Precision Spectroscopy of Polarized Molecules in an Ion Trap

Polar molecules are desirable systems for quantum simulations and cold chemistry. Molecular ions are easily trapped, but a bias electric field applied to polarize them tends to accelerate them out of the trap. We present a general solution to this issue by rotating the bias field slowly enough for the molecular polarization axis to follow but rapidly enough for the ions to stay trapped. We demonstrate Ramsey spectroscopy between Stark-Zeeman sublevels in 180Hf19F+ with a coherence time of 100 ms. Frequency shifts arising from well-controlled topological (Berry) phases are used to determine magnetic g-factors. The rotating-bias-field technique may enable using trapped polar molecules for precision measurement and quantum information science, including the search for an electron electric dipole moment.Comment: Accepted to Scienc

Antinociceptive Effects of Herkinorin, a MOP Receptor Agonist Derived from Salvinorin A in the Formalin Test in Rats: New Concepts in Mu Opioid Receptor Pharmacology

Herkinorin is the first μ opioid (MOP) selective agonist derived from salvinorin A, a hallucinogenic natural product. Previous work has shown that, unlike other opioids, herkinorin does not promote the recruitment of β-arrestin-2 to the MOP receptor and does not lead to receptor internalization. This paper presents the first in vivo evaluation of herkinorin’s antinociceptive effects in rats, using the formalin test as a model of tonic inflammatory pain. Herkinorin was found to produce a dose-dependent decrease in the number of flinches evoked by formalin. These antinociceptive effects were substantially blocked by pretreatment with the nonselective antagonist naloxone, indicating that the antinociception is mediated by opioid receptors. Contralateral administration of herkinorin did not attenuate the number of flinches evoked by formalin, indicating that its effects are peripherally restricted to the site of injection. Following chronic administration (5-day), herkinorin maintained antinociceptive efficacy in both phases of the formalin test. Furthermore, unlike morphine, herkinorin was still able to inhibit flinching in both phases of the formalin test in animals made tolerant to chronic systemic morphine treatment. Collectively, these results suggest that herkinorin may produce peripheral antinociception with decreased tolerance liability and thereby represents a promising template for the development of agents for the treatment of a variety of pain states

Investigation of the role of βarrestin2 in kappa opioid receptor modulation in a mouse model of pruritus

The kappa opioid receptor (KOR) is involved in mediating pruritus; agonists targeting this receptor have been used to treat chronic intractable itch. Conversely, antagonists induce an inch response at the site of injection. As a G protein-coupled receptor (GPCR), the KOR has potential for signaling via G proteins and βarrestins, however, it is not clear which of these pathways are involved in the KOR modulation of itch. In this study asked whether the actions of KOR in pruritus involve βarrestins by using βarrestin2 knockout (βarr2-KO) mice as well as a recently described biased KOR agonist that biases receptor signaling toward G protein pathways over βarrestin2 recruitment. We find that the KOR antagonists nor-binaltorphimine (NorBNI) and 5′-guanidinonaltrindole (5′GNTI) induce acute pruritus in C57BL/6J mice, with reduced effects in KOR-KO mice. βarr2-KO mice display less of a response to KOR antagonist-induced itch compared to wild types, however no genotype differences are observed from chloroquine phosphate (CP)-induced itch, suggesting that the antagonists may utilize a KOR-βarrestin2 dependent mechanism. The KOR agonist U50,488H was equally effective in both WT and βarr2-KO mice in suppressing CP-induced itch. Furthermore, the G protein biased agonist, Isoquinolinone 2.1 was as effective as U50,488H in suppressing the itch response induced by KOR antagonist NorBNI or CP in C57BL/6J mice. Together these data suggest that the antipruritic effects of KOR agonists may not require βarrestins

Characterization of kappa opioid receptor mediated, dynorphin-stimulated [35S]GTPγS binding in mouse striatum for the evaluation of selective KOR ligands in an endogenous setting

