Azaphosphinines and their derivatives.

Six-membered heterocycles containing one phosphorus and one nitrogen atom, known as azaphosphinines, have existed in the shadows of their single heteroatom-containing analogues for almost 150 years. Despite this, recent chemistry has seen a rapid increase in publications concerning this uncommon scaffold. Azaphosphinines exist in one of six isomers-there are three possible orientations of the pnictogen atoms and in each of these, the phosphorus is in one of two valences (PIIIvs. PV). This review aims to outline and inform on the synthesis and applications of all six isomers. PV-oxo azaphosphinines are of particular interest to this review as many of the discussed heterocycles either form as the pentavalent species directly or oxidize to this over time. In very recent years the published applications of azaphosphinines have blossomed into subjects spanning several fields of chemistry such as asymmetric catalysis, supramolecular association, cellular imaging, and medicinal chemistry.

Impact of Internal Charge Transfer on the Photophysical Properties of Pyridine-Fused Phosphorus-Nitrogen Heterocycles.

The phosphaquinolinone scaffold has been previously studied as a modular core for a variety of fluorescent species where use of substituent effects has focused on increasing or decreasing electron density in the core rings. We now report the synthesis and analysis of several pyridine-containing phosphaquinolinone species exhibiting notable linear conjugation from the aryl-substituent to electron-withdrawing pyridyl nitrogen. Varying the nature of the aryl substituent from electron-withdrawing to electron-donating leads to the generation of an internal charge-transfer (ICT) band in the absorbance spectrum, which becomes the dominant absorbance in terms of intensity in the most electron-rich -NMe2 example. This heterocycle exhibits improved photophysical properties compared to others in the set including high quantum yield and considerably red-shifted emission. The enhanced ICT can be observed in the X-ray data where a rare example of molecule co-planarity is observed. Computational data show increased localization of negative charge on the pyridyl nitrogen as the electron-donating character of the aryl-substituent increases.

2-λ5-Phosphaquinolin-2-ones as Non-cytotoxic, Targetable, and pH-Stable Fluorophores.

Several phosphaquinolinone derivatives have been synthesized and characterized to explore their usefulness in the realm of cell imaging. Solution-state photophysical properties in both aqueous and organic solutions were collected for these derivatives. Additionally, CCK-8 cell viability assays and fluorescent imaging in HeLa cells incubated with the new heterocyclic derivatives show evidence of favorable cell permeability, cell viability, and moderate intracellular localization when appended with the well-known morpholine targeting motif.

Controlling Tautomerization in Pyridine-Fused Phosphorus-Nitrogen Heterocycles.

Inclusion of a second nitrogen atom in the aromatic core of phosphorus-nitrogen (PN) heterocycles results in unexpected tautomerization to a nonaromatic form. This tautomerization, initially observed in the solid state through X-ray crystallography, is also explained by computational analysis. We prepared an electron deficient analogue (2 e) with a fluorine on the pyridine ring and showed that the weakly basic pyridine resisted tautomerization, providing key insights to why the transformation occurs. To study the difference in solution vs. solid-state heterocycles, alkylated analogues that lock in the quinoidal tautomer were synthesized and their different 1 H NMR and UV/Vis spectra studied. Ultimately, we determined that all heterocycles are the aromatic tautomer in solution and all but 2 e switch to the quinoidal tautomer in the solid state. Better understanding of this transformation and under what circumstances it occurs suggest future use in a switchable on/off hydrogen-bond-directed receptor that can be tuned for complementary hydrogen bonding.

Hydrous mantle transition zone indicated by ringwoodite included within diamond.

The ultimate origin of water in the Earth's hydrosphere is in the deep Earth--the mantle. Theory and experiments have shown that although the water storage capacity of olivine-dominated shallow mantle is limited, the Earth's transition zone, at depths between 410 and 660 kilometres, could be a major repository for water, owing to the ability of the higher-pressure polymorphs of olivine--wadsleyite and ringwoodite--to host enough water to comprise up to around 2.5 per cent of their weight. A hydrous transition zone may have a key role in terrestrial magmatism and plate tectonics, yet despite experimental demonstration of the water-bearing capacity of these phases, geophysical probes such as electrical conductivity have provided conflicting results, and the issue of whether the transition zone contains abundant water remains highly controversial. Here we report X-ray diffraction, Raman and infrared spectroscopic data that provide, to our knowledge, the first evidence for the terrestrial occurrence of any higher-pressure polymorph of olivine: we find ringwoodite included in a diamond from Juína, Brazil. The water-rich nature of this inclusion, indicated by infrared absorption, along with the preservation of the ringwoodite, is direct evidence that, at least locally, the transition zone is hydrous, to about 1 weight per cent. The finding also indicates that some kimberlites must have their primary sources in this deep mantle region.

