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Cyclodextrins (CDs) have been previously shown to display modest equilibrium binding affinities ( K a  ~ 100–200 M -1 ) for the synthetic opioid analgesic fentanyl. In this work, we describe the synthesis of new CDs possessing extended thioalkylcarboxyl or thioalkylhydroxyl moieties and assess their binding affinity towards fentanyl hydrochloride. The optimal CD studied displays a remarkable affinity for the opioid of K a  = 66,500 M −1 , the largest value reported for such an inclusion complex to date. One dimensional 1 H Nuclear Magnetic Resonance (NMR) as well as Rotational Frame Overhauser Spectroscopy (2D-ROESY) experiments supported by molecular dynamics (MD) simulations suggest an unexpected binding behavior, with fentanyl able to bind the CD interior in one of two distinct orientations. Binding energies derived from the MD simulations work correlate strongly with NMR-derived affinities highlighting its utility as a predictive tool for CD candidate optimization. The performance of these host molecules portends their utility as platforms for medical countermeasures for opioid exposure, as biosensors, and in other forensic science applications.

We present a structurally dynamic model for nucleotide- and actin-induced closure of the actin-binding cleft of myosin, based on site-directed spin labeling and electron paramagnetic resonance (EPR) in Dictyostelium myosin II. The actin-binding cleft is a solvent-filled cavity that extends to the nucleotide-binding pocket and has been predicted to close upon strong actin binding. Single-cysteine labeling sites were engineered to probe mobility and accessibility within the cleft. Addition of ADP and vanadate, which traps the posthydrolysis biochemical state, influenced probe mobility and accessibility slightly, whereas actin binding caused more dramatic changes in accessibility, consistent with cleft closure. We engineered five pairs of cysteine labeling sites to straddle the cleft, each pair having one label on the upper 50-kDa domain and one on the lower 50-kDa domain. Distances between spin-labeled sites were determined from the resulting spin-spin interactions, as measured by continuous wave EPR for distances of 0.7-2 nm or pulsed EPR (double electron-electron resonance) for distances of 1.7-6 nm. Because of the high distance resolution of EPR, at least two distinct structural states of the cleft were resolved. Each of the biochemical states tested (prehydrolysis, posthydrolysis, and rigor), reflects a mixture of these structural states, indicating that the coupling between biochemical and structural states is not rigid. The resulting model is much more dynamic than previously envisioned, with both open and closed conformations of the cleft interconverting, even in the rigor actomyosin complex.

Low thermal-equilibrium nuclear spin polarizations and the need for sophisticated instrumentation render conventional nuclear magnetic resonance (NMR) spectroscopy and imaging (MRI) incompatible with small-scale microfluidic devices. Hyperpolarized Xe gas has found use in the study of many materials but has required very large and expensive instrumentation. Recently a microfabricated device with modest instrumentation demonstrated all-optical hyperpolarization and detection of Xe gas. This device was limited by Xe polarizations less than 1%, Xe NMR signals smaller than 20 nT, and transport of hyperpolarized Xe over millimeter lengths. Higher polarizations, versatile detection schemes, and flow of Xe over larger distances are desirable for wider applications. Here we demonstrate an ultra-sensitive microfabricated platform that achieves Xe polarizations reaching 7%, NMR signals exceeding 1 μT, lifetimes up to 6 s, and simultaneous two-mode detection, consisting of a high-sensitivity in situ channel with signal-to-noise of 10 and a lower-sensitivity ex situ detection channel which may be useful in a wider variety of conditions. Xe is hyperpolarized and detected in locations more than 1 cm apart. Our versatile device is an optimal platform for microfluidic magnetic resonance in particular, but equally attractive for wider nuclear spin applications benefitting from ultra-sensitive detection, long coherences, and simple instrumentation.

Low thermal-equilibrium nuclear spin polarizations and the need for sophisticated instrumentation render conventional nuclear magnetic resonance (NMR) spectroscopy and imaging (MRI) incompatible with small-scale microfluidic devices. Hyperpolarized 129 Xe gas has found use in the study of many materials but has required very large and expensive instrumentation. Recently a microfabricated device with modest instrumentation demonstrated all-optical hyperpolarization and detection of 129 Xe gas. This device was limited by 129 Xe polarizations less than 1%, 129 Xe NMR signals smaller than 20 nT, and transport of hyperpolarized 129 Xe over millimeter lengths. Higher polarizations, versatile detection schemes, and flow of 129 Xe over larger distances are desirable for wider applications. Here we demonstrate an ultra-sensitive microfabricated platform that achieves 129 Xe polarizations reaching 7%, NMR signals exceeding 1 μT, lifetimes up to 6 s, and simultaneous two-mode detection, consisting of a high-sensitivity in situ channel with signal-to-noise of 10 5 and a lower-sensitivity ex situ detection channel which may be useful in a wider variety of conditions. 129 Xe is hyperpolarized and detected in locations more than 1 cm apart. Our versatile device is an optimal platform for microfluidic magnetic resonance in particular, but equally attractive for wider nuclear spin applications benefitting from ultra-sensitive detection, long coherences, and simple instrumentation.

