This week in PLOS Biology

In PLOS Biology this week you can read about neurons involved in circadian rhythms, decision-making in rats, modulation of a key cancer cell pathway, glucocorticoid receptor function and anti-fungal drug-resistance.

• Yeast infections can be at best annoying, and at worst life-threatening. Unlike bacterial infections, there are relatively few drugs available to treat them. One of the most commonly used is Fluconazole, but resistance to this drug is increasing. In a research article this week (with accompanying synopsis), Benjamin Harrison, Judith Berman, and colleagues showed that Fluconazole may actually unwittingly collude in the steps leading to resistance. When Fluconazole was used to treat yeast (Candida albicans) infections in the ears of mice, some yeast cells showed abnormal growth, forming ‘trimeras’ of three-lobed cells. The progeny of these trimeras (yeasts reproduce by budding) had abnormal numbers of chromosomes, increasing the odds of some cells containing large numbers of drug-resistance genes.

• The glucocorticoid receptor (GR) is a transcription factor expressed in almost every cell in the vertebrate body. It binds steroid hormones from the glucocorticoid family, which are often used in a therapeutic capacity. After binding these molecules, GR has two different modes of action – transactivation and transrepression. In an article in this week’s PLOS Biology Gordon L. Hager and colleagues (with an accompanying synopsis) attempt to clarify GR’s different activites. Their results challenge the prevailing view that GR’s dimerization state (whether the receptor exists as a single molecule or two tightly bound ones) determines whether it initiates transactivation or transrepression. As transactivation is linked to many of the side effects that GCs cause when used therapeutically, a deeper understanding of these mechanisms could have clinical relevance.

• The RAS/MAPK pathway was the focus of research by Dariel Ashton-Beaucage, Marc Therrien and colleagues. This pathway has a notable involvement in cancer as mutations in the components of the pathway are associated with uncontrolled cell proliferation. A global screen in Drosophila cells using RNAi to systematically knock down genes identifies a large group of transcription and splicing factors that modulate RAS/MAPK signalling by altering the expression of MAPK.

• How do you prioritise decisions? Irene Avila & Shih-Chieh Lin looked at neurons in the brains of rats that determine responses to motivationally salient stimuli (those which are related to important outcomes). Their study shows that neurons in a region of the brain called the basal forebrain (BF) play a major role in determining the speed of decisions. When a stimulus (white noise or clicking) preceded a reward, decision-making speeds were increased. This research has implications for the potential role of BF neurons in neurological conditions characterised by slow reaction times, such as dementia and schizophrenia. More information is available in an accompanying synopsis.

• The circadian clock runs as an intricate molecular oscillator in many separate cells, but these need to be synchronised in order to provide a consensus signal to control behaviour and other circadian traits. This syncing job is known to be done by the Pigment Dispersing Factor (PDF) neuropeptide signalling pathway. A study of Drosophila circadian neurons, by Adam Seluzicki, Ravi Allada and colleagues reveals that the PDF pathway splits in two, independently using cyclic AMP to sync circadian clocks via protein kinase A and to acutely control neuronal excitability, possibly via a cyclic nucleotide-gated channel.