Inter-observer reliability of preoperative cardiopulmonary exercise test interpretation: a cross-sectional study.

BACKGROUND: Despite the increasing importance of cardiopulmonary exercise testing (CPET) for preoperative risk assessment, the reliability of CPET interpretation is unclear. We aimed to assess inter-observer reliability of preoperative CPET. METHODS: We conducted a prospective, multi-centre, observational study of preoperative CPET interpretation. Participants were professionals with previous experience or training in CPET, assessed by a standardized questionnaire. Each participant interpreted 100 tests using standardized software. The CPET variables of interest were oxygen consumption at the anaerobic threshold (AT) and peak oxygen consumption (VO2 peak). Inter-observer reliability was measured using intra-class correlation coefficient (ICC) with a random effects model. Results are presented as ICC with 95% confidence interval, where ICC of 1 represents perfect agreement and ICC of 0 represents no agreement. RESULTS: Participants included 8/28 (28.6%) clinical physiologists, 10 (35.7%) junior doctors, and 10 (35.7%) consultant doctors. The median previous experience was 140 (inter-quartile range 55-700) CPETs. After excluding the first 10 tests (acclimatization) for each participant and missing data, the primary analysis of AT and VO2 peak included 2125 and 2414 tests, respectively. Inter-observer agreement for numerical values of AT [ICC 0.83 (0.75-0.90)] and VO2 peak [ICC 0.88 (0.84-0.92)] was good. In a post hoc analysis, inter-observer agreement for identification of the presence of a reportable AT was excellent [ICC 0.93 (0.91-0.95)] and a reportable VO2 peak was moderate [0.73 (0.64-0.80)]. CONCLUSIONS: Inter-observer reliability of interpretation of numerical values of two commonly used CPET variables was good (>80%). However, inter-observer agreement regarding the presence of a reportable value was less consistent.

The Trans Youth Justice Project: A Political Education and Leadership Development Program.

Research has demonstrated that systemic transphobia and cissexism harms transgender youth in terms of social, educational, and health outcomes. All too often, research and policy emphasizes vulnerability among trans youth in a way that denies their capabilities as agents of change or active participants in their liberation. This article analyzes the development of Trans Youth Justice Project, a political education and youth leadership development program for trans youth ages 15-22. Based in principles of gender minority stress and social justice youth development, the 6-week remote program aims to increase the capacity and resilience of trans youth, develop youth leaders, and contribute to addressing social, educational, and health inequalities. We conducted a formative program evaluation of 2 cycles of the program with a total of 25 youth. Pre- and post-test surveys indicated increased feelings of belongingness to a trans community. Follow-up interviews highlighted the impact the program had on skills for social justice, self-efficacy, and community connection. We offer suggestions for implementing the open-source program more broadly.

Effect of vanadate on elevated blood glucose and depressed cardiac performance of diabetic rats.

The trace element vanadium has an unclear biological function. Vanadate, an oxidized form of vanadium, appears to have an insulin-like action. The effect of vanadate on blood glucose and cardiac performance was assessed in female Wistar rats 6 weeks after they were made diabetic with streptozotocin. When vanadate was administered for a 4-week period to the diabetic rats, their blood glucose was not significantly different from that of nondiabetic controls despite a low serum insulin. In contrast, blood glucose was increased about threefold in the diabetic rats that were not treated with vanadate; these rats also had low insulin levels. Cardiac performance was depressed in the untreated diabetic animals, but the cardiac performance of the vanadate-treated diabetic animals was not significantly different from that of nondiabetic controls. Thus vanadate controlled the high blood glucose and prevented the decline in cardiac performance due to diabetes.

Endothelin-1 modulates angiotensin II in the development of hypertension in fructose-fed rats.

