Stable and unstable cadherin dimers: mechanisms of formation and roles in cell adhesion

Numerous attempts to elucidate the strength of cadherin dimerization that mediates intercellular adhesion have produced controversial and inconclusive results. To clarify this issue, we compared E-cadherin dimerization on the surface of living cells with how the same process unfolds on agarose beads. In both cases, dimerization was monitored by the same site-specific cross-linking assay, greatly simplifying data interpretation. We showed that on the agarose surface under physiological conditions, E-cadherin produced a weak dimer that immediately dissociated after the depletion of calcium ions. However, either at pH 5 or in the presence of cadmium ions, E-cadherin produced a strong dimer that was unable to dissociate upon calcium depletion. Both types of dimers were W156-dependent. Remarkably, only the strong dimer was found on the surface of living cells. We also showed that the intracellular cadherin region, the clustering of which through catenins had been proposed as stabilizer of weak intercadherin interactions, was not needed, in fact, for cadherin junction assembly. Taken together, our data present convincing evidence that cadherin adhesion is based on high-affinity cadherin-cadherin interactions.     

The effect of acute moderate hypoxia on accumulated oxygen deficit during intermittent exercise in nonacclimatized men

The objective of this study was to determine the effect of acute moderate hypoxia and rest duration on performance and on the accumulated oxygen deficit (AOD) in high-intensity intermittent efforts. After preliminary tests, 2 groups of nonacclimatized men (resident at 690 m above sea level) carried out 3 randomized protocols of effort (EXP1, EXP2, and EXP5) on 3 different days. These tests were performed at acute moderate altitude (2,320 m) by the hypoxia group (H) and in normoxia by the normoxia group (N). During EXP1 the subjects ran a maximum of five 400-m sprints (90% intensity) on a treadmill, with a pause between efforts of 1 minute. In EXP2 and EXP5 the same protocol was repeated, increasing the rest period between sprints to 2 and 5 minutes, respectively. Lactate accumulation and exhaled gases were measured during the tests. Accumulated oxygen deficit was calculated for each sprint. The total AOD (SigmaAOD) for each type of protocol was determined to be the sum of the corresponding accumulated deficits. The AODs were influenced by the length of rest period (p < 0.05) but not by H. The increase in recovery time between sprints increased the SigmaAOD (7,843 +/- 4,435 vs. 7,137 +/- 2,117 ml; 11,013 +/- 4,616 vs. 9,931 +/- 2,731 ml; 12,611 +/- 4,594 vs. 12,907 +/- 3,085 ml for H and N in EXP1, EXP2, and EXP5, respectively). The AOD increased in value when the same sprint was compared from EXP1 to EXP5 (p < 0.05). The results obtained show that exposure to acute moderate altitude does not affect the anaerobic pathway contribution in intermittent high-intensity exercises. Performance during this type of repeated effort is not altered during acute exposure to moderate altitude, which should be taken into account when an acclimatizing period is not possible.     

Analysis of the spatio-temporal parameters of gaits in Dasypus novemcinctus (Xenarthra: Dasypodidae)

Armadillos comprise a particular group of armoured animals whose functional morphology of locomotion remains unclear. For the first time, the kinematic patterns of Dasypus novemcinctus are analysed. Eight specimens of nine-banded armadillos were studied at a research institute in São Paulo State, Brazil. The individuals were induced to cross a horizontal corridor and each gait performed during the time each of them was kept inside this structure was recorded to a detailed analysis posteriorly performed in a computer program. Four parameters regarding speed range were considered: stride frequency (Hz) (1/stride period), stride length (m), speed (ms⁻¹) and duty factor (%). A total of 89 strides have been analysed among symmetrical (60.6%) and asymmetrical gaits (39.4%), and six footfall patterns were here reported as follows: lateral sequences (symmetrical), transverse gallop, canter, bound, half-bound and crutch walk (asymmetrical). This kind of analysis implements our knowledge on the locomotory aspects of these animals, hence contributing to the improvement of our knowledge on this still poorly known group.     

