On the origins of sleep disordered breathing, cardiorespiratory and metabolic dysfunction: which came first, the chicken or the egg?

Sleep disordered breathing (SDB) is a complex, sex specific and highly heterogeneous group of respiratory disorders. Nevertheless, sleep fragmentation and repeated fluctuations of arterial blood gases for several hours per night are at the core of the problem; together, they impose significant stress to the organism with deleterious consequences on physical and mental health. SDB increases the risk of obesity, diabetes, depression and anxiety disorders; however, the same health issues are risk factors for SDB. So, which came first, the chicken or the egg? What causes the appearance of the first significant apnoeic events during sleep? These are important questions because although moderate to severe SDB affects ∼500 million adults globally, we still have a poor understanding of the origins of the disease, and the main treatments (and animal models) focus on the symptoms rather than the cause. Because obesity, metabolic dysfunction and stress-related neurological disorders generally appear progressively, we discuss how the development of these diseases can lead to specific anatomical and non-anatomical traits of SDB in males and females while considering the impacts of sex steroids. In light of the growing evidence indicating that the carotid bodies are important sensors of key metabolic and endocrine signals associated with stress and dysmetabolism, we propose that these organs play a key role in the process.

Shining light on fluoride detection: a comprehensive study exploring the potential of coumarin precursors as selective turn-on fluorescent chemosensors.

In this study, we report a fluoride chemosensor based on the use of a non-fluorescent pre-coumarin, compound 1. This compound undergoes selective fluoride-triggered formation of coumarin 2, with a concomitant turn-on fluorescence signal. Although compound 1 exists as a mixture of alkene isomers (2 : 1 in favor of the E isomer), only the minor Z-isomer undergoes cyclization. Nonetheless, comprehensive computational and experimental studies provide evidence that in situ isomerization of E-1 to Z-1, followed by fluoride-triggered phenolate evolution and intramolecular cyclization, facilitates the generation of coumarin 2 in high yield. Moreover, this system is an effective turn-on fluorescence sensor for fluoride anions, which displays outstanding selectivity (limited response to other commonly occurring analytes), sensitivity (lowest reported limits of detection for this sensor class), and practicality (works in solution and on paper to generate both fluorometric and colorimetric responses). Ongoing efforts are focused on expanding this paradigm to other pre-coumarin scaffolds, which also undergo analyte-specific coumarin formation accompanied by turn-on fluorescence.

Intermittent Hypoxia and Weight Loss: Insights into the Etiology of the Sleep Apnea Phenotype.

Sleep apnea (SA) is a major respiratory disorder with increased risk for hypertension and obesity; however, our understanding of the origins of this complex disorder remains limited. Because apneas lead to recurrent drops in O2 during sleep, intermittent hypoxia (IH) is the main animal model to explore the pathophysiology of SA. Here, we assessed the impacts of IH on metabolic function and related signals. Adult male rats were exposed to 1 week of moderate IH (FiO2 = 0.10-30 s, ten cycles/hour, 8 h/day). Using whole-body plethysmography, we measured respiratory variability and apnea index during sleep. Blood pressure and heart rate were measured by the tail-cuff method; blood samples were taken for multiplex assay. At rest, IH augmented arterial blood pressure, respiratory instability, but not apnea index. IH induced weight, fat, and fluid loss. IH also reduced food intake and plasma leptin, adrenocorticotropic hormone (ACTH), and testosterone levels but increased inflammatory cytokines. We conclude that IH does not replicate the metabolic clinical features of SA patient, thus raising our awareness of the limitations of the IH model. The fact that the risk for hypertension occurs before the appearance of apneas provides new insights into the progression of the disease.

Additive effects of orchiectomy and intermittent hypoxia on lung mechanics and inflammation in C57BL/6J male mice.