Two of the most potent vasoconstrictors, endothelin-1 (ET-1) and angiotensin II (Ang II), are upregulated in fructose hypertensive rats. It is unknown whether an interrelationship exists between these peptides that may contribute to the development of fructose-induced hypertension. The objective of this study was to investigate the existence of an interaction between the endothelin and renin angiotensin systems that may play a role in the development of fructose-induced hypertension. High fructose feeding and treatment with either bosentan, a dual endothelin receptor antagonist, or with L-158,809, an angiotensin type 1 receptor antagonist, were initiated simultaneously in male Wistar rats. Systolic blood pressure, fasted plasma parameters, insulin sensitivity, plasma Ang II, and vascular ET-1-immunoreactivity were determined following 6 weeks of high fructose feeding. Rats fed with a high fructose diet exhibited insulin resistance, hyperinsulinemia, hypertriglyceridemia, hypertension, and elevated plasma Ang II. Treatment with either bosentan or L-158,809 significantly attenuated the rise in blood pressure with no effect on insulin levels or insulin sensitivity in fructose-fed rats. Bosentan treatment significantly reduced plasma Ang II levels, while L-158,809 treatment significantly increased vascular ET-1-immunoreactivity in fructose-fed rats. Thus, treatment with the endothelin receptor antagonist prevented the development of fructose-induced hypertension and decreased plasma Ang II levels. These data suggest that ET-1 contributes to the development of fructose-induced hypertension through modulation of Ang II levels.

Gold nanoparticles as a contrast agent for in vivo tumor imaging with photoacoustic tomography.

Photoacoustic tomography (PAT) is a rapidly emerging non-invasive imaging technology that integrates the merits of high optical contrast with high ultrasound resolution. The ability to quantitatively and non-invasively image nanoparticles has important implications for the development of nanoparticles as in vivo cancer diagnostic and therapeutic agents. In this study, the ability of systemically administered poly(ethylene glycol)-coated (PEGylated) gold nanoparticles as a contrast agent for in vivo tumor imaging with PAT has been evaluated. We demonstrate that gold nanoparticles (20 and 50 nm) have high photoacoustic contrast as compared to mouse tissue ex vivo. Gold nanoparticles can be visualized in mice in vivo following subcutaneous administration using PAT. Following intravenous administration of PEGylated gold nanoparticles to tumor-bearing mice, accumulation of gold nanoparticles in tumors can be effectively imaged with PAT. With gold nanoparticles as a contrast agent, PAT has important potential applications in the image guided therapy of superficial tumors such as breast cancer, melanoma and Merkel cell carcinoma.

Anatomic subdivisions in human temporal cortical neuronal activity related to recent verbal memory.

We identified functional anatomical subdivisions of human lateral and basal temporal cortex related to recent verbal memory for object names, text and auditory words. Extracellular neuronal activity was recorded during memory encoding compared to identification, during encoding, storage or recall retrieval stages of the memory task, during recognition memory, and during implicit memory as measured by repetition priming. Changes in frequency of activity during encoding were recorded from most neurons. In lateral temporal cortex, these encoding changes in the dominant hemisphere were more likely to be polymodal, whereas those in nondominant hemisphere were unimodal. There was substantial separation of neurons with changes in other aspects of memory, defining additional subdivisions. Inferior lateral and basal cortex were related to memory stages, and superior-posterior lateral cortex was related to implicit and recognition memory.

The effects of vanadium treatment on bone in diabetic and non-diabetic rats.