Differential modulation of kappa opioid receptor (KOR) signaling has been a proposed strategy for developing therapies for drug addiction and depression by either activating or blocking this receptor. Hence, there have been significant efforts to generate ligands with diverse pharmacological properties including partial agonists, antagonists, allosteric modulators as well as ligands that selectively activate some pathways while not engaging others (biased agonists). It is becoming increasingly evident that G protein coupled receptor signaling events are context dependent and that what may occur in cell based assays may not be fully indicative of signaling events that occur in the naturally occurring environment. As new ligands are developed, it is important to assess their signaling capacity in relevant endogenous systems in comparison to the performance of endogenous agonists. Since KOR is considered the cognate receptor for dynorphin peptides we have evaluated the selectivity profiles of dynorphin peptides in wild-type (WT), KOR knockout (KOR-KO), and mu opioid receptor knockout (MOR-KO) mice using [35S]GTPγS binding assay in striatal membrane preparations. We find that while the small molecule KOR agonist U69,593, is very selective for KOR, dynorphin peptides promiscuously stimulate G protein signaling in striatum. Furthermore, our studies demonstrate that norBNI and 5′GNTI are highly nonselective antagonists as they maintain full potency and efficacy against dynorphin signaling in the absence of KOR. Characterization of a new KOR antagonist, which may be more selective than NorBNI and 5′GNTI, is presented using this approach

Treatment evolution in high-risk congenital diaphragmatic hernia: ten years\u27 experience with diaphragmatic agenesis.

OBJECTIVE: The objective of this study was to evaluate the impact of newer therapies on the highest risk patients with congenital diaphragmatic hernia (CDH), those with agenesis of the diaphragm. SUMMARY BACKGROUND DATA: CDH remains a significant cause of neonatal mortality. Many novel therapeutic interventions have been used in these infants. Those children with large defects or agenesis of the diaphragm have the highest mortality and morbidity. METHODS: Twenty centers from 5 countries collected data prospectively on all liveborn infants with CDH over a 10-year period. The treatment and outcomes in these patients were examined. Patients were followed until death or hospital discharge. RESULTS: A total of 1,569 patients with CDH were seen between January 1995 and December 2004 in 20 centers. A total of 218 patients (14%) had diaphragmatic agenesis and underwent repair. The overall survival for all patients was 68%, while survival was 54% in patients with agenesis. When patients with diaphragmatic agenesis from the first 2 years were compared with similar patients from the last 2 years, there was significantly less use of ECMO (75% vs. 52%) and an increased use of inhaled nitric oxide (iNO) (30% vs. 80%). There was a trend toward improved survival in patients with agenesis from 47% in the first 2 years to 59% in the last 2 years. The survivors with diaphragmatic agenesis had prolonged hospital stays compared with patients without agenesis (median, 68 vs. 30 days). For the last 2 years of the study, 36% of the patients with agenesis were discharged on tube feedings and 22% on oxygen therapy. CONCLUSIONS: There has been a change in the management of infants with CDH with less frequent use of ECMO and a greater use of iNO in high-risk patients with a potential improvement in survival. However, the mortality, hospital length of stay, and morbidity in agenesis patients remain significant

Effects of black tea on body composition and metabolic outcomes related to cardiovascular disease risk: a randomized controlled trial

This article is licensed under a Creative Commons Attribution 3.0 Unported Licence (http://creativecommons.org/licenses/by/3.0/)There is increasing evidence that tea and its non-caffeine components (primarily flavonoids) contribute to cardiovascular health. Randomized controlled trials have shown that tea can improve cardiovascular disease risk factors. We have previously reported a non-caffeine associated beneficial effect of regular black tea consumption on blood pressure and its variation. Objective: To explore the non-caffeine associated effects of black tea on body weight and body fat distribution, and cardiovascular disease related metabolic outcomes. Design: regular tea-drinking men and women (n ¼ 111; BMI 20–35 kg m 2) were recruited to a randomized controlled double-blind 6 month parallel-designed trial. Participants consumed 3 cups per day of either powdered black tea solids (tea) or a flavonoid-free flavour- and caffeine-matched placebo (control). Body weight, waist- and hip-circumference, endothelial function and plasma biomarkers were assessed at baseline, 3 months and 6 months. Results: Compared to control, regular ingestion of black tea over 3 months inhibited weight gain ( 0.64 kg, p ¼ 0.047) and reduced waist circumference ( 1.88 cm, P ¼ 0.035) and waist-to-hip ratio ( 0.03, P ¼ 0.005). These effects were no longer significant at 6 months. There were no significant effects observed on fasting glucose, insulin, plasma lipids or endothelial function. Conclusion: Our study suggests that short-term regular ingestion of black tea over 3 months can improve body weight and body fat distribution, compared to a caffeine-matched control beverage. However, there was no evidence that these effects were sustained beyond 3 months

