Rapid Synthesis of Psychoplastogenic Tropane Alkaloids.

Tropane alkaloids are an important class of biologically active small molecules characterized by their 8-azabicyclo[3.2.1]octane core. Because of their numerous medicinal applications, microbial biosynthesis and a variety of chemical syntheses have been designed for individual family members. However, current approaches are not amenable to late-stage structural diversification at N8, C3, C6, or C7, positions that are critical for modulating the biological properties of these molecules. Here, we describe a general approach to the synthesis of tropane alkaloids and their analogues that relies on the construction of the 8-azabicyclo[3.2.1]octane core through aziridination of a cycloheptadiene intermediate, followed by vinyl aziridine rearrangement. Using this strategy, we synthesized six tropane alkaloids and several analogues in only 5-7 steps. Given that the tropane alkaloid scopolamine has been reported to promote structural neuroplasticity and produce antidepressant effects, we tested five tropane-containing compounds for their ability to promote dendritic spine growth in cultured cortical neurons. We found that the orientation of the C3 substituent may play a role in the psychoplastogenic effects of tropane alkaloids. Our work provides a robust platform for producing tropane analogs for future structure-activity relationship studies.

Pregnancy-Associated Diabetes Mellitus and Stillbirths by Race and Ethnicity among Hospitalized Pregnant Women in the United States.

OBJECTIVES: Racial disparities in preexisting diabetes mellitus (PDM) and gestational diabetes mellitus (GDM) remain largely unexplored. We examined national PDM and GDM prevalence trends by race/ethnicity and the association between these conditions and fetal death. METHODS: This was a retrospective cross-sectional analysis of 69,539,875 pregnancy-related hospitalizations from 2002 to 2017 including 674,040 women with PDM (1.0%) and 2,960,797 (4.3%) with GDM from the US Nationwide Inpatient Sample Survey. Joinpoint regression was used to evaluate trends in prevalence. Survey logistic regression was used to evaluate the association between exposures (PDM and GDM) and outcome. RESULTS: Overall, the average annual increase in prevalence was 5.2% (95% confidence interval [CI] 4.2-6.2) for GDM and 1.0% (95% CI -0.1 to 2.0) for PDM, during the study period. Hispanic (average annual percentage change 5.3, 95% CI 3.6 - 7.1) and non-Hispanic Black (average annual percentage change 0.9, 95% CI 0.1 - 1.7) women had the highest average annual percentage increase in the prevalence of GDM and PDM, respectively. After adjustment, the odds of stillbirth were highest for Hispanic women with PDM (odds ratio 2.41, 95% CI 2.23-2.60) and decreased for women with GDM (odds ratio 0.51, 95% CI 0.50-0.53), irrespective of race/ethnicity. CONCLUSIONS: PDM and GDM prevalence is increasing in the United States, with the highest average annual percentage changes seen among minority women. Furthermore, the reasons for the variation in the occurrence of stillbirths among mothers with PDM and GDM by race/ethnicity are not clear and warrant additional research.

Voltage Imaging with a NIR-Absorbing Phosphine Oxide Rhodamine Voltage Reporter.

The development of fluorescent dyes that emit and absorb light at wavelengths greater than 700 nm and that respond to biochemical and biophysical events in living systems remains an outstanding challenge for noninvasive optical imaging. Here, we report the design, synthesis, and application of near-infrared (NIR)-absorbing and -emitting optical voltmeter based on a sulfonated, phosphine-oxide (po) rhodamine for voltage imaging in intact retinas. We find that po-rhodamine based voltage reporters, or poRhoVRs, display NIR excitation and emission profiles at greater than 700 nm, show a range of voltage sensitivities (13 to 43% ΔF/F per 100 mV in HEK cells), and can be combined with existing optical sensors, like Ca2+-sensitive fluorescent proteins (GCaMP), and actuators, like light-activated opsins ChannelRhodopsin-2 (ChR2). Simultaneous voltage and Ca2+ imaging reveals differences in activity dynamics in rat hippocampal neurons, and pairing poRhoVR with blue-light based ChR2 affords all-optical electrophysiology. In ex vivo retinas isolated from a mouse model of retinal degeneration, poRhoVR, together with GCaMP-based Ca2+ imaging and traditional multielectrode array (MEA) recording, can provide a comprehensive physiological activity profile of neuronal activity, revealing differences in voltage and Ca2+ dynamics within hyperactive networks of the mouse retina. Taken together, these experiments establish that poRhoVR will open new horizons in optical interrogation of cellular and neuronal physiology in intact systems.

An Activity-Based Methionine Bioconjugation Approach To Developing Proximity-Activated Imaging Reporters.

Chemical probes that report on protein activity, rather than protein abundance, with spatial and temporal resolution can enable studies of their native function in biological contexts as well as provide opportunities for developing new types of biochemical reporters. Here we present a sensing platform, termed proximity-activated imaging reporter (PAIR), which combines activity-based methionine bioconjugation and antibody labeling with proximity-dependent oligonucleotide-based amplification to monitor dynamic changes of a given analyte in cells and animals through context-dependent methionine labeling of specific protein targets. We establish this PAIR method to develop sensors for imaging reactive oxygen species (ROS) and calcium ions through oxaziridine-directed labeling of reactive methionine residues on ß-actin and calmodulin (CaM), respectively, where the extent of methionine bioconjugation on these protein targets can serve as an indicator of oxidative stress or calcium status. In particular, application of PAIR to activity-based CaM detection provides a method for imaging integrated calcium activity in both in vitro cell and in vivo zebrafish models. By relying on native protein biochemistry, PAIR enables redox and metal imaging without introduction of external small molecules or genetically encoded indicators that can potentially buffer the natural/existing pools. This approach can be potentially generalized to target a broader range of analytes by pairing appropriate activity-based protein probes with protein detection reagents in a proximity-driven manner, providing a starting point not only for designing new sensors but also for monitoring endogenous activity of specific protein targets in biological specimens with spatial and temporal fidelity.

Photochemical degradation of imazosulfuron under simulated California rice field conditions.

BACKGROUND: The photodegradation of imazosulfuron (IMZ), a potent broad-spectrum herbicide, was investigated under simulated rice field conditions. Previous reports have indicated that it is photolabile, but have failed to report radiation intensity or determine a quantum yield, precluding extrapolation to environmental rates. Therefore, the objective of this investigation was to determine the photolytic rate of IMZ under simulated rice field conditions and how it is influenced by environmental factors such as turbidity, salinity and temperature. RESULTS: IMZ was efficiently photolyzed in all solutions and fitted pseudo-first-order kinetics. Degradation was faster in HPLC-grade water than in field water. Field-relevant variances in temperature, turbidity and salinity did not significantly influence degradation. The experimentally derived quantum yield for direct photolysis (2.94 × 10(3) ) was used to predict the half-life of IMZ in a California rice field (3.6 days). CONCLUSIONS: Aqueous photolysis is predicted to be an important process in the overall degradation of IMZ in the environment, regardless of variances in salinity, organic matter and temperature. Based on the predicted half-life of IMZ in a California rice field (3.6 days), state-mandated holding periods for field water post-IMZ application (30 days) are expected to allow for sufficient clearance of the herbicide (>98%), preventing significant contamination of the environment upon release of tailwater. © 2015 Society of Chemical Industry.