Vanadium-based drugs lower glucose by enhancing the effects of insulin. Oral vanadium drugs are being tested for the treatment of diabetes. Vanadium accumulates in bone, though it is not known if incorporated vanadium affects bone quality. Nine- to 12-month-old control and streptozotocin-induced diabetic female Wistar rats were given bis(ethylmaltolato)oxovanadium(IV) (BEOV), a vanadium-based anti-diabetic drug, in drinking water for 12 weeks. Non-diabetic rats received 0, 0.25 or 0.75 mg/ml BEOV. Groups of diabetic rats were either untreated or treated with 0.25-0.75 mg/ml BEOV as necessary to lower blood glucose in each rat. In diabetic rats, this resulted in a Controlled Glucose group, simulating relatively well-managed diabetes, and an Uncontrolled Glucose group, simulating poorly managed diabetes. Plasma insulin, glucose and triglyceride assays assessed the diabetic state. Bone mineral density (BMD), mechanical testing, mineral assessment and histomorphometry measured the effects of diabetes on bone and the effects of BEOV on non-diabetic and diabetic bone. Diabetes decreased plasma insulin and increased plasma glucose and triglycerides. In bone, diabetes decreased BMD, strength, mineralization, bone crystal length, and bone volume and connectivity. Treatment was effective in incorporating vanadium into bone. In all treated groups, BEOV increased osteoid volume. In non-diabetic bone, BEOV increased cortical bone toughness, mineralization and bone formation. In controlled glucose rats, BEOV lowered plasma glucose and improved BMD, mechanical strength, mineralization, bone crystal length and bone formation rate. In poorly controlled rats, BEOV treatment slightly lowered plasma glucose but did not improve bone properties. These results suggest that BEOV improves diabetes-related bone dysfunction primarily by improving the diabetic state. BEOV also appeared to increase bone formation. Our study found no negative effects of vanadium accumulation in bone in either diabetic or non-diabetic rats at the dose given.

EDHF-mediated rapid restoration of hypotensive response to acetylcholine after chronic, but not acute, nitric oxide synthase inhibition in rats.

Several in vitro studies have shown that endothelium-dependent vasodilatation is maintained by endothelium-derived hyperpolarizing factor (EDHF) or prostacyclin in vessels isolated from endothelial nitric oxide synthase knockout mice. Since this has not been addressed by in vivo studies, we sought to define the magnitude and the onset time of this compensation by recording blood pressure responses to endothelium-dependent vasodilators in rats treated acutely or chronically with the NOS inhibitor, N(omega)-nitro-L-arginine methyl ester (L-NAME). Groups of male Sprague-Dawley rats were given plain water (control) or L-NAME (0.7 mg/ml) in drinking water for 1 day, 5 days, 3 wks or 6 wks. Dose-dependent hypotensive responses to acetylcholine, bradykinin and sodium nitroprusside were determined in anesthetized rats before and after acute intravenous infusion of either L-NAME or a combination of apamin plus charybdotoxin that would selectively inhibit EDHF. Acute L-NAME treatment increased the mean arterial pressure and inhibited acetylcholine- and bradykinin-induced fall in blood pressure in control but not in chronic L-NAME treated rats. The endothelium-dependent hypotensive responses to acetylcholine and bradykinin were restored in rats treated with L-NAME after a time period of 24 h along with increased sensitivity to sodium nitroprusside and reduced plasma nitrate+nitrite levels. While apamin+charybdotoxin pretreatment inhibited the responses to acetylcholine and bradykinin in both acute and chronic L-NAME treated groups, it was more pronounced in the latter group. In conclusion, chronic inhibition of nitric oxide synthase results in the development of a compensatory hypotensive response to acetylcholine within 24 h and this is mediated by EDHF.

The Anthropocene is functionally and stratigraphically distinct from the Holocene.

Human activity is leaving a pervasive and persistent signature on Earth. Vigorous debate continues about whether this warrants recognition as a new geologic time unit known as the Anthropocene. We review anthropogenic markers of functional changes in the Earth system through the stratigraphic record. The appearance of manufactured materials in sediments, including aluminum, plastics, and concrete, coincides with global spikes in fallout radionuclides and particulates from fossil fuel combustion. Carbon, nitrogen, and phosphorus cycles have been substantially modified over the past century. Rates of sea-level rise and the extent of human perturbation of the climate system exceed Late Holocene changes. Biotic changes include species invasions worldwide and accelerating rates of extinction. These combined signals render the Anthropocene stratigraphically distinct from the Holocene and earlier epochs.

An assessment of phospholipid methylation in sarcolemma and sarcoplasmic reticulum of the aging myocardium.

The stepwise N-methylation of phosphatidylethanolamine (PE) to phosphatidylcholine (PC) (phospholipid methylation) was assessed in cardiac sarcolemma and sarcoplasmic reticulum of aging rats. This phenomenon was depressed in aging hearts relative to young ones. A decrease in activity of catalytic sites appears to be involved in the depressed phospholipid methylation of aging myocardium.

