Hypobaric impact on clinical tolerance and 24-h patterns in iron metabolism markers and plasma proteins in men

Long-distance flights can cause a number of clinical problems due to mild hypoxia resulting from cabin pressurization. Using a chronobiological approach, the aim of this work was to assess the clinical tolerance and biological impact of daytime exposure to hypobaric hypoxia on markers of iron metabolism and plasma proteins. Fourteen healthy, male volunteers, ages 23 to 39 yrs, spent 8.5 h in a hypobaric chamber (from 07:45 to 16:15 h) simulating an altitude of 8000 ft. This was followed by another 8.5-h session 4 wks later simulating conditions at an altitude of 12,000 ft. Biological variables were assayed every 2 h over two 24-h spans (control and hypoxia spans, respectively) per simulated altitude. Whereas most of the subjects tolerated the 8000 ft exposure well, eight subjects (57%) presented clear clinical signs of hypoxic intolerance at 12,000 ft. The 24-h blood iron profile showed a biphasic pattern at both altitude simulations, with a significant (～40%) increase during hypoxia, followed by a (～25%) decrease during the first hours of recovery. The iron circadian rhythm showed a significant phase delay during the hypoxic exposure at 8000 ft vs. reference. Mean 24-h ferritin levels decreased at both altitudes, but mainly during the nighttime after the 12,000 ft exposure in accordance with Cosinor analysis. The transferrin and total plasma proteins 24-h profiles did not show significant change. Moreover, significant differences, mainly in iron, ferritin, and transferrin, were found at 12,000 ft according to the clinical tolerance to hypoxia, and significant correlations were found between the mid-range crossing times, i.e., here half-descent times (d-T(50)), for ferritin and total plasma proteins and the reported level of clinical discomfort under hypoxia. This study shows that an 8.5-h exposure to mild hypoxia is able to alter very quickly the 24-h pattern of iron and ferritin. These alterations seem to depend, at least in part, on the clinical tolerance to hypoxia and may help explain the interindividual differences observed in the tolerance to hypoxia.     

Synthesis and pharmacological evaluation of thieno[2,3-b]pyridine derivatives as novel c-Src inhibitors

Among the recently investigated targets for cancer therapy is the c-Src non-receptor tyrosine kinase. Indeed research around deregulated activity of this enzyme has proven its role in tumor progression, while the beneficial effects of c-Src inhibitors in several pathological models has also been demonstrated. We report here the preparation and pharmacological profile of a novel series of c-Src inhibitors that was elaborated around a 3-amino-thieno[2,3-b]pyridine discovered during an HTS campaign. c-Src enzyme inhibition and c-Src inhibition were investigated in a series of related compounds derived from the initial hit. Molecular modeling as well as X-ray studies on one active compound allowed us to hypothesize on ligand orientation and interactions within the ATP hydrophobic pocket. Design and synthesis of structural analogs then led to new ligands possessing quite efficient enzymatic and c-Src inhibition. The structure-activity elements disclosed in this study shed light on the role played by substituents on the thienopyridine ring as well as the impact of other aromatic moieties in the molecule when interacting with the enzyme.     

miR-141 and miR-200a act on ovarian tumorigenesis by controlling oxidative stress response

Although there is evidence that redox regulation has an essential role in malignancies, its impact on tumor prognosis remains unclear. Here we show crosstalk between oxidative stress and the miR-200 family of microRNAs that affects tumorigenesis and chemosensitivity. miR-141 and miR-200a target p38α and modulate the oxidative stress response. Enhanced expression of these microRNAs mimics p38α deficiency and increases tumor growth in mouse models, but it also improves the response to chemotherapeutic agents. High-grade human ovarian adenocarcinomas that accumulate miR-200a have low concentrations of p38α and an associated oxidative stress signature. The miR200a-dependent stress signature correlates with improved survival of patients in response to treatment. Therefore, the role of miR-200a in stress could be a predictive marker for clinical outcome in ovarian cancer. In addition, although oxidative stress promotes tumor growth, it also sensitizes tumors to treatment, which could account for the limited success of antioxidants in clinical trials.     

Contribution of interleukin-1 receptor accessory protein B to interleukin-1 actions in neuronal cells

Interleukin (IL)-1 is an important neuroimmunomodulator and a key mediator of inflammation during brain disorders. It acts on neuronal and glial cells via binding to the IL-1 type 1 receptor and IL-1 receptor accessory protein (IL-1RAcP). More recently, a neuronal-specific isoform of IL-1RAcP, named IL-1RAcPb, has been identified. Our aim was to determine the role of IL-1RAcPb in IL-1 actions in neuronal and glial cells, and to further explore the signaling mechanisms of IL-1 in neurons. We found that IL-1RAcPb deletion had no effect on IL-1α- and IL-1β-induced activation of the extracellular signal-regulated kinase 1/2 or IL-6 release in glial cultures, although IL-6 release in response to high IL-1α concentration (30 IU/ml) was significantly reduced. We identified the p38 kinase as a key signaling element in IL-1α- and IL-1β-induced IL-6 synthesis and release in neuronal cultures. IL-1RAcPb deletion had no effect on IL-1α- and IL-1β-induced IL-6 release in neurons, but significantly reduced IL-1α- but not IL-1β-induced p38 phosphorylation. Our data demonstrate that the p38 signaling pathway plays an important role in IL-1 actions in neurons, and that IL-1RAcP may regulate some, but not all, neuronal activities in response to IL-1α.     

