Biology subjects

May, J.

Publications and source records attributed to May, J..

3 recordsLinked to original sources

bioRxiv2021

Prefrontal cortex neural compensation during an operant devaluation task

Deficits in goal-directed action are reported in multiple neuropsychiatric conditions, including schizophrenia. However, dysfunction is not always apparent in early stages of schizophrenia, possibly due to neural compensation. We designed a novel devaluation task in which goal-directed action could be guided by stimulus-outcome (S-O) [presumably orbitofrontal cortex (OFC)-mediated] or response-outcome (R-O) associations [presumably prelimbic cortex (PL)-mediated]. We previously found suggestive evidence that OFC and PL could compensate for each other in this task, and we more directly assessed this potential compensation here. In Experiment 1, rats received OFC, PL, combined OFC+PL, or sham lesions and then completed our devaluation task. The OFC+PL lesion group exhibited impaired devaluation. In Experiment 2, rats received cholera-toxin-b (CTb) into OFC and either neurotoxic or sham PL lesions. Rats were then sacrificed on the last training day to double-label for Arc and CTb. We found increased Arc+CTb in mediodorsal thalamus (MD) and increased Arc+ neurons in OFC when PL was lesioned, suggesting that PL lesions lead to a compensatory increased activation of the MD[->]OFC circuit. Our results suggest that our devaluation task can model neural compensation between OFC and PL and this compensation may be regulated by MD. Significance StatementTo detect compensatory responses, behavioral models that use different strategies must be developed to determine if the strategies shift when a brain area or circuit is incapacitated. Neural compensation is commonly observed in human research but only a few models of neural compensation exist, and few identify compensation within the prefrontal cortex. This research is among the first to show neural compensation between prefrontal cortex regions and implicate a thalamocortical circuit in modulating this compensation. Not only will this model provide a way to behaviorally identify subtle neurological shifts, it can also elucidate basic neurological mechanisms that mediate how circuits interact with each other and how dysfunction in one circuit can affect connectivity in other brain areas.

neuroscience↗

bioRxiv2020

The genomic epidemiology of multi-drug resistant nontyphoidal Salmonella causing invasive disease in sub-Saharan Africa

BackgroundInvasive nontyphoidal Salmonella (iNTS) is one of the leading causes of bacteraemia in sub-Saharan Africa. Multi-drug resistance (MDR) and further resistance to third generation cephalosporins and fluoroquinolones have emerged in multiple iNTS serotypes. Molecular epidemiological investigations of nontyphoidal Salmonella are needed to better understand the genetic characteristics and transmission dynamics associated with major MDR iNTS serotypes across the continent. MethodsA total of 166 nontyphoidal Salmonella isolates causing invasive disease were collected from a multi-centre study in eight African countries between 2010 and 2014, and whole-genome sequenced to investigate the geographical distribution, antimicrobial genetic determinants and population structure of iNTS serotypes-genotypes. Phylogeographical reconstruction was further conducted in context of the existing genomic framework of iNTS serotypes Typhimurium and Enteritidis. Population-based incidence of MDR-iNTS disease was also estimated. ResultsSalmonella enterica subsp. Enterica serotype Typhimurium (S. Typhimurium) sequence-type (ST) 313 and Salmonella enterica subsp. Enterica serotype Enteritidis (S. Enteritidis) ST11 were predominant, and both exhibited high frequencies of MDR. Salmonella enterica subsp. Enterica serotype Dublin (S. Dublin) ST10 emerged in West Africa. Mutations in the gyrA gene were identified in S. Enteritidis and S. Typhimurium in Ghana; and ST313 carrying blaCTX-M-15 was found in Kenya. Inter-country transmission of MDR ST313 lineage II and the West African Clade of MDR ST11 between Ghana and neighbouring countries including Mali, Burkina Faso, and Nigeria were evident. The incidence of MDR-iNTS disease exceeded 100/100,000-person years-of-observation (PYO) in children aged <5 years in several West African countries. ConclusionsMultiple MDR iNTS serotypes-sequence types, predominantly S. Typhimurium ST313 and S. Enteritidis ST11, are co-circulating in sub-Saharan Africa with evidence of transmission between West African countries. The development of safe and effective iNTS vaccines coupled with appropriate antimicrobial stewardship and adequate epidemiological monitoring are essential to limit the impact of these pathogens in Africa.

genomics↗

bioRxiv2020

Ebselen Exhibits Antimicrobial Activity Against Clostridioides difficile By Disrupting Redox Associated Metabolism

High recurrence rates and spread of antibiotic-resistant strains necessitate the need for alternative therapeutics for Clostridioides difficile infections (CDIs). Ebselen, a reactive organoselenium compound inhibits C. difficile virulence toxins TcdA and TcdB, by covalently binding to their cysteine protease domains. Ebselen is thought to lack antibacterial activity against C. difficile cells and its anti-toxin action is suggested to be solely responsible for its efficacy. However, C. difficile has several essential cysteine-containing enzymes that could be potential sites for covalent modification by ebselen; hence, we re-evaluated its anti-C. difficile properties. In BHI agar, ebselen inhibited almost all C. difficile strains (MICs of 2-8 {micro}g/ml), with ribotype 078 being intrinsically resistant (MIC>64 {micro}g/ml). Wilkins-Chalgren and Brucella agars are recommended media for anaerobic susceptibility testing. Ebselen was either slightly attenuated by pyruvate found in Wilkins-Chalgren agar or obliterated by blood in Brucella agars. Transcriptome analysis showed ebselen altered redox-associated processes, cysteine metabolism and significantly enhanced the expression of Stickland proline metabolism to likely regenerate NAD+ from NADH. Intracellularly cells increased the uptake of cysteines, depleted non-protein thiols and disrupted NAD+/NADH redox ratio. Growth inhibitory concentrations of ebselen also reduced toxin and spore production. Taken together, ebselen has bactericidal activity against C. difficile, with multiple mechanisms of action that negatively impacts toxin production and sporulation. To harness the polypharmacological properties of ebselen, chemical optimization is warranted, especially to obtain derivatives that could be effective in severe CDI, where intestinal bleeding could occur.

microbiology↗