A Novel Oral GyrB/ParE Dual Binding Inhibitor Effective against Multidrug-Resistant and Other High-Threat Pathogens.

Drug-resistant Neisseria gonorrhoeae is a serious global health concern. New drugs are needed that can overcome existing drug resistance and limit the development of new resistances. Here, we describe the small molecule tricyclic pyrimidoindole JSF-2414 [8-(6-fluoro-8-(methylamino)-2-((2-methylpyrimidin-5-yl)oxy)-9H-pyrimido[4,5-b]indol-4-yl)-2-oxa-8-azaspiro[4.

Antitubercular Triazines: Optimization and Intrabacterial Metabolism.

The triazine antitubercular JSF-2019 was of interest due to its in vitro efficacy and the nitro group shared with the clinically relevant delamanid and pretomanid. JSF-2019 undergoes activation requiring FH and one or more nitroreductases in addition to Ddn. An intrabacterial drug metabolism (IBDM) platform was leveraged to demonstrate the system kinetics, evidencing formation of NO and a des-nitro metabolite.

Discovery of camphor-derived pyrazolones as 11β-hydroxysteroid dehydrogenase type 1 inhibitors.

Starting from screening hit, (4S,7R)-1,7,8,8-tetramethyl-2-phenyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (7), we optimized the potency and pharmacokinetic properties. This led to the identification of compounds with good in vivo activity in a mouse pharmacodynamic model of inhibition of 11βHSD1.

Heterobiaryl purine derivatives as potent antiproliferative agents: inhibitors of cyclin dependent kinases. Part II.

C-6 Biarylmethylamino purine derivatives of roscovitine (1) inhibit cyclin dependent kinases and demonstrate potent antiproliferative activity. Replacement of the aryl rings of the C-6 biarylmethylamino group with heterobiaryl rings has provided compounds with significantly improved activity. In particular, derivatives 18 g and 9 c demonstrated 1000-fold and 1250-fold improvements, respectively, in the growth inhibition of HeLa cells compared to roscovitine (1).

Assessing appetitive choice discrimination learning in zebrafish.

Within the last decade, the zebrafish (Danio rerio) has emerged as an important vertebrate model in developmental biology and medicine for problems typically associated with humans. However, where behavioral assays are needed, the utility of the zebrafish model has been limited by the narrow range of procedures so far developed to investigate zebrafish learning. The purpose of this study was to further develop and test procedures to study appetitive choice discrimination learning in zebrafish.

Noncell-autonomous photoreceptor degeneration in a zebrafish model of choroideremia.

Choroideremia is an X-linked hereditary retinal degeneration resulting from mutations in the Rab escort protein-1 (REP1). The Rep1 protein facilitates posttranslational modification of Rab proteins, which regulate intracellular trafficking in the retinal pigment epithelium (RPE) and photoreceptors and are likely involved in the removal of outer segment disk membranes by the RPE. A critical question for potential treatment of choroideremia is whether photoreceptor degeneration results from autonomous defects in opsin transport within the photoreceptor or as a nonautonomous and secondary consequence of RPE degeneration.

Cone survival despite rod degeneration in XOPS-mCFP transgenic zebrafish.

Purpose: In animal models of retinitis pigmentosa, rod photoreceptor degeneration eventually leads to loss of cone photoreceptors. The purpose of this study was to characterize a transgenic model of rod degeneration in zebrafish.

Methods: Zebrafish transgenic for XOPS-mCFP, a membrane-targeted form of cyan fluorescent protein driven by the Xenopus rhodopsin promoter, were generated by plasmid injection.

Ultraviolet- and short-wavelength cone contributions alter the early components of the ERG of young zebrafish.

The electroretinogram (ERG) is a commonly used measure to examine retinal processing in both basic and clinical research. The purpose of this study was to determine the retinal mechanisms responsible for the developmental differences found in the zebrafish ERG waveform. The ERG of young zebrafish possesses a voltage-negative response to ultraviolet- and short-wavelength stimuli, but not to middle- and long-wavelength stimuli; the ERG of adult zebrafish does not possess this response component.

Effects of restricted spectral rearing on the development of zebrafish retinal physiology.

Research has shown that rearing in abnormal lighting environments affects both visual behavior and retinal physiology in zebrafish larvae. These studies, however, used only constant dark and constant white light as the experimental rearing conditions. This study assessed the effects of rearing larvae in restricted spectral lighting environments on zebrafish retinal physiology.

Ethanol exposure alters zebrafish development: a novel model of fetal alcohol syndrome.

Prenatal exposure to alcohol has been shown to produce the overt physical and behavioral symptoms known as fetal alcohol syndrome (FAS) in humans. Also, it is believed that low concentrations and/or short durations of alcohol exposure can produce more subtle effects. The purpose of this study was to investigate the effects of embryonic ethanol exposure on the zebrafish (Danio rerio) in order to determine whether this species is a viable animal model for studying FAS.

Visual processing of the zebrafish optic tectum before and after optic nerve damage.

Although the zebrafish has become an important model in visual neuroscience, little has been done to examine the processing of its higher visual centers. The purpose of this work was twofold. The first purpose was to examine the physiology of the zebrafish retinotectal system and its relationship to retinal physiology.

APB differentially affects the cone contributions to the zebrafish ERG.

APB (DL-2-amino-4-phosphonobutyric acid) has been found to affect the retinal processing of many vertebrate species as evidenced by the suppression of the b-wave component of the electroretinogram (ERG). The present study examined the effects of APB on the cone contributions to the ERG response of adult zebrafish (Danio rerio). ERG responses were obtained from light-adapted adult zebrafish following intravitreal injection of either saline alone or saline with various concentrations of APB ranging from 10 microm to 500 microM.

Effects of embryonic exposure to ethanol on zebrafish visual function.

Across a variety of species, including humans, it has been shown that embryos exposed to ethanol display eye abnormalities as well as deficiencies in visual physiology and behavior. The purpose of this study was to examine the effects of embryonic exposure to ethanol on visual function in zebrafish. Visual function was assessed physiologically, via electroretinogram (ERG) recordings, and behaviorally, by measuring visual acuity with the optomotor response.