The heritability of multiple male mating in a promiscuous mammal

The tendency of females to mate with multiple males is often explained by direct and indirect benefits that could outweigh the many potential costs of multiple mating. However, behaviour can only evolve in response to costs and benefits if there is sufficient genetic variation on which selection can act. We followed 108 mating chases of 85 North American red squirrels (Tamiasciurus hudsonicus) during 4 years, to measure each female's degree of multiple male mating (MMM), and used an animal model analysis of our multi-generational pedigree to provide what we believe is the first estimate of the heritability of MMM in the wild. Female red squirrels were highly polyandrous, mating with an average of 7.0 ± 0.2 males on their day of oestrus. Although we found evidence for moderate levels of additive genetic variation (CV(A) = 5.1), environmental variation was very high (CV(E) = 32.3), which resulted in a very low heritability estimate (h(2) < 0.01). So, while there is genetic variation in this trait, the large environmental variation suggests that any costs or benefits associated with differences among females in MMM are primarily owing to environmental and not genetic differences, which could constrain the evolutionary response to natural selection on this trait.     

Predictive integration of gene functional similarity and co-expression defines treatment response of endothelial progenitor cells

Background  

Endothelial progenitor cells (EPCs) have been implicated in different processes crucial to vasculature repair, which may offer the basis for new therapeutic strategies in cardiovascular disease. Despite advances facilitated by functional genomics, there is a lack of systems-level understanding of treatment response mechanisms of EPCs. In this research we aimed to characterize the EPCs response to adenosine (Ado), a cardioprotective factor, based on the systems-level integration of gene expression data and prior functional knowledge. Specifically, we set out to identify novel biosignatures of Ado-treatment response in EPCs.     

Large-scale structural analysis of the core promoter in mammalian and plant genomes

DNA encodes at least two independent levels of functional information. The first level is for encoding proteins and sequence targets for DNA-binding factors, while the second one is contained in the physical and structural properties of the DNA molecule itself. Although the physical and structural properties are ultimately determined by the nucleotide sequence itself, the cell exploits these properties in a way in which the sequence itself plays no role other than to support or facilitate certain spatial structures. In this work, we focus on these structural properties, comparing them between different organisms and assessing their ability to describe the core promoter. We prove the existence of distinct types of core promoters, based on a clustering of their structural profiles. These results indicate that the structural profiles are much conserved within plants (Arabidopsis and rice) and animals (human and mouse), but differ considerably between plants and animals. Furthermore, we demonstrate that these structural profiles can be an alternative way of describing the core promoter, in addition to more classical motif or IUPAC-based approaches. Using the structural profiles as discriminatory elements to separate promoter regions from non-promoter regions, reliable models can be built to identify core-promoter regions using a strictly computational approach.     

Hypoxic alterations of cortisol circadian rhythm in man after simulation of a long duration flight

Fatigue is often reported after long duration flights. Mild hypobaric hypoxia caused by pressurisation may be involved in this effect through disruption of circadian rhythms, independently of the number of time zones crossed. In this controlled crossover study, we assessed the effects of two levels of hypoxia equivalent to 8000 and 12,000 ft on the circadian rhythm of plasma cortisol, a marker of the circadian time structure. Sixteen healthy young male volunteers (23-39 years) were exposed in a hypobaric chamber for 8 h (08:00-16:00 h) to 8000 ft, followed 4 weeks later to 12,000 ft. Plasma cortisol was assayed during two 24-h cycles (control and hypoxic exposure) every 2h in all subjects. We found a significant change in the pattern of cortisol secretion during both hypoxic exposures, with an initial fall in cortisol followed by a transient rebound, whereas the phase and the 24-h mean level remained unchanged. The change in cortisol pattern followed the alterations in autonomic balance assessed by heart rate variability (HRV) spectral analysis. The normalised high frequencies and the low-to-high frequencies ratio showed a significant shift toward sympathetic dominance with some differences in time course for both altitudes studied. HRV analysis improved the interpretation of cortisol 24-h profiles. Our data, which strongly suggest that prolonged mild hypoxia alters the expression of cortisol circadian rhythm, should be taken into account to interpret secretory rhythm changes after transmeridian flights.