Modelling distributions of Aedes aegypti and Aedes albopictus using climate, host density and interspecies competition.

Florida faces the challenge of repeated introduction and autochthonous transmission of arboviruses transmitted by Aedes aegypti and Aedes albopictus. Empirically-based predictive models of the spatial distribution of these species would aid surveillance and vector control efforts. To predict the occurrence and abundance of these species, we fit a mixed-effects zero-inflated negative binomial regression to a mosquito surveillance dataset with records from more than 200,000 trap days, representative of 53% of the land area and ranging from 2004 to 2018 in Florida. We found an asymmetrical competitive interaction between adult populations of Aedes aegypti and Aedes albopictus for the sampled sites. Wind speed was negatively associated with the occurrence and abundance of both vectors. Our model predictions show high accuracy (72.9% to 94.5%) in validation tests leaving out a random 10% subset of sites and data since 2017, suggesting a potential for predicting the distribution of the two Aedes vectors.

E-cigarette aerosols containing nicotine modulate nicotinic acetylcholine receptors and astroglial glutamate transporters in mesocorticolimbic brain regions of chronically exposed mice.

Nicotine exposure increases the release of glutamate in part through stimulatory effects on pre-synaptic nicotinic acetylcholine receptors (nAChRs). To assess the impact of chronic electronic (e)-cigarette use on these drug dependence pathways, we exposed C57BL/6 mice to three types of inhalant exposures for 3 months; 1) e-cigarette aerosol generated from liquids containing nicotine (ECN), 2) e-cigarette aerosol generated from liquids containing vehicle chemicals without nicotine (Veh), and 3) air only (AC). We investigated the effects of daily e-cigarette exposure on protein levels of α7 nAChR and α4/ß2 nAChR, gene expression and protein levels of astroglial glutamate transporters, including glutamate transporter-1 (GLT-1) and cystine/glutamate antiporter (xCT), in the frontal cortex (FC), striatum (STR) and hippocampus (HIP). We found that chronic inhalation of ECN increased α4/ß2 nAChR in all brain regions, and increased α7 nAChR expression in the FC and STR. The total GLT-1 relative mRNA and protein expression were decreased in the STR. Moreover, GLT-1 isoforms (GLT-1a and GLT-1b) were downregulated in the STR in ECN group. However, inhalation of e-cigarette aerosol downregulated xCT expression in STR and HIP compared to AC and Veh groups. ECN group had increased brain-derived neurotrophic factor in the STR compared to control groups. Finally, mass spectrometry detected high concentrations of the nicotine metabolite, cotinine, in the FC and STR in ECN group. This work demonstrates that chronic inhalation of nicotine within e-cigarette aerosols significantly alters the expression of nAChRs and astroglial glutamate transporters in specific mesocorticolimbic brain regions.

Combining Neurobehavioral Analysis and In Vivo Photoaffinity Labeling to Understand Protein Targets of Methamphetamine in Casper Zebrafish.

Photoaffinity labeling (PAL) remains one of the most widely utilized methods of determining protein targets of drugs. Although useful, the scope of this technique has been limited to in vitro applications because of the inability of UV light to penetrate whole organisms. Herein, pigment-free Casper zebrafish were employed to allow in vivo PAL. A methamphetamine-related phenethylamine PAL probe, designated here as 2, demonstrated dose-dependent effects on behavior similar to methamphetamine and permitted concentration-dependent labeling of protein binding partners. Click chemistry was used to analyze binding partners via fluoroimaging. Conjugation to a biotin permitted streptavidin pull-down and proteomic analysis to define direct binding partners of the methamphetamine probe. Bioinformatic analysis revealed the probe was chiefly bound to proteins involved in phagocytosis and mitochondrial function. Future applications of this experimental paradigm combining examination of drug-protein binding interactions alongside neurobehavioral readouts via in vivo PAL will significantly enhance our understanding of drug targets, mechanism(s) of action, and toxicity/lethality.

The Effect of Electronic-Cigarette Vaping on Cardiac Function and Angiogenesis in Mice.

