Sex differences in murine cardiac pathophysiology with hyperoxia exposure

Hyperoxia (>90% oxygen) is commonly implemented in mechanically ventilated patients. Reports suggest that hyperoxia is directly associated with in-hospital mortality in ventilated patients. Certain studies also show that mortality in women undergoing mechanical ventilation is significantly higher than that in men. Additionally, females are predisposed to certain cardiac electrophysiological risks, including QTc prolongation. In this study, we assessed the impact of hyperoxia in male and female mice (C57BL/6J) at age 8–10 weeks. On completion of either hyperoxia or normoxia exposures, physical, hemodynamic, biochemical, functional, electrophysiological, and molecular assessments were conducted. Hyperoxia-exposed mice lost a significant amount of body mass, compared with normoxia controls, in both sexes. However, while both genders developed brady-arrhythmia after hyperoxia exposure, female mice exhibited significantly reduced heart rates compared with males, with significantly elevated RR intervals. Additionally, 50% mortality was observed in females, whereas no mortality was reported in males. Furthermore, unlike in male mice, we observed no hypertrophy upon hyperoxia exposure in female mice. We reported that both hyperoxia-treated male and female mice exhibit significant hyperdynamic left ventricular ejection fraction, which is marked by % ejection fraction > 70 compared with the normoxia controls. We also noted significant reductions in stroke volume and cardiac output in both mice with hyperoxia. Surface ECG also demonstrated that hyperoxia exposure significantly augments RR, PR, QRS, QTc, and JT intervals in both sexes. Molecular analysis of left ventricular tissue demonstrated dysregulation of potassium ion channels in hyperoxia-treated males and females. In summary, we determined that sex differences are present with 72 hr hyperoxia exposure.     

Potential roles of nuclear receptors in mediating neurodevelopmental toxicity of known endocrine‐disrupting chemicals in ascidian embryos

Endocrine Disrupting Chemicals (EDCs) are molecules able to interfere with the vertebrate hormonal system in different ways, a major one being the modification of the activity of nuclear receptors (NRs). Several NRs are expressed in the vertebrate brain during embryonic development and these NRs are suspected to be responsible for the neurodevelopmental defects induced by exposure to EDCs in fishes or amphibians and to participate in several neurodevelopmental disorders observed in humans. Known EDCs exert toxicity not only on vertebrate forms of marine life but also on marine invertebrates. However, because hormonal systems of invertebrates are poorly understood, it is not clear whether the teratogenic effects of known EDCs are because of endocrine disruption. The most conserved actors of endocrine systems are the NRs which are present in all metazoan genomes but their functions in invertebrate organisms are still insufficiently characterized. EDCs like bisphenol A have recently been shown to affect neurodevelopment in marine invertebrate chordates called ascidians. Because such phenotypes can be mediated by NRs expressed in the ascidian embryo, we review all the information available about NRs expression during ascidian embryogenesis and discuss their possible involvement in the neurodevelopmental phenotypes induced by EDCs.     

Malleable skin coloration in cephalopods: selective reflectance, transmission and absorbance of light by chromatophores and iridophores

Nature's best-known example of colorful, changeable, and diverse skin patterning is found in cephalopods. Color and pattern changes in squid skin are mediated by the action of thousands of pigmented chromatophore organs in combination with subjacent light-reflecting iridophore cells. Chromatophores (brown, red, yellow pigment) are innervated directly by the brain and can quickly expand and retract over underlying iridophore cells (red, orange, yellow, green, blue iridescence). Here, we present the first spectral account of the colors that are produced by the interaction between chromatophores and iridophores in squid (Loligo pealeii). Using a spectrometer, we have acquired highly focused reflectance measurements of chromatophores, iridophores, and the quality and quantity of light reflected when both interact. Results indicate that the light reflected from iridophores can be filtered by the chromatophores, enhancing their appearance. We have also measured polarization aspects of iridophores and chromatophores and show that, whereas structurally reflecting iridophores polarize light at certain angles, pigmentary chromatophores do not. We have further measured the reflectance change that iridophores undergo during physiological activity, from "off" to various degrees of "on", revealing specifically the way that colors shift from the longer end (infra-red and red) to the shorter (blue) end of the spectrum. By demonstrating that three color classes of pigments, combined with a single type of reflective cell, produce colors that envelop the whole of the visible spectrum, this study provides an insight into the optical mechanisms employed by the elaborate skin of cephalopods to give the extreme diversity that enables their dynamic camouflage and signaling.     

Functional assignment of MAPK phosphatase domains

Mitogen-activated protein kinase (MAPK) pathways are well conserved in most organisms, from yeast to humans. The principal components of these pathways are MAP kinases whose activity is regulated by phosphorylation, implicating various MAPK protein effectors-in particular, protein phosphatases that inactivate MAPKs by dephosphorylation. The molecular basis of binding specificity of such regulatory phosphatases to MAPKs is poorly understood. To try to pinpoint potential functional regions within the sequences and to help identify new family members, we have applied a multimotif pattern-recognition approach to characterize two MAPK phosphatase subfamilies (tyrosine-specific and dual specificity) that are crucial in the regulation of MAPKs. We built "fingerprints" for these two subfamilies that are unique to, and highly discriminatory for, each group of proteins. The fingerprints were used in a genome-wide screen, identifying more than 80 MAPK phosphatase domains, several of which were in partial sequences or unclassified proteins. We confirmed experimentally that one predicted MAPK phosphatase orthologue in Xenopus binds to ERK1/2, suggesting a role in MAPK signaling and thus supporting our functional predictions. Further analysis, mapping the fingerprints on the three-dimensional structure of MAPK phosphatases, revealed that some of the fingerprint motifs reside in the N-terminal noncatalytic regions coinciding with reported MAPK binding sites, while others lie within the catalytic phosphatase domain. These results also suggest the presence of putative allosteric sites in the catalytic region for modulation of protein-protein interactions, and provide a framework for future experimental validation.     

Nicotinic Acid Adenine Dinucleotide Phosphate (NAADP) and Endolysosomal Two-pore Channels Modulate Membrane Excitability and Stimulus-Secretion Coupling in Mouse Pancreatic β Cells

Pancreatic β cells are electrically excitable and respond to elevated glucose concentrations with bursts of Ca²⁺ action potentials due to the activation of voltage-dependent Ca²⁺ channels (VDCCs), which leads to the exocytosis of insulin granules. We have examined the possible role of nicotinic acid adenine dinucleotide phosphate (NAADP)-mediated Ca²⁺ release from intracellular stores during stimulus-secretion coupling in primary mouse pancreatic β cells. NAADP-regulated Ca²⁺ release channels, likely two-pore channels (TPCs), have recently been shown to be a major mechanism for mobilizing Ca²⁺ from the endolysosomal system, resulting in localized Ca²⁺ signals. We show here that NAADP-mediated Ca²⁺ release from endolysosomal Ca²⁺ stores activates inward membrane currents and depolarizes the β cell to the threshold for VDCC activation and thereby contributes to glucose-evoked depolarization of the membrane potential during stimulus-response coupling. Selective pharmacological inhibition of NAADP-evoked Ca²⁺ release or genetic ablation of endolysosomal TPC1 or TPC2 channels attenuates glucose- and sulfonylurea-induced membrane currents, depolarization, cytoplasmic Ca²⁺ signals, and insulin secretion. Our findings implicate NAADP-evoked Ca²⁺ release from acidic Ca²⁺ storage organelles in stimulus-secretion coupling in β cells.