Optically hyperpolarized 129 Xe gas has become a powerful contrast agent in nuclear magnetic resonance (NMR) spectroscopy and imaging, with applications ranging from studies of the human lung to the targeted detection of biomolecules. Equally attractive is its potential use to enhance the sensitivity of microfluidic NMR experiments, in which small sample volumes yield poor sensitivity. Unfortunately, most 129 Xe polarization systems are large and non-portable. Here we present a microfabricated chip that optically polarizes 129 Xe gas. We have achieved 129 Xe polarizations >0.5% at flow rates of several microlitres per second, compatible with typical microfluidic applications. We employ in situ optical magnetometry to sensitively detect and characterize the 129 Xe polarization at magnetic fields of 1 μT. We construct the device using standard microfabrication techniques, which will facilitate its integration with existing microfluidic platforms. This device may enable the implementation of highly sensitive 129 Xe NMR in compact, low-cost, portable devices. Hyperpolarized 129 Xe gas is used as a contrast agent in nuclear magnetic resonance imaging. Here, the authors demonstrate a microfluidic chip that optically polarizes 129 Xe gas for compact nuclear magnetic resonance imaging applications.

To determine if renal dose dopamine (3 microg/kg/min) alters the heart rate (HR) by itself, or if a dopamine infusion alters the HR response to bolus doses of the beta-adrenergic agonist isoproterenol in healthy human subjects. Prospective study. Clinical laboratory of a university-affiliated academic medical center. A total of 15 healthy nonpregnant women and men aged 21 to 44 years. Subjects were monitored continuously with bedside ECG, pulse oximetry, and ambulatory ECG recording to measure the maximal HR response to separate injections of 10, 20, and 30 ng/kg of isoproterenol, given before, during, and after the infusion of 3 microg/kg/min of dopamine. Dopamine in the absence of isoproterenol did not alter baseline HR significantly (62.7+/-2.2 beats/min without dopamine; 65.4+/-2.2 with dopamine; p=0.15). All three doses of isoproterenol increased HR significantly above baseline, both in the presence and absence of dopamine (p<0.001). Dopamine infusion resulted in a higher HR following isoproterenol only for the 20-ng/kg dose. The incremental increases in HR, defined as the difference between peak HR following isoproterenol and baseline HR, were not increased during dopamine infusion for any of the doses of isoproterenol. Nausea was reported by 5 of the 15 subjects during the dopamine infusion. In healthy human subjects, infusion of 3 microg/kg/min of dopamine does not significantly increase the HR when combined with beta-adrenergic stimulation using isoproterenol, suggesting neither an additive nor antagonistic interaction between the two drugs. While our study did not demonstrate an increase in HR in healthy subjects, the risk of increasing the chronotropic response to beta-adrenergic inotropic medications with \"renal dose\" dopamine in critically ill patients needs to be investigated. The frequency of nausea during dopamine infusion also may influence consideration of using dopamine to augment splanchnic blood flow and renal function in conscious patients.