NEW FINDINGS: What is the central question of this study? Does endogenous testosterone modulate the consequences of intermittent hypoxia (IH) in the lungs of male mice? What is the main finding and its importance? Orchiectomized mice exposed to IH develop a pattern that is similar to emphysema or obstructive lung disease with elevated lung volumes, low pulmonary elastance during a methacholine challenge test and high counts of lymphocytes in bronchoalveolar lavages. Since low testosterone levels and other respiratory diseases are common in sleep apnoea, there is a clear clinical relevance to these results. ABSTRACT: We tested the hypothesis that low testosterone levels modulate the pulmonary responses to intermittent hypoxia (IH; used as a model of sleep apnoea (SA)) in male mice. We used intact (SHAM) or orchiectomized (ORX) mice exposed to IH for 14 days (12 h/day, 10 cycles/h, 6% oxygen) or to normoxia (Nx). We first measured ventilation and metabolic rates in freely behaving mice (whole-body plethysmography) and then respiratory mechanics in tracheotomized mice (flexiVent). We assessed the respiratory system resistance and elastance (Ers ), Newtonian resistance (resistance of the large airways), tissue damping and tissue elastance (H) under baseline conditions and during a methacholine challenge test. We also measured the quasi-static compliance and inspiratory capacity with partial pressure-volume loops. Finally, inflammatory cells were counted in the broncho-alveolar lavage (BAL) and we measured lung volume by water displacement. ORX-IH mice had higher tidal volume, inspiratory capacity and lung volume compared to the other groups, but showed signs of low efficiency of O2 exchange rate relative to minute ventilation. During the methacholine challenge, orchiectomy decreased the values of most mechanical parameters and IH reduced Ers and H leading to very low values in ORX-IH mice. Finally, the total number of cells and the number of lymphocytes in BAL were both increased by IH in ORX mice. Since reduced lung elasticity, low O2 extraction, increased lung volumes and inflammation are signs of emphysematous lung disease, we conclude that testosterone might prevent lung emphysema during IH exposures.

Double Rydberg anions, Rydberg radicals and micro-solvated cations with ammonium-water kernels.

Highly accurate ab initio electron-propagator and coupled-cluster methods are employed to predict the vertical electron attachment energies (VEAEs) of NH4+(H2O)n (n = 1-4) cationic clusters. The VEAEs decrease with increasing n and the corresponding Dyson orbitals are diffused over peripheral, non-hydrogen bonded protons. Clusters formed from NH4- double Rydberg anions (DRAs) and stabilized by hydrogen bonding or electrostatic interactions are studied through calculations on NH4-(H2O)n complexes and are compared with more stable H-(NH3)(H2O)n isomers. Structures that have cationic and anionic congeners have notable changes in geometry. For all values of n, the hydride-molecule complex H-(NH3)(H2O)n is always the most stable, with large vertical electron detachment energies (VEDEs). NH4-(H2O)n DRA isomers are predicted to have VEDEs that correspond to energetically well-separated peaks in an anion photoelectron spectrum. Less stable DRA isomers display proton donation from the tetrahedral NH4- fragment to water molecules and VEDEs close to those of previously discovered DRAs. The most stable DRA isomers feature tetrahedral NH4- fragments without H bridges to water molecules and VEDEs that increase with n. Dyson orbitals of NH4-(H2O)n DRAs occupy regions beyond the exterior non-bridging O-H and N-H bonds. Thus, the Rydberg electrons in the uncharged Rydberg radicals and DRAs are held near the outer protons of the water and ammonia molecules. Several bound low-lying excited states of the doublet Rydberg radicals have single electrons occupying delocalized Dyson orbitals of s-like, p-like, d-like, or f-like nodal patterns with the following Aufbau principle: 1s, 1p, 1d, 2s, 2p, 1f.

Metabolic responses to intermittent hypoxia are regulated by sex and estradiol in mice.