17beta-estradiol decreases endothelin-1 levels in the coronary circulation of postmenopausal women with coronary artery disease.

BACKGROUND: Estrogen reverses acetylcholine-induced coronary vasoconstriction via the possible facilitation of endothelium-derived NO. Estrogen also affects endothelium-derived constrictor factors. We therefore investigated the effects of 17beta-estradiol on coronary vasomotor responses to substance P (SP), and coronary sinus endothelin-1 and NO metabolite levels in postmenopausal women with coronary heart disease. METHODS AND RESULTS: We studied 20 women; 14 received estrogen (mean age 65+/-2 years) and 6 served as ethanol control subjects (age 63+/-3 years). Intracoronary infusions of papaverine (8 mg) and SP were administered before and 20 minutes after 50 pg/min 17beta-estradiol or 0.2 microL/min control. Coronary blood flow was calculated from the diameter, as measured with quantitative coronary angiography, and flow velocity, as measured with intracoronary Doppler. Coronary sinus plasma endothelin-1 and nitrite/nitrate (NO(2)/NO(3)) were measured at baseline, at peak velocity response to each infusion, and every 5 minutes during the estradiol infusion. Endothelin-1 levels were decreased after 20 minutes of estradiol (1.12+/-0.18 versus 0.86+/-0.17 pmol/L baseline2 versus estradiol, P:=0.05). Endothelin-1 levels to SP decreased after 17beta-estradiol (1.29+/-0. 18 versus 1.04+/-0.15 and 1.3+/-0.16 versus 0.99+/-0.17 pmol/L for before versus after estradiol, 10 and 25 pmol/min SP; both P:<0.05). NO(2)/NO(3) levels did not change. There was no change in vasomotor responses to estradiol alone or to papaverine or SP before versus after estradiol. CONCLUSIONS: Short-term intracoronary 17beta-estradiol administration decreases coronary endothelin-1 levels. There was no enhancement of vasomotor responses to SP after the administration of estrogen, suggesting that the effects of estrogen on coronary acetylcholine responses may be a specific and not a generalized effect on coronary vasoreactivity.

Effects of testosterone on coronary vasomotor regulation in men with coronary heart disease.

BACKGROUND: The increased incidence of coronary artery disease in men compared with premenopausal women suggests a detrimental role of male hormones on the cardiovascular system. However, testosterone has direct relaxing effects on coronary arteries in animals, as shown both in vitro and in vivo. The effect of testosterone on the human coronary circulation remains unknown. METHODS AND RESULTS: We studied 13 men (aged 61+/-11 years) with coronary artery disease. They underwent measurement of coronary artery diameter and blood flow after a 3-minute intracoronary infusion of vehicle control (ethanol) followed by 2-minute intracoronary infusions of acetylcholine (10(-7) to 10(-5) mol/L) until peak velocity response. A dose-response curve to 3-minute infusions of testosterone (10(-10) to 10(-7) mol/L) was then determined, and the acetylcholine infusions were repeated. Finally, an intracoronary bolus of isosorbide dinitrate (1000 microgram) was given. Coronary blood flow was calculated from measurements of blood flow velocity using intracoronary Doppler and coronary artery diameter using quantitative coronary angiography. Testosterone significantly increased coronary artery diameter compared with baseline (2.78+/-0. 74 mm versus 2.86+/-0.72 mm [P=0.05], 2.87+/-0.71 mm [P=0.038], and 2.90+/-0.75 mm [P=0.005] for baseline versus testosterone 10(-9) to 10(-7) mol/L, respectively). A significant increase in coronary blood flow occurred at all concentrations of testosterone compared with baseline (geometric mean [95% CI]: 32 [25, 42] versus 36.3 [27, 48] (P=0.006), 35.3 [26, 47] (P=0.029), 36.8 [28, 49] (P=0.002), and 37 [28, 48] (P=0.002), mL/min for baseline versus testosterone 10(-10) to 10(-7) mol/L, respectively). No differences existed in coronary diameter or blood flow responses to acetylcholine before versus after testosterone. CONCLUSIONS: Short-term intracoronary administration of testosterone, at physiological concentrations, induces coronary artery dilatation and increases coronary blood flow in men with established coronary artery disease.

