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The fungal pathogen Candida auris represents a severe threat to hospitalized patients. Its resistance to multiple classes of antifungal drugs and ability to spread and resist decontamination in healthcare settings make it especially dangerous. We screened 1,990 clinically approved and late-stage investigational compounds for the potential to be repurposed as antifungal drugs targeting C. auris and narrowed our focus to five Food and Drug Administration (FDA)-approved compounds with inhibitory concentrations under 10 µM for C. auris and significantly lower toxicity to three human cell lines. These compounds, some of which had been previously identified in independent screens, include three dihalogenated 8-hydroxyquinolines: broxyquinoline, chloroxine, and clioquinol. A subsequent structure-activity study of 32 quinoline derivatives found that 8-hydroxyquinolines, especially those dihalogenated at the C5 and C7 positions, were the most effective inhibitors of C. auris. To pursue these compounds further, we exposed C. auris to clioquinol in an extended experimental evolution study and found that C. auris developed only twofold to fivefold resistance to the compound. DNA sequencing of resistant strains and subsequent verification by directed mutation in naive strains revealed that resistance was due to mutations in the transcriptional regulator CAP1 (causing upregulation of the drug transporter MDR1) and in the drug transporter CDR1. These mutations had only modest effects on resistance to traditional antifungal agents, and the CDR1 mutation rendered C. auris more susceptible to posaconazole. This observation raises the possibility that a combination treatment involving an 8-hydroxyquinoline and posaconazole might prevent C. auris from developing resistance to this established antifungal agent. IMPORTANCE The rapidly emerging fungal pathogen Candida auris represents a growing threat to hospitalized patients, in part due to frequent resistance to multiple classes of antifungal drugs. We identify a class of compounds, the dihalogenated 8-hydroxyquinolines, with broad fungistatic ability against a diverse collection of 13 strains of C. auris. Although this compound has been identified in previous screens, we extended the analysis by showing that C. auris developed only modest twofold to fivefold increases in resistance to this class of compounds despite long-term exposure; a noticeable difference from the 30- to 500-fold increases in resistance reported for similar studies with commonly used antifungal drugs. We also identify the mutations underlying the resistance. These results suggest that the dihalogenated 8-hydroxyquinolines are working inside the fungal cell and should be developed further to combat C. auris and other fungal pathogens. Lohse and colleagues characterize a class of compounds that inhibit the fungal pathogen C. auris. Unlike many other antifungal drugs, C. auris does not readily develop resistance to this class of compounds.

An unusual feature of the opportunistic pathogen Candida albicans is its ability to switch stochastically between two distinct, heritable cell types called white and opaque. Here, we show that only opaque cells, in response to environmental signals, massively upregulate a specific group of secreted proteases and peptide transporters, allowing exceptionally efficient use of proteins as sources of nitrogen. We identify the specific proteases [members of the secreted aspartyl protease (SAP) family] needed for opaque cells to proliferate under these conditions, and we identify four transcriptional regulators of this specialized proteolysis and uptake program. We also show that, in mixed cultures, opaque cells enable white cells to also proliferate efficiently when proteins are the sole nitrogen source. Based on these observations, we suggest that one role of white-opaque switching is to create mixed populations where the different phenotypes derived from a single genome are shared between two distinct cell types.

The fitness effects of new mutations determine key properties of evolutionary processes. Beneficial mutations drive evolution, yet selection is also shaped by the frequency of small-effect deleterious mutations, whose combined effect can burden otherwise adaptive lineages and alter evolutionary trajectories and outcomes in clonally evolving organisms such as viruses, microbes, and tumors. The small effect sizes of these important mutations have made accurate measurements of their rates difficult. In microbes, assessing the effect of mutations on growth can be especially instructive, as this complex phenotype is closely linked to fitness in clonally evolving organisms. Here, we perform high-throughput time-lapse microscopy on cells from mutation-accumulation strains to precisely infer the distribution of mutational effects on growth rate in the budding yeast, Saccharomyces cerevisiae. We show that mutational effects on growth rate are overwhelmingly negative, highly skewed towards very small effect sizes, and frequent enough to suggest that deleterious hitchhikers may impose a significant burden on evolving lineages. By using lines that accumulated mutations in either wild-type or slippage repair-defective backgrounds, we further disentangle the effects of 2 common types of mutations, single-nucleotide substitutions and simple sequence repeat indels, and show that they have distinct effects on yeast growth rate. Although the average effect of a simple sequence repeat mutation is very small (approximately 0.3%), many do alter growth rate, implying that this class of frequent mutations has an important evolutionary impact. The fitness effects of new mutations determine key properties of evolutionary processes. This study uses image-based growth measurements of budding yeast and statistical modeling to show that most new mutations are weakly deleterious, and distinguish the distributions of effects caused by single-nucleotide substitutions from those caused by microsatellite mutations. [ABSTRACT FROM AUTHOR]