The roles of sex and sex-hormones on the metabolic consequences of intermittent hypoxia (IH, a reliable model of sleep apnea) are unknown. We used intact male or female mice and ovariectomized (OVX) females treated with vehicle (Veh) or estradiol (E2) and exposed to normoxia (Nx) or IH (6% O2, 10 cycles/h, 12 h/day, 2 wk). Mice were then fasted for 6 h, and we measured fasting glucose and insulin levels and performed insulin or glucose tolerance tests (ITT or GTT). We also assessed liver concentrations of glycogen, triglycerides (TGs), and expression levels of genes involved in aerobic or anaerobic metabolism. In males, IH lowered fasting levels of glucose and insulin, slightly improved glucose tolerance, but altered glucose tolerance in females. In OVX-Veh females, IH reduced fasting glucose and insulin levels and strongly impaired glucose tolerance. E2 supplementation reversed these effects and improved homeostasis model assessment of ß-cell function (HOMA-ß), a marker of pancreatic glucose-induced insulin released. IH decreased liver TG concentration in males and slightly increased glycogen in OVX-Veh females. Liver expression of glycolytic (Ldha) and mitochondrial (citrate synthase, Pdha1) genes was reduced by IH in males and in OVX-Veh females, but not in intact or OVX-E2 females. We conclude that 1) IH reduced fasting levels of glycemia in males and in ovariectomized females. 2) IH improves glucose tolerance only in males. 3) In females IH decreased glucose tolerance, this effect was amplified by ovariectomy, and reversed by E2 supplementation. 4) During IH exposures, E2 supplementation appears to improve pancreatic ß cells functions.NEW & NOTEWORTHY We assessed fasting glycemic control, and tolerance to insulin and glucose in male and female mice exposed to intermittent hypoxia. IH improves glucose tolerance in males but had opposite effects in females. This response was amplified following ovariectomy in females and prevented by estradiol supplementation. Metabolic consequences of IH differ between males and females and are regulated by estradiol in female mice.

Ionization Energies and Dyson Orbitals of the Iso-electronic SO2, O3, and S3 Molecules from Electron Propagator Calculations.

Adiabatic and vertical ionization energies corresponding to the X̃ A12, à B22, and B̃ A22 final states of SO2+, O3+, and S3+ have been calculated with a variety of electron-propagator and coupled-cluster methods. The BD-T1 electron-propagator method for vertical ionization energies and coupled-cluster adiabatic and zero-point corrections yield agreement with experiment to within 0.1 eV in all cases but one. The remaining discrepancies for the à B22 state of SO2+ indicate a need for higher levels of theory in determining cationic minima and their accompanying vibrational frequencies. Predictions for the still unobserved à B22 and B̃ A22 final states of S3+ are included. To account for increased biradical character in O3 and S3, highly correlated reference states are required to produce the correct order of final states. Electron correlation plays a subtle role in determining the contours of the Dyson orbitals obtained with BD-T1 and NR2 electron-propagator calculations.

Ronald C.D. Breslow (1931-2017): A career in review.

Reviewed herein are key research accomplishments of Professor Ronald Charles D. Breslow (1931-2017) throughout his more than 60 year research career. These accomplishments span a wide range of topics, most notably physical organic chemistry, medicinal chemistry, and bioorganic chemistry. These topics are reviewed, as are topics of molecular electronics and origin of chirality, which combine to make up the bulk of this review. Also reviewed briefly are Breslow's contributions to the broader chemistry profession, including his work for the American Chemical Society and his work promoting gender equity. Throughout the article, efforts are made to put Breslow's accomplishments in the context of other work being done at the time, as well as to include subsequent iterations and elaborations of the research.

Electron binding energies and Dyson orbitals of OnH2n+1 +,0,- clusters: Double Rydberg anions, Rydberg radicals, and micro-solvated hydronium cations.

