.7 mmol.L-1) or running (e.g., (V) over dotO(2PEAK) = 43.9 +/- 1.5 ml.kg(-1) per minute and [La]PEAK = 10.0 +/- 0.7 mmol.L-1), but higher than during arm cranking (e.g., (V) over dotO(2PEAK) = 26.6 +/- 1.6 ml.kg(-1) per minute and [La]PEAK = 8.9 +/- 0.6 mmol.L-1). At respiratory compensation point intensity (RCP), only the variables measured on arm cranking were lower (P < 0.05) than on the other ergometers. Stepwise multiple regression analysis showed significant correlation between table tennis performance and lactate concentration ([La]) and also rate of perceived effort (RPE) at RCP during cycling (r = 0.89; P < 0.05).Conclusion. - In conclusion, the significant differences obtained between the specific and laboratory ergometers demonstrate the need to use a specific test to measure physiological parameters in table tennis and the physiological parameters measured, independent of the ergometer used, are unable to predict table tennis performance. (C) 2013 Elsevier Masson SAS. All rights reserved.

Metabolic profiling by ultra-performance liquid chromatography-mass spectrometry and parallel factor analysis for the determination of disease biomarkers in Eucalyptus

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Analysis of criteria for metabolic syndrome in a population-based study of Japanese-Brazilians

Objective: Criteria for metabolic syndrome (MS) differ particularly regarding the definition of central obesity and consequently, there could be differences in the assessment of cardiovascular risk. We estimated the prevalence of metabolic syndrome, compared the agreement of the World Health Organization (WHO) criteria with the standard and a modified National Cholesterol Education Program (NCEP) criterion and investigated whether additional factors were associated with the diagnosis of the syndrome in a Japanese descendant population.Methods: In this cross-sectional, population-based survey, 1166 Japanese-Brazilians (533 men, 633 women) aged 57.4 +/- 12.4 years with mean body mass index (BMI) and waist of 25.2 +/- 4.0 kg/m(2) and 84.5 +/- 10.6 cm, respectively, were included. McNemar and kappa statistics were used to assess the concordance between WHO criteria with the standard and a modified NCEP criteria (waist of 90 and 80 cm, for men and women, respectively). in logistic regression analysis, a number of metabolic variables and albumin-to-creatinine ratio were included to test independent associations with metabolic syndrome defined by the modified NCEP criteria.Results: According to WHO, 55.4% (95% Cl 52.5-58.2%) of the subjects had MS and to NCEP 47.4% (95% Cl 44.6-50.0%). WHO criterion detected 48.3% of central obese subjects while NCEP only 14.0%. Kappa statistics showed a good strength of agreement (k = 0.67, p < 0.01) between WHO and NCEP standard definitions of MS. Using the modified NCEP criterion for Asians, more subjects with metabolic syndrome were identified (58%) and agreement with WHO was improved (k = 0.72, p < 0.001). However, similar Framingham risk scores were attributed to the subsets of subjects classified by any of the three criteria. Areas under the receiver operating characteristic curves, obtained for the modified waist values to diagnose metabolic syndrome according to WHO, were > 0.80 and corresponded, respectively, to sensitivity and specificity of 63 and 83% for men and 77 and 72% for women. In final logistic regression model, age, male sex, BMI and homeostasis model assessment-insulin resistance but not with albumin-to-creatinine ratio (ACR) were independently associated with the syndrome.Conclusions: High prevalence of MS, independent of the criterion considered, was found in this Japanese-Brazilian population. The replacement of waist cutoff by those proposed by WHO for Asians lead to this diagnosis in a higher number of subjects with elevated cardiovascular risk. Our data did not support that ACR should be included in the classical definition of MS in Japanese descendants as previously suggested by WHO.

Analysis on the formation of a FRC by flux measurements and MHD simulations

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Analysis of metabolic pools in broilers chicks

This paper shows the possibility of obtaining new parameters for the mathematical modelling of data on stable isotopes in biological systems and its application in obtaining data on metabolic pools of blood plasma, blood serum, liver and muscle of broilers. This theory states that the modelling of turnover used for studies of isotopic incorporation when the metabolism has a single metabolic pool is feasible by the technique of setting an exponential. However, when the metabolism has more than one metabolic pool, it is necessary to apply the linearization technique, linear regression adjustment and evaluation of the assumptions of regression to obtain the kinetic parameters such as half-life (T1/2) and isotope exchange rate (k). The application of this technique on carbon-13 data from 100 one-day-old chicks, with the change of diet composed of grains of the photosynthetic cycle of plants from C4 to C3, in broilers has enabled the discovery that the liver, blood plasma and blood serum have a single metabolic pool; however, the pectoral muscle has two metabolic pools. For the liver, blood plasma and blood serum, the half-life values were found by the exponential fit being T1/2 = 1.4 days with the rate of exchange of k = 0.502, T1/2 = 2.4 days with k = 0.293 and T1/2 = 2.0 days with k = 0.348, respectively. For the pectoral muscle, after linearization, the half-life values were found for T1/2(1) = 1.7 and T1/2(2) = 3 days, with exchange rates of k1 = 0.405 and k2 = 0.235, representing approximately 66 and 34 %, respectively.