School bullying is a source of growing concern. A number of intervention programs emphasize the importance of a positive school climate in preventing bullying behavior. The aim of the presented pilot study was to examine whether calming background music, through its effect on arousal and mood, could create a pleasant atmosphere and reduce bullying occurrence. On the first week, 56 sixth-grade students from two classes completed a bullying and arousal questionnaire after the big recess on three consecutive days, as a baseline measurement. On the second week, calming background music was played during the big recess on three consecutive days and children completed the same questionnaires. On the final week, music was removed and participants completed the questionnaires again on three consecutive days. Results showed significantly reduced bullying occurrence, lower arousal levels, and higher enjoyment of recess when music was played. Bullying occurrence increased on the third week, though it remained lower than on the first week. Arousal levels returned to baseline level once music was removed. Results suggest calming background music may be used in combination with other intervention actions to create a positive school atmosphere and reduce aggressive behavior.

Background music is often used in ads as a means of persuasion. Previous research has studied the effect of music in advertising using neutral or uncontroversial products. The aim of the studies reported here was to examine the effect of music on the perception of products promoting unethical behavior. Each of the series of three studies described examined the effect of background music on recall and evaluation of a fictive radio ad promoting different types of cheating. The studies consider the effect of involvement, attitudes, priming and presentation context, and music's valence. In all the studies, background music led to reduced recall of information. Positive-valence music reduced awareness of the unethical message, and increased acceptance of the product. The results demonstrate the power of music to manipulate and bias moral judgment. (Contains 4 tables and 4 figures.)

A fundamental question in biology is how a eukaryotic cell type can be stably maintained through many rounds of DNA replication and cell division. In this paper, we investigate this question in a fungal species, Candida albicans, where two different cells types (white and opaque) arise from the same genome. Once formed, each cell type is stable for thousands of generations. Here, we investigate the mechanisms underlying opaque cell "memory." Using an auxin-mediated degradation system, we rapidly removed Wor1, the primary transcription activator of the opaque state and, using a variety of methods, determined how long cells can maintain the opaque state. Within approximately 1 h of Wor1 destruction, opaque cells irreversibly lose their memory and switch to the white cell state. This observation rules out several competing models for cell memory and demonstrates that the continuous presence of Wor1 is needed to maintain the opaque cell state--even across a single cell division cycle. We also provide evidence for a threshold concentration of Wor1 in opaque cells, below which opaque cells irreversibly switch to white cells. Finally, we provide a detailed description of the gene expression changes that occur during this switch in cell types. [ABSTRACT FROM AUTHOR]

Children hear music in the background of a large variety of situations and activities. Throughout development, they acquire knowledge both about the syntactical norms of tonal music, and about the relationship between musical form and emotion. Five to six-year-old children heard a story, with a background "happy", "sad" or no melody. Results show that background music affected children's interpretation of the story: "happy" background music led to positive interpretations, whereas "sad" background music led to more negative interpretations of the story. The effect of "happy" music was stronger than that of "sad" music. Implications for education are discussed.

During stay-at-home orders in response to COVID-19, individuals had to deal with both health-related fear and anxiety and the difficulties related to social distancing and isolation. The present study, conducted in Israel shortly after the first lockdown was lifted, at the end of May 2020, examined individuals' subjective evaluation of differences in their music listening habits and emotional reaction to music compared with normal times. A total of 200 participants filled an online questionnaire focusing on three issues: (1) changes in amount and situations of music listening. These included reference to new music clip types recently created and directly related to COVID-19 and its effects (Corona Clips); (2) changes in intensity of emotions experienced in reaction to music; and (3) changes in general emotions. For most participants music listening and uses remained similar or increased. Both emotional reaction to music general negative and socially related emotions were stronger than under normal circumstances. Music uses and emotion scales were correlated with socially related emotions. The results support previous findings regarding the use of music for mood regulation and the importance of music as a means for social contact and provide a demonstration of subjective evaluation of these functions in real-time coping during a global crisis. [ABSTRACT FROM AUTHOR]

Music is commonly used in political contexts, to strengthen attitudes and group cohesion. The reported research examined reactions to music representing national values or contesting them in individuals with different political orientations, on issues related to national pride, cohesion and free expression. In Study 1, 100 Israeli participants heard three “patriotic” or “protest” songs and rated their agreement with statements regarding them. Beyond a number of main effects of music and of political orientation, several interactions between these two variables were found. For right-wing participants, patriotic music increased pride whereas protest music increased shame and fear of social disintegration. For left-wing participants, protest music led to higher agreement with the right to free expression. Study 2 included 78 participants and repeated the procedure with parallel texts. Main effects of texts were found, but no main effects of political orientation or interactions were found. Results are discussed in terms of the role and impact of music in political settings. [ABSTRACT FROM AUTHOR]