Ab initio electron propagator methods are employed to predict the vertical electron attachment energies (VEAEs) of OH3 +(H2O)n clusters. The VEAEs decrease with increasing n, and the corresponding Dyson orbitals are diffused over exterior, non-hydrogen bonded protons. Clusters formed from OH3 - double Rydberg anions (DRAs) and stabilized by hydrogen bonding or electrostatic interactions between ions and polar molecules are studied through calculations on OH3 -(H2O)n complexes and are compared with more stable H-(H2O)n+1 isomers. Remarkable changes in the geometry of the anionic hydronium-water clusters with respect to their cationic counterparts occur. Rydberg electrons in the uncharged and anionic clusters are held near the exterior protons of the water network. For all values of n, the anion-water complex H-(H2O)n+1 is always the most stable, with large vertical electron detachment energies (VEDEs). OH3 -(H2O)n DRA isomers have well separated VEDEs and may be visible in anion photoelectron spectra. Corresponding Dyson orbitals occupy regions beyond the peripheral O-H bonds and differ significantly from those obtained for the VEAEs of the cations.

Complete-active-space extended Koopmans theorem method.

The complete-active-space (CAS) extended Koopmans theorem (EKT) method is defined as a special case of the EKT in which the reference state is a CAS configuration interaction (CI) expansion and the electron removal operator acts only on the active orbitals. With these restrictions, the EKT is equivalent to the CI procedure involving all hole-state configurations derived from the active space of the reference wavefunction and has properties analogous to those of the original Koopmans theorem. The equivalence is used to demonstrate in a transparent manner that the first ionization energy predicted by the EKT is in general not exact, i.e., not equal to the difference between the full CI energies of the neutral and the ion, but can approach the full CI result with arbitrary precision even within a finite basis set. The findings also reconcile various statements about the EKT found in the literature.

Metabolic Adaptation of Airway Smooth Muscle Cells to an SPHK2 Substrate Precedes Cytostasis.

Thickening of the airway smooth muscle is central to bronchial hyperreactivity. We have shown that the sphingosine analog (R)-2-amino-4-(4-heptyloxyphenyl)-2-methylbutanol (AAL-R) can reverse preestablished airway hyperreactivity in a chronic asthma model. Because sphingosine analogs can be metabolized by SPHK2 (sphingosine kinase 2), we investigated whether this enzyme was required for AAL-R to perturb mechanisms sustaining airway smooth muscle cell proliferation. We found that AAL-R pretreatment reduced the capacity of live airway smooth muscle cells to use oxygen for oxidative phosphorylation and increased lactate dehydrogenase activity. We also determined that SPHK2 was upregulated in airway smooth muscle cells bearing the proliferation marker Ki67 relative to their Ki67-negative counterpart. Comparing different stromal cell subsets of the lung, we found that high SPHK2 concentrations were associated with the ability of AAL-R to inhibit metabolic activity assessed by conversion of the tetrazolium dye MTT. Knockdown or pharmacological inhibition of SPHK2 reversed the effect of AAL-R on MTT conversion, indicating the essential role for this kinase in the metabolic perturbations induced by sphingosine analogs. Our results support the hypothesis that increased SPHK2 levels in proliferating airway smooth muscle cells could be exploited to counteract airway smooth muscle thickening with synthetic substrates.

Progesterone decreases apnoea and reduces oxidative stress induced by chronic intermittent hypoxia in ovariectomized female rats.

