Baclofen alters gustatory discrimination capabilities and induces a conditioned taste aversion (CTA)

<p>Abstract</p> <p>Background</p> <p>Studies intending to measure drug-induced changes in learning and memory are challenged to parse out the effects of drugs on sensory, motor, and associative systems in the brain. In the context of conditioned taste aversion (CTA), drugs that alter the sensorium of subjects and affect their ability to taste and/or feel malaise may limit the ability of investigators to make conclusions about associative effects of these substances. Since the GABAergic system is implicated in inhibition, the authors were hopeful to use the GABA agonist, baclofen (BAC), to enhance extinction of a CTA, but first a preliminary evaluation of BAC's peripheral effects on animals' sensorium had to be completed due to a lack of published literature in this area.</p> <p>Findings</p> <p>Our first experiment aimed to evaluate the extent to which the GABA_Bagonist, BAC, altered the ability of rats to differentiate between 0.3% and 0.6% saccharin (SAC) in a two bottle preference test. Here we report that 2 or 3 mg/kg (i.p.) BAC, but not 1 mg/kg BAC, impaired animals' gustatory discrimination abilities in this task. Furthermore, when SAC consumption was preceded by 2 or 3 mg/kg (i.p.) BAC, rats depressed their subsequent SAC drinking.</p> <p>A second experiment evaluated if the suppression of SAC and water drinking (revealed in Experiment 1) was mediated by amnesiac effects of BAC or whether BAC possessed US properties in the context of the CTA paradigm. The time necessary to reach an asymptotic level of CTA extinction was not significantly different in those animals that received the 3 mg/kg dose of BAC compared to more conventionally SAC + lithium chloride (LiCl, 81 mg/kg) conditioned animals.</p> <p>Conclusions</p> <p>Our findings were not consistent with a simple amnesia-of-neophobia explanation. Instead, results indicated that 2 and 3 mg/kg (i.p.) BAC were capable of inducing a CTA, which was extinguishable via repeated presentations of SAC only. Our data indicate that, depending on the dose, BAC can alter SAC taste discrimination and act as a potent US in the context of a CTA paradigm.</p

AI is a viable alternative to high throughput screening: a 318-target study

: High throughput screening (HTS) is routinely used to identify bioactive small molecules. This requires physical compounds, which limits coverage of accessible chemical space. Computational approaches combined with vast on-demand chemical libraries can access far greater chemical space, provided that the predictive accuracy is sufficient to identify useful molecules. Through the largest and most diverse virtual HTS campaign reported to date, comprising 318 individual projects, we demonstrate that our AtomNet® convolutional neural network successfully finds novel hits across every major therapeutic area and protein class. We address historical limitations of computational screening by demonstrating success for target proteins without known binders, high-quality X-ray crystal structures, or manual cherry-picking of compounds. We show that the molecules selected by the AtomNet® model are novel drug-like scaffolds rather than minor modifications to known bioactive compounds. Our empirical results suggest that computational methods can substantially replace HTS as the first step of small-molecule drug discovery

Apoptin protein multimers form distinct higher-order nucleoprotein complexes with DNA

The chicken anaemia virus-derived protein apoptin is a tumour-specific cell-killing agent. It is biologically active as a highly stable, multimeric complex, consisting of 30-40 monomers. In tumour cells, but negligibly in normal cells, apoptin is imported into the nucleus prior to the induction of apoptosis. Immunoelectron microscopic data we report here indicate that apoptin predominantly co-localises with heterochromatin and nucleoli within tumour cells. Apoptin's preference for these DNA-dense nuclear bodies may be explained by our finding that apoptin cooperatively forms distinct superstructures with DNA in vitro. These superstructures do not grow beyond a diameter of similar to200 nm, containing up to 20 multimeric apoptin complexes and similar to3 kb of DNA. Furthermore, we show a single apoptin multimer to have eight independent, non-specific DNA-binding sites which preferentially bind strand ends, but which can also collaborate to bind longer stretches of DNA. Apoptin's high affinity for naked, undecorated double- and single-stranded DNA and for DNA fibre ends suggests that it may also capture such DNA in superstructures in vivo. Since these forms of DNA are predominantly found in transcriptionally active, replicating and damaged DNA, apoptin could be triggering apoptosis by interfering with DNA transcription and synthesis