Structure–Activity Relationship Studies of Functionally Selective Kappa Opioid Receptor Agonists that Modulate ERK 1/2 Phosphorylation While Preserving G Protein Over βArrestin2 Signaling Bias

Kappa opioid receptor (KOR) modulation is a promising target for drug discovery efforts due to KOR involvement in pain, depression, and addiction behaviors. We recently reported a new class of triazole KOR agonists that displays significant bias toward G protein signaling over βarrestin2 recruitment; interestingly, these compounds also induce less activation of ERK1/2 map kinases than the balanced agonist, U69,593. We have identified structure–activity relationships around the triazole scaffold that allows for decreasing the bias for G protein signaling over ERK1/2 activation while maintaining the bias for G protein signaling over βarrestin2 recruitment. The development of novel compounds, with different downstream signaling outcomes, independent of G protein/βarrestin2 bias, provides a more diverse pharmacological toolset for use in defining complex KOR signaling and elucidating the significance of KOR-mediated signaling

Potency enhancement of the κ-opioid receptor antagonist probe ML140 through sulfonamide constraint utilizing a tetrahydroisoquinoline motif

Optimization of the sulfonamide-based kappa opioid receptor (KOR) antagonist probe molecule ML140 through constraint of the sulfonamide nitrogen within a tetrahydroisoquinoline moiety afforded a marked increase in potency. This strategy, when combined with additional structure-activity relationship exploration, has led to a compound only six-fold less potent than norBNI, a widely utilized KOR antagonist tool compound, but significantly more synthetically accessible. The new optimized probe is suitably potent for use as an in vivo tool to investigate the therapeutic potential of KOR antagonists

A Proposed High-Power UV Industrial Demonstration Laser at CEBAF

The Laser Processing Consortium, a collaboration of industries, universities, and the Continuous Electron Beam Accelerator Facility (CEBAF) in Newport News, Virginia, has proposed building a demonstration industrial processing laser for surface treatment and micro-machining. The laser is a free-electron laser (FEL) with average power output exceeding 1 kW in the ultraviolet (UV). The design calls for a novel driver accelerator that recovers most of the energy of the exhaust electron beam to produce laser light with good wall-plug efficiency. The laser and accelerator design use technologies that are scalable to much higher power. The authors will describe the critical design issues in the laser such as the stability, power handling, and losses of the optical resonator, and the quality, power, and reliability of the electron beam. They will also describe the calculated laser performance. Finally progress to date on accelerator development and resonator modeling will be reported

The EnMAP imaging spectroscopy mission towards operations

EnMAP (Environmental Mapping and Analysis Program) is a high-resolution imaging spectroscopy remote sensing mission that was successfully launched on April 1st, 2022. Equipped with a prism-based dual-spectrometer, EnMAP performs observations in the spectral range between 418.2 nm and 2445.5 nm with 224 bands and a high radiometric and spectral accuracy and stability. EnMAP products, with a ground instantaneous field-of-view of 30 m x 30 m at a swath width of 30 km, allow for the qualitative and quantitative analysis of surface variables from frequently and consistently acquired observations on a global scale. This article presents the EnMAP mission and details the activities and results of the Launch and Early Orbit and Commissioning Phases until November 1st, 2022. The mission capabilities and expected performances for the operational Routine Phase are provided for existing and future EnMAP users