Cardiac performance and plasma lipids of omega-3 fatty acid-treated streptozocin-induced diabetic rats.

We studied the effect of omega-3 fatty acid (omega 3FA) treatment on plasma lipids and cardiomyopathy in the diabetic rat. The omega 3FA preparation used was Promega. Male Wistar rats (250-275 g) were rendered diabetic by streptozocin (STZ; 55 mg.kg-1). Nondiabetic control rats received the vehicle alone. Two weeks after STZ or vehicle injection, control and diabetic rats were randomly assigned to either a treated or untreated group. Promega was administered at a dose of 0.5 ml.kg-1.day-1 by oral gavage for 4 wk, after which the rats were decapitated, plasma collected, and isolated working heart performance studied. Promega treatment did not affect plasma glucose, triglyceride, or cholesterol concentrations of either the control or diabetic rats. Cardiac performance was assessed by measuring the left ventricular response to changing left atrial filling pressures (7.5-20 cm H2O). The treatment had no effect on peak left ventricular developed pressure (LVDP) or maximal rate of change of left ventricular pressure during systole (+dP/dtmax) or diastole (-dP/dtmax) in the nondiabetic control rats. LVDP and +/- dP/dt were significantly improved (P less than .05) in the treated diabetic rats compared with untreated diabetic rats, although cardiac performance did not improve to the nondiabetic level. Cardiac sarcoplasmic reticulum (SR) calcium transport activity was not affected by the treatment in the control rats but was significantly improved (P less than .05) in the treated diabetic rats. These data suggest that omega 3FA treatment partially blocks the development of experimental diabetic cardiomyopathy, possibly by affecting SR calcium transport activity.

Effect of choline and methionine treatment on cardiac dysfunction of diabetic rats.

There is an abnormal lipid accumulation in the myocardium that might be involved in the congestive heart failure frequently associated with individuals with diabetes mellitus. Because choline and methionine have been reported to modify the incidence of myocardial necrosis in rats fed various fat diets, we decided in our study to assess their effect on the cardiac dysfunction of diabetic rats. Female Wistar rats were made diabetic with streptozocin (STZ, 55 mg/kg i.v.). One week after diabetes induction, one group received choline (0.3 mg/ml), another received methionine (0.25 mg/ml), a third received a combination of the same doses of choline and methionine, and a fourth received neither of these agents; all were administered in the drinking water. Animals were treated for 7 wk. Insulin levels were lower and glucose values higher in the serum of STZ rats relative to controls. Serum cholesterol and triglycerides were significantly elevated in all diabetic animals, and they were also elevated (P less than .05) in the hearts of untreated diabetics. In contrast, the myocardial values of the same lipids were drastically reduced in the treated diabetic animals. Cardiac performance was depressed in all STZ animals, but there was a significant improvement in heart function in treated diabetics relative to untreated ones. Thus, it appears that the buildup of cholesterol and triglycerides in the myocardium are important contributors to the cardiac dysfunction that frequently accompanies diabetes mellitus.

Effect of L-carnitine treatment on lipid metabolism and cardiac performance in chronically diabetic rats.

The beneficial effects of L-carnitine administration were studied in vivo in isolated perfused working hearts from control and diabetic rats. Control and streptozocin-induced diabetic (STZ-D) rats were treated daily for 6 wk with high-dose L-carnitine (3 g.kg-1.day-1 i.p.). STZ-D results in loss of body weight and hypoinsulinemia. These effects were not altered by L-carnitine treatment. Myocardial free-carnitine levels were decreased in the untreated diabetic rats. L-Carnitine treatment of the diabetic rats increased myocardial free-carnitine levels, which were comparable with those of control rats. Six weeks after STZ administration, hearts from untreated diabetic animals exhibited depressed left ventricular developed pressure, cardiac contractility, and ventricular relaxation rates compared with control animals. However, this depression was not seen in the L-carnitine-treated diabetic animals. L-Carnitine treatment of diabetic rats significantly reduced plasma glucose and lipid levels but had no effect on control rats. Furthermore, thyroid hormone levels were higher in the L-carnitine-treated diabetic rats than in the untreated diabetic group. The data suggest that high-dose L-carnitine treatment may reduce the severity of diabetes and result in improved cardiac performance.