NEW FINDINGS: What is the central question of this study? Does progesterone reduce the effect of chronic intermittent hypoxia (CIH) on arterial blood pressure, respiratory control and oxidative stress in the central nervous system in ovariectomized rats? What is the main finding and its importance? Progesterone does not prevent the elevation of arterial blood pressure in rats exposed to CIH, but normalizes respiratory control, and reduces cerebral oxidative stress. This study draws focus to a potential role of progesterone and the consequences of sleep apnoea in menopausal women. ABSTRACT: We tested the hypothesis that progesterone (Prog) reduces the effect of chronic intermittent hypoxia (CIH) on arterial blood pressure, respiratory chemoreflexes and oxidative stress in the central nervous system. Ovariectomized female rats were implanted with osmotic pumps delivering vehicle (Veh) or Prog (4 mg kg-1  day-1 ). Two weeks following the surgery, rats were exposed to room air (Air) or CIH (7 days, 10% O2 , 10 cycles h-1 , 8 h day-1 ). We studied three groups: Veh-Air, Veh-CIH and Prog-CIH. After the CIH exposures, we measured the mean arterial pressure (MAP; tail cuff) and assessed the frequency of apnoeas at rest and ventilatory responses to hypoxia and hypercapnia (whole body plethysmography). The activities of the pro-oxidant enzyme NADPH oxidase (NOX) and antioxidant enzymes superoxide dismutase (SOD; in mitochondrial and cytosolic fractions) and glutathione peroxidase (GPx), as well as the concentration of malondialdehyde (MDA), a marker of lipid peroxidation, were measured in brain cortex and brainstem samples. CIH exposure increased the MAP, the frequency of apnoeas, and the respiratory frequency response to hypoxia and hypercapnia. Prog did not prevent the CIH-induced elevation in MAP, but it reduced the CIH-induced frequency of apnoeas and increased hypoxic and hypercapnic ventilatory responses. In the brain cortex, CIH increased NOX activity, and decreased the cytosolic and mitochondrial SOD activities. These effects were prevented by Prog. NOX activity was increased by CIH in the brainstem, and this was also blocked by Prog. The study draws focus to the links between ovarian hormones and the consequences of sleep apnoea in women.

Excess electrons bound to H2S trimer and tetramer clusters.

We have prepared the hydrogen sulfide trimer and tetramer anions, (H2S)3- and (H2S)4-, measured their anion photoelectron spectra, and applied high-level quantum chemical calculations to interpret the results. The sharp peaks at low electron binding energies in their photoelectron spectra and their diffuse Dyson orbitals are evidence for them both being dipole-bound anions. While the dipole moments of the neutral (H2S)3 and (H2S)4 clusters are small, the excess electron induces structural distortions that enhance the charge-dipolar attraction and facilitate the binding of diffuse electrons.

Aufbau Principle for Diffuse Electrons of Double-Shell Metal Ammonia Complexes: The Case of M(NH3)4@12NH3, M = Li, Be+, B2.

Positively charged or neutral metal ammonia complexes can form molecular species called solvated electron precursors (SEPs) that accommodate peripheral electrons in approximately hydrogenic diffuse orbitals. This work expands the notion of SEPs to metal ammonia complexes wherein a second coordination shell with 12 ammonia molecules is attached to M(NH3)4 (M = Li, Be+, B2+) SEPs via hydrogen bonding. In such complexes, denoted M(NH3)4@12NH3, the 12 outer ammonia molecules displace the peripheral electrons even further away from the first shell of ammonia molecules. We have benchmarked several density functional methods against CCSD(T) results and found that CAM-B3LYP provides the best M(NH3)4@12NH3 structures. The electron attachment energies of the closed-shell cores calculated with electron-propagator methods and the corresponding Dyson orbitals reveal the Aufbau principle for the ground and excited states of M(NH3)4@12NH3 to be 1s, 1p, 1d, 1f, 2s, 2p, 1g, 2d. These orbitals are diffuse and delocalized over the periphery of the second solvation shell.

Distinct dampening effects of progesterone on the activity of nucleus tractus solitarii neurons in rat pups.