Browning reduces the availability—but not the transfer—of essential fatty acids in temperate lakes

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Environmental heterogeneity and dispersal limitation explain different aspects of β‐diversity in Neotropical fish assemblages

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Metformin inhibits mitochondrial adaptations to aerobic exercise training in older adults

Metformin and exercise independently improve insulin sensitivity and decrease the risk of diabetes. Metformin was also recently proposed as a potential therapy to slow aging. However, recent evidence indicates that adding metformin to exercise antagonizes the exercise‐induced improvement in insulin sensitivity and cardiorespiratory fitness. The purpose of this study was to test the hypothesis that metformin diminishes the improvement in insulin sensitivity and cardiorespiratory fitness after aerobic exercise training (AET) by inhibiting skeletal muscle mitochondrial respiration and protein synthesis in older adults (62 ± 1 years). In a double‐blinded fashion, participants were randomized to placebo (n = 26) or metformin (n = 27) treatment during 12 weeks of AET. Independent of treatment, AET decreased fat mass, HbA1c, fasting plasma insulin, 24‐hr ambulant mean glucose, and glycemic variability. However, metformin attenuated the increase in whole‐body insulin sensitivity and VO₂max after AET. In the metformin group, there was no overall change in whole‐body insulin sensitivity after AET due to positive and negative responders. Metformin also abrogated the exercise‐mediated increase in skeletal muscle mitochondrial respiration. The change in whole‐body insulin sensitivity was correlated to the change in mitochondrial respiration. Mitochondrial protein synthesis rates assessed during AET were not different between treatments. The influence of metformin on AET‐induced improvements in physiological function was highly variable and associated with the effect of metformin on the mitochondria. These data suggest that prior to prescribing metformin to slow aging, additional studies are needed to understand the mechanisms that elicit positive and negative responses to metformin with and without exercise.     

Liposcale: a novel advanced lipoprotein test based on 2D diffusion-ordered 1H NMR spectroscopy

Determination of lipoprotein particle size and number using advanced lipoprotein tests (ALTs) is of particular importance to improve cardiovascular risk prediction. Here we present the Liposcale test, a novel ALT based on 2D diffusion-ordered ¹H NMR spectroscopy. Our method uses diffusion coefficients to provide a direct measure of the mean particle sizes and numbers. Using 177 plasma samples from healthy individuals and the concentration of ApoB and ApoA from isolated lipoprotein fractions, our test showed a stronger correlation between the NMR-derived lipoprotein particle numbers and apolipoprotein concentrations than the LipoProfile^® test commercialized by Liposcience. We also converted LDL particle numbers to ApoB equivalents (milligrams per deciliter) and our test yielded similar values of LDL-ApoB to the LipoProfile^® test (absolute mean bias of 8.5 and 7.4 mg/dl, respectively). In addition, our HDL particle number values were more concordant with the calibrated values determined recently using ion mobility. Finally, principal component analysis distinguished type 2 diabetic patients with and without atherogenic dyslipidemia (AD) on a second cohort of 307 subjects characterized using the Liposcale test (area under the curve = 0.88) and showed concordant relationships between variables explaining AD. Altogether, our method provides reproducible and reliable characterization of lipoprotein particles and it is applicable to pathological states such as AD.     

Widespread Signals of Convergent Adaptation to High Altitude in Asia and America

Living at high altitude is one of the most difficult challenges that humans had to cope with during their evolution. Whereas several genomic studies have revealed some of the genetic bases of adaptations in Tibetan, Andean, and Ethiopian populations, relatively little evidence of convergent evolution to altitude in different continents has accumulated. This lack of evidence can be due to truly different evolutionary responses, but it can also be due to the low power of former studies that have mainly focused on populations from a single geographical region or performed separate analyses on multiple pairs of populations to avoid problems linked to shared histories between some populations. We introduce here a hierarchical Bayesian method to detect local adaptation that can deal with complex demographic histories. Our method can identify selection occurring at different scales, as well as convergent adaptation in different regions. We apply our approach to the analysis of a large SNP data set from low- and high-altitude human populations from America and Asia. The simultaneous analysis of these two geographic areas allows us to identify several candidate genome regions for altitudinal selection, and we show that convergent evolution among continents has been quite common. In addition to identifying several genes and biological processes involved in high-altitude adaptation, we identify two specific biological pathways that could have evolved in both continents to counter toxic effects induced by hypoxia.