Objectives: To determine if renal dose dopamine (3 µg/kg/min) alters the heart rate (HR) by itself, or if a dopamine infusion alters the HR response to bolus doses of the β-adrenergic agonist isoproterenol in healthy human subjects. Design: Prospective study. Setting: Clinical laboratory of a university-affiliated academic medical center. Subjects: A total of 15 healthy nonpregnant women and men aged 21 to 44 years. Interventions: Subjects were monitored continuously with bedside ECG, pulse oximetry, and ambulatory ECG recording to measure the maximal HR response to separate injections of 10, 20, and 30 ng/kg of isoproterenol, given before, during, and after the infusion of 3 µg/kg/min of dopamine. Measurements and main results: Dopamine in the absence of isoproterenol did not alter baseline HR significantly (62.7±2.2 beats/min without dopamine; 65.4±2.2 with dopamine; p=0.15). All three doses of isoproterenol increased HR significantly above baseline, both in the presence and absence of dopamine (p<0.001). Dopamine infusion resulted in a higher HR following isoproterenol only for the 20-ng/kg dose. The incremental increases in HR, defined as the difference between peak HR following isoproterenol and baseline HR, were not increased during dopamine infusion for any of the doses of isoproterenol. Nausea was reported by 5 of the 15 subjects during the dopamine infusion. Conclusions: In healthy human subjects, infusion of 3 µg/kg/min of dopamine does not significantly increase the HR when combined with β-adrenergic stimulation using isoproterenol, suggesting neither an additive nor antagonistic interaction between the two drugs. While our study did not demonstrate an increase in HR in healthy subjects, the risk of increasing the chronotropic response to β-adrenergic inotropic medications with \"renal dose\" dopamine in critically ill patients needs to be investigated. The frequency of nausea during dopamine infusion also may influence consideration of using dopamine to augment splanchnic blood flow and renal function in conscious patients. dopamine drug interactions heart rate inotropes isoproterenol renal dose dopamine tachycardia

To determine if renal dose dopamine (3 μg/kg/min) alters the heart rate (HR) by itself, or if a dopamine infusion alters the HR response to bolus doses of the ß-adrenergic agonist isoproterenol in healthy human subjects. Prospective study. Clinical laboratory of a university-affiliated academic medical center. A total of 15 healthy nonpregnant women and men aged 21 to 44 years. Subjects were monitored continuously with bedside ECG, pulse oximetry, and ambulatory ECG recording to measure the maximal HR response to separate injections of 10, 20, and 30 ng/kg of isoproterenol, given before, during, and after the infusion of 3 μg/kg/min of dopamine. Dopamine in the absence of isoproterenol did not alter baseline HR significantly (62.7±2.2 beats/min without dopamine; 65.4±2.2 with dopamine; p=0.15). All three doses of isoproterenol increased HR significantly above baseline, both in the presence and absence of dopamine (p<0.001). Dopamine infusion resulted in a higher HR following isoproterenol only for the 20-ng/kg dose. The incremental increases in HR, defined as the difference between peak HR following isoproterenol and baseline HR, were not increased during dopamine infusion for any of the doses of isoproterenol. Nausea was reported by 5 of the 15 subjects during the dopamine infusion. In healthy human subjects, infusion of 3 pg/kg/min of dopamine does not significantly increase the HR when combined with ß-adrenergic stimulation using isoproterenol, suggesting neither an additive nor antagonistic interaction between the two drugs. While our study did not demonstrate an increase in HR in healthy subjects, the risk of increasing the chronotropic response to ß-adrenergic inotropic medications with “renal dose” dopamine in critically ill patients needs to be investigated. The frequency of nausea during dopamine infusion also may influence consideration of using dopamine to augment splanchnic blood flow and renal function in conscious patients.

We operate a nitrogen vacancy (NV-) diamond magnetometer at ambient temperatures and study the dependence of its bandwidth on experimental parameters including optical and microwave excitation powers. We introduce an analytical theory that yields an explicit formula for the response of an ensemble of NV- spins to an oscillating magnetic field, such as in NMR applications. We measure a detection bandwidth of 1.6 MHz and a sensitivity of 4.6 nT/Hz^(1/2), unprecedented in a detector with this active volume and close to the photon shot noise limit of our experiment.

Optically hyperpolarized \\(^{129}\\)Xe gas has become a powerful contrast agent in nuclear magnetic resonance (NMR) spectroscopy and imaging, with applications ranging from studies of the human lung to the targeted detection of biomolecules. Equally attractive is its potential use to enhance the sensitivity of microfluidic NMR experiments, in which small sample volumes yield poor sensitivity. Unfortunately, most \\(^{129}\\)Xe polarization systems are large and non-portable. Here we present a microfabricated chip that optically polarizes \\(^{129}\\)Xe gas. We have achieved \\(^{129}\\)Xe polarizations greater than 0.5\\(\\%\\) at flow rates of several microliters per second, compatible with typical microfluidic applications. We employ in situ optical magnetometry to sensitively detect and characterize the \\(^{129}\\)Xe polarization at magnetic fields of 1 \\(\\mu\\)T. We construct the device using standard microfabrication techniques, which will facilitate its integration with existing microfluidic platforms. This device may enable the implementation of highly sensitive \\(^{129}\\)Xe NMR in compact, low-cost, portable devices.