Pregnenolone sulfate analogues differentially modulate GABAA receptor closed/desensitised states

BACKGROUND AND PURPOSE: GABAA receptors are regulated by numerous classes of allosteric modulators. However, regulation of receptor macroscopic desensitisation remains largely unexplored and may offer new therapeutic opportunities. Here, we report the emerging potential for modulating desensitisation with analogues of the endogenous inhibitory neurosteroid, pregnenolone sulfate. EXPERIMENTAL APPROACH: New pregnenolone sulfate analogues were synthesised incorporating various heterocyclic substitutions located at the C-21 position on ring D. The pharmacological profiles of these compounds were assessed using electrophysiology and recombinant GABAA receptors together with mutagenesis, molecular dynamics simulations, structural modelling and kinetic simulations. KEY RESULTS: All seven analogues retained a negative allosteric modulatory capability whilst exhibiting diverse potencies. Interestingly, we observed differential effects on GABA current decay by compounds incorporating either a six- (compound 5) or five-membered heterocyclic ring (compound 6) on C-21, which was independent of their potencies as inhibitors. We propose that differences in molecular charges, and the targeted binding of analogues to specific states of the GABAA receptor, are the most likely cause of the distinctive functional profiles. CONCLUSIONS AND IMPLICATIONS: Our findings reveal that heterocyclic addition to inhibitory neurosteroids not only affected their potency and macroscopic efficacy but also affected innate receptor mechanisms that underlie desensitisation. Acute modulation of macroscopic desensitisation will determine the degree and duration of GABA inhibition, which are vital for the integration of neural circuit activity. Discovery of this form of modulation could present an opportunity for next-generation GABAA receptor drug design and development

Phage Hunting at the University of Mary Washington: Genome Annotation of Hari and JackRabbit

Bacillus thuringiensis subspecies Kurstaki (BTK) is often used as a microbial insecticide for pest control and as a simulant for Bacillus anthracis in biowarfare and bioterrorism studies. Students in 2021 Phage Hunters class at University of Mary Washington isolated nine bacteriophages using the host Bacillus thuringiensis subspecies Kurstaki. Two phages, Hari and Jackrabbit, were sent to SEAPHAGES for sequencing are currently being annotated in the lab during the Spring semester. Hari was found in a soil sample obtained from King George, VA while JackRabbit was isolated from Linton, VA. Both samples were isolated from enriched cultures. Hari has a genome length of 161,978 bp, which auto-annotated with 286 features, and a direct terminal repeat of 2,633 bp. Hari is most similar to DIGNKC, SBP8a and PPIsBest by BLAST. JackRabbit has a genome length of 161,552 bp, which auto-annotated with 288 features, and a direct terminal repeat of 2,821 bp

Robots As Intentional Agents: Using Neuroscientific Methods to Make Robots Appear More Social

Robots are increasingly envisaged as our future cohabitants. However, while considerable progress has been made in recent years in terms of their technological realization, the ability of robots to interact with humans in an intuitive and social way is still quite limited. An important challenge for social robotics is to determine how to design robots that can perceive the user’s needs, feelings, and intentions, and adapt to users over a broad range of cognitive abilities. It is conceivable that if robots were able to adequately demonstrate these skills, humans would eventually accept them as social companions. We argue that the best way to achieve this is using a systematic experimental approach based on behavioral and physiological neuroscience methods such as motion/eye-tracking, electroencephalography, or functional near-infrared spectroscopy embedded in interactive human–robot paradigms. This approach requires understanding how humans interact with each other, how they perform tasks together and how they develop feelings of social connection over time, and using these insights to formulate design principles that make social robots attuned to the workings of the human brain. In this review, we put forward the argument that the likelihood of artificial agents being perceived as social companions can be increased by designing them in a way that they are perceived as intentional agents that activate areas in the human brain involved in social-cognitive processing. We first review literature related to social-cognitive processes and mechanisms involved in human–human interactions, and highlight the importance of perceiving others as intentional agents to activate these social brain areas. We then discuss how attribution of intentionality can positively affect human–robot interaction by (a) fostering feelings of social connection, empathy and prosociality, and by (b) enhancing performance on joint human–robot tasks. Lastly, we describe circumstances under which attribution of intentionality to robot agents might be disadvantageous, and discuss challenges associated with designing social robots that are inspired by neuroscientific principles