NEW FINDINGS: What is the central question of the study? Progesterone is considered a respiratory stimulant drug, but its effect on medullary respiratory neurons are poorly documented. We investigated whether progesterone alters spontaneous activity of neurons in the nucleus of the solitary tract (NTS). What is the main finding and its importance? In NTS neurons, progesterone decreases the action potential firing frequency in response to current injections and the amplitude of excitatory postsynaptic currents. Based on the established neuroprotective effect of progesterone against excitotoxicity resulting from insults, this inhibitory effect is likely to reflect inhibition of ion fluxes. These results are important because they further our understanding of the mechanisms underlying the diversity of respiratory effects of progesterone. ABSTRACT: Progesterone is known to stimulate breathing, but its actions on the respiratory control system have received limited attention. We addressed this issue at the cellular level by testing the hypothesis that progesterone augments excitatory currents at the level of the nucleus tractus solitarii (NTS). Medullary slices from juvenile male rats (14-17 days of age) containing the commissural region of the NTS (NTScom) were incubated with progesterone (1 µm) or vehicle (0.004% DMSO) for 60 min. We performed whole-cell voltage-clamp recordings of spontaneous excitatory postsynaptic currents (EPSCs) in the NTScom and determined membrane properties by applying depolarizing current steps. In comparison to vehicle-treated cells, progesterone exposure attenuates the firing frequency response to current injection and reduces the EPSC amplitude without modifying the EPSC frequency or the basal membrane properties. These data do not support our hypothesis, because they indicate that incubation with progesterone attenuates intrinsic action potential generation and inhibits excitatory synaptic inputs in the NTS. Given that these results are more in line with the protective effect of progesterone against excitotoxicity resulting from various insults, we propose that progesterone acts via inhibition of ionic flux.

Transition-metal solvated-electron precursors: diffuse and 3d electrons in V(NH3).

Ground and excited electronic states of V(NH3)0,±6 complexes, investigated with ab initio electronic structure theory, consist of a V(NH3)62+ core with up to three electrons distributed over its periphery. This result extends the concept of super-atomic, solvated-electron precursors from alkali and alkaline-earth complexes to a transition metal. In the approximately octahedral ground state of V(NH3)6, three unpaired electrons occupy 3dxz, 3dyz and 3dxy (t2g) orbitals of vanadium and two electrons occupy a diffuse 1s outer orbital. The lowest excitations involve promotion of diffuse 1s electrons to 1p or 1d diffuse orbitals, followed by a 3d (t2g → eg) transition. V(NH3)6+ is produced by removing a diffuse 1s electron, whereas the additional electron in V(NH3)6- populates a 1p diffuse orbital. The adiabatic ionization energy and electron affinity of V(NH3)6 equal 3.50 and 0.48 eV, respectively.

Dyson Orbitals and Double Rydberg Anions: Methylated, Annulated, and Paramagnetic.

A double Rydberg anion (DRA) consists of a saturated, closed-shell, molecular cation and two electrons that occupy diffuse orbitals. Techniques of ab initio electron propagator theory (EPT) predict the existence and spectra of three new classes of DRAs. The first, with the formula NH4-n(CH3)n-, has vertical electron detachment energies (VEDEs) that vary between 0.24 and 0.39 eV and corresponding Dyson orbitals that accumulate near the periphery of N-H bonds. An internal hydrogen bond that forms a ring with five members occurs in the second class. In paramagnetic DRA isomers, electrons are assigned to two, diffuse, triplet-coupled spin-orbitals that localize outside the N-H bonds of a cationic, tetrahedral center or outside bonds on a nearby amide or methyl group. Effects of delocalization, dispersion, and radial correlation between diffuse electrons on VEDEs are described in terms of Dyson orbitals and their pole strengths. These concepts of EPT connect ground-state and spectral properties to each other and provide a rigorous, systematic, and insightful approach to predicting and characterizing novel patterns of chemical bonding and molecular electronic structure.

Respiratory regulation by steroids in newborn rats: a sex-specific balance between allopregnanolone and progesterone receptors.