The rapid increase in use of electronic-cigarettes (e-cigarettes), especially among youth, raises the urgency for regulating bodies to make informed decisions, guidance, and policy on these products. This study evaluated cardiac function in an experimental model following exposure to e-cigarettes. We subjected C57BL/6 mice to e-cigarette vaping for 2-weeks, and cardiac function was assessed using echocardiography. Cardiac tissues were collected at the end of e-cigarette exposure for pathological analysis. The experimental data showed that e-cigarette vaping (3 h/day for 14 days) had no significant effect on cardiac contractility as measured by ejection fraction. However, it significantly increased angiogenesis in mouse heart tissue. We found that e-cigarette exposure increased the endothelial cell marker CD31 and CD34 to approximately 2 fold (p < 0.05) in heart tissue from female mice and about 150% (p < 0.05) in male mice. E-cigarette vaping also caused slower weight gain compared to mice exposed to room air. In addition, short-term e-cigarette exposure slightly increased collagen content in heart tissue but did not result in significant tissue fibrosis. These results suggest that short-term exposure to e-cigarettes has no acute effect on cardiac contractile function or tissue fibrosis, but it increases cardiac angiogenesis.

Pharmacokinetics and pharmacodynamics of nitric oxide mimetic agents.

Drug discovery focusing on NO mimetics has been hamstrung due to its unconventional nature. Central to these challenges is the fact that direct measurement of molecular NO in biological systems is exceedingly difficulty. Hence, drug development of NO mimetics must rely upon measurement of the NO donating specie (i.e., a prodrug) and a downstream marker of efficacy without directly measuring the molecule, NO, that is responsible for biological effect. The focus of this review is to catalog in vivo attempts to monitor the pharmacokinetics (PK) of the NO donating specie and the pharmacodynamic (PD) readout of NO bioactivity.

Furoxans (Oxadiazole-4 N-oxides) with Attenuated Reactivity are Neuroprotective, Cross the Blood Brain Barrier, and Improve Passive Avoidance Memory.

Nitric oxide (NO) mimetics and other agents capable of enhancing NO/cGMP signaling have demonstrated efficacy as potential therapies for Alzheimer's disease. A group of thiol-dependent NO mimetics known as furoxans may be designed to exhibit attenuated reactivity to provide slow onset NO effects. The present study describes the design, synthesis, and evaluation of a furoxan library resulting in the identification of a prototype furoxan, 5a, which was profiled for use in the central nervous system. Furoxan 5a demonstrated negligible reactivity toward generic cellular thiols under physiological conditions. Nonetheless, cGMP-dependent neuroprotection was observed, and 5a (20 mg/kg) reversed cholinergic memory deficits in a mouse model of passive avoidance fear memory. Importantly, 5a can be prepared as a pharmaceutically acceptable salt and is observed in the brain 12 h after oral administration, suggesting potential for daily dosing and excellent metabolic stability. Continued investigation into furoxans as attenuated NO mimetics for the CNS is warranted.

Identification and characterization of 5α-cyprinol-sulfating cytosolic sulfotransferases (Sults) in the zebrafish (Danio rerio).

5α-Cyprinol 27-sulfate is the major biliary bile salt present in cypriniform fish including the zebrafish (Danio rerio). The current study was designed to identify the zebrafish cytosolic sulfotransferase (Sult) enzyme(s) capable of sulfating 5α-cyprinol and to characterize the zebrafish 5α-cyprinol-sulfating Sults in comparison with human SULT2A1. Enzymatic assays using zebrafish homogenates showed 5α-cyprinol-sulfating activity. A systematic analysis, using a panel of recombinant zebrafish Sults, revealed two Sult2 subfamily members, Sult2st2 and Sult2st3, as major 5α-cyprinol-sulfating Sults. Both enzymes showed higher activities using 5α-cyprinol as the substrate, compared to their activity with DHEA, a representative substrate for mammalian SULT2 family members, particularly SULT2A1. pH-Dependence and kinetics experiments indicated that the catalytic properties of zebrafish Sult2 family members in mediating the sulfation of 5α-cyprinol were different from those of either zebrafish Sult3st4 or human SULT2A1. Collectively, these results imply that both Sult2st2 and Sult2st3 have evolved to sulfate specifically C27-bile alcohol, 5α-cyprinol, in Cypriniform fish, whereas the enzymatic characteristics of zebrafish Sult3 members, particularly Sult3st4, correlated with those of human SULT2A1.