NEW FINDINGS: What is the central question of this study? What are the contributions of allopregnanolone, the neuroactive metabolite of progesterone, and nuclear (nPR) and membrane (mPR) progesterone receptors to the respiratory effect of progesterone in newborn rats? What is the main finding and its importance? Acute progesterone injection increases the apnoea frequency, whereas finasteride (which blocks the conversion of progesterone to allopregnanolone) reduces apnoea frequency. An nPR agonist decreases apnoea frequency in males and an mPR agonist decreases apnoea frequency in males and females. Chronic injection of progesterone decreases the frequency of apnoea more efficiently in males than in females. We tested the hypothesis that the effects of progesterone on apnoea frequency in newborn rats are the result of a balance between its neuroactive metabolite, allopregnanolone (GABAA receptor modulator), and progesterone receptors. We used male and female rats between 10 and 12 days of age and recorded respiratory and metabolic parameters (whole-body plethysmography), and assessed the frequency and duration of apnoeas in normoxia. We tested the effects of a single injection of progesterone (4 mg kg-1 , i.p.), finasteride (10 mg kg-1 , i.p.; a 5α-reductase antagonist, which blocks the conversion of progesterone to allopregnanolone), finasteride plus progesterone, or agonists of the nuclear or membrane progesterone receptors (R5020 or Org-od-02-0, 4 mg kg-1 ). To test the hypothesis that chronic exposure to progesterone reduces the frequency of apnoeas, we used male and female rats treated daily with progesterone between postnatal days 3 and 12. The acute injection of progesterone reduced minute ventilation and metabolic rate and increased the frequency of apnoeas. Finasteride decreased the frequency of apnoeas, and finasteride plus progesterone did not increase apnoea frequency but decreased minute ventilation in female rats. Although R5020 decreased apnoea frequency only in males, Org-od-02-0 decreased apnoea frequency in males and females and decreased respiratory frequency in females. Chronic progesterone treatment reduced apnoea frequency more efficiently in males than in females, but in females (not in males) an acute injection of caffeine (the gold standard for the treatment of apnoea in preterm neonates) further reduced apnoea frequency. Apnoea frequency in newborn rats is, in part, determined by a sex-specific balance between allopregnanolone, GABAA receptors and progesterone receptors.

Molecules mimicking atoms: monomers and dimers of alkali metal solvated electron precursors.

Tetra-amino lithium and sodium complexes M(NH3) (M = Li, Na) have one or two electrons that occupy diffuse orbitals distributed chiefly outside the M(NH3) core. The lowest-energy 1s, 1p, and 1d orbitals follow Aufbau principles found earlier for beryllium tetra-ammonia complexes. Two ground state M(NH3)4 complexes can bind covalently by coupling their 1s1 electrons into a σ-type molecular orbital. The lowest excited states of the [M(NH3)4]2 species are obtained by promoting one or two electrons from this σ to other bonding or anti-bonding σ and π-type molecular orbitals. The electronic structure of solvated electron precursors provides insights into chemical bonding between super-atomic species that are present in concentrated alkali-metal-ammonia solutions.

Role of Estradiol Receptor Beta (ERß) on Arterial Pressure, Respiratory Chemoreflex and Mitochondrial Function in Young and Aged Female Mice.

We tested the hypothesis that ERß is involved in respiratory control in female mice. We used young adult (5-6 months-old) and aged (17-18 months-old) ERßKO or wild-type controls (WT) female mice to assess arterial blood pressure (via a tail-cuff sensor) and indices of respiratory pattern (sighs and apneas - recorded by whole body plethysmography at rest). We also measured respiratory parameters at rest and in response to brief (<10 min) exposure to hypoxia (12% O2) or hypercapnia (5% CO2). Because ERß is localized in mitochondria, and because estradiol and ERß agonist increase mitochondrial O2 consumption, we assessed the mitochondrial respiration (with a high-resolution oxygraph system) and the in vitro activity of the complex I of the electron transfer chain in samples of brain cortex in aged wild-type and ERßKO female mice. Compared to young WT mice, young ERßKO mice had elevated arterial blood pressure, but similar ventilatory responses to hypoxia and hypercapnia. In old ERßKO female mice compared to old WT mice, the arterial blood pressure was lower, the frequency of sighs was higher and the frequency of apneas was lower, and the hypoxic and hypercapnic ventilatory responses were reduced. In old ERßKO mice mitochondrial respiration and complex I activities in the brain cortex were lower than in WT mice. We conclude that ERß has age-specific effects on vascular and respiratory functions in female mice.