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The genus Paracoccidioides consists of thermodymorphic fungi responsible for Paracoccidioidomycosis (PCM), a systemic mycosis that has been registered to affect ~10 million people in Latin America. Biogeographical data subdivided the genus Paracoccidioides in five divergent subgroups, which have been recently classified as different species. Genomic sequencing of five Paracoccidioides isolates, representing each of these subgroups/species provided an important framework for the development of post-genomic studies with these fungi. However, functional annotations of these genomes have not been submitted to manual curation and, as a result, ~60-90% of the Paracoccidioides protein-coding genes (depending on isolate/annotation) are currently described as responsible for hypothetical proteins, without any further functional/structural description. The present work reviews the functional assignment of Paracoccidioides genes, reducing the number of hypothetical proteins to ~25-28%. These results were compiled in a relational database called ParaDB, dedicated to the main representatives of Paracoccidioides spp. ParaDB can be accessed through a friendly graphical interface, which offers search tools based on keywords or protein/DNA sequences. All data contained in ParaDB can be partially or completely downloaded through spreadsheet, multi-fasta and GFF3-formatted files, which can be subsequently used in a variety of downstream functional analyses. Moreover, the entire ParaDB environment has been configured in a Docker service, which has been submitted to the GitHub repository, ensuring long-term data availability to researchers. This service can be downloaded and used to perform fully functional local installations of the database in alternative computing ecosystems, allowing users to conduct their data mining and analyses in a personal and stable working environment. These new annotations greatly reduce the number of genes identified solely as hypothetical proteins and are integrated into a dedicated database, providing resources to assist researchers in this field to conduct post-genomic studies with this group of human pathogenic fungi.

Autoinducer 2 (or AI-2) is one of the molecules used by bacteria to trigger the Quorum Sensing (QS) response, which activates expression of genes involved in a series of alternative mechanisms, when cells reach high population densities (including bioluminescence, motility, biofilm formation, stress resistance, and production of public goods, or pathogenicity factors, among others). Contrary to most autoinducers, AI-2 can induce QS responses in both Gram-negative and Gram-positive bacteria, and has been suggested to constitute a trans-specific system of bacterial communication, capable of affecting even bacteria that cannot produce this autoinducer. In this work, we demonstrate that the ethanologenic Gram-negative bacterium Zymomonas mobilis (a non-AI-2 producer) responds to exogenous AI-2 by modulating expression of genes involved in mechanisms typically associated with QS in other bacteria, such as motility, DNA repair, and nitrogen fixation. Interestingly, the metabolism of AI-2-induced Z. mobilis cells seems to favor ethanol production over biomass accumulation, probably as an adaptation to the high-energy demand of N2 fixation. This opens the possibility of employing AI-2 during the industrial production of second-generation ethanol, as a way to boost N2 fixation by these bacteria, which could reduce costs associated with the use of nitrogen-based fertilizers, without compromising ethanol production in industrial plants.

Paracoccidioides brasiliensis is a thermodimorphic fungus associated with paracoccidioidomycosis (PCM), the most common systemic mycosis in Latin America. PCM treatment involves a long-term chemotherapeutic approach and relapses occur at an alarming frequency. Moreover, the emergence of strains with increased drug-resistance phenotypes puts constant pressure on the necessity to develop new alternatives to treat systemic mycoses. In this work, we show that the phenothiazine (PTZ) derivative thioridazine (TR) inhibits in vitro growth of P. brasiliensis yeasts at micromolar concentrations. We employed microarray hybridization to examine how TR affects gene expression in this fungus, identifying ~1800 genes that were modulated in response to this drug. Dataset evaluation showed that TR inhibits the expression of genes that control the onset of the cell wall integrity (CWI) response, hampering production of all major structural polysaccharides of the fungal cell wall (chitin, α-glucan and β-glucan). Although TR and other PTZs have been shown to display antimicrobial activity by various mechanisms, inhibition of CWI signaling has not yet been reported for these drugs. Thus, TR may provide a novel approach to treat fungal infections by targeting cell wall biogenesis.

Paracoccidioides brasiliensis is a thermodimorphic fungus associated with paracoccidioidomycosis (PCM), the most common systemic mycosis in Latin America. PCM treatment involves a long-term chemotherapeutic approach and relapses occur at an alarming frequency. Moreover, the emergence of strains with increased drug-resistance phenotypes puts constant pressure on the necessity to develop new alternatives to treat systemic mycoses. In this work, we show that the phenothiazine (PTZ) derivative thioridazine (TR) inhibits in vitro growth of P. brasiliensis yeasts at micromolar concentrations. We employed microarray hybridization to examine how TR affects gene expression in this fungus, identifying ~1800 genes that were modulated in response to this drug. Dataset evaluation showed that TR inhibits the expression of genes that control the onset of the cell wall integrity (CWI) response, hampering production of all major structural polysaccharides of the fungal cell wall (chitin, α-glucan and β-glucan). Although TR and other PTZs have been shown to display antimicrobial activity by various mechanisms, inhibition of CWI signaling has not yet been reported for these drugs. Thus, TR may provide a novel approach to treat fungal infections by targeting cell wall biogenesis.

Cachexia (CC) is devastating metabolic syndrome associated with a series of underlying diseases that greatly affects life quality and expectancy among cancer patients. Studies involving mouse models, in which CC was induced through inoculation with tumor cells, originally suggested the existence of a direct correlation between the development of this syndrome and changes in the relative proportions of several bacterial groups present in the digestive tract. However, these analyses have focus solely on the characterization of bacterial dysbiosis, ignoring the possible existence of changes in the relative populations of fungi, during the development of CC. Thus, the present study sought to expand such analyses, by characterizing changes that occur in the gut fungal population (mycobiota) of mice, during the development of cancer-induced cachexia. Our results confirm that the mycobiota of CC animals display significant differences, when compared to healthy controls and identification of dysbiotic fungi showed remarkable consistency across successive levels of taxonomic hierarchy. Many of these fungi have also been associated with dysbioses observed in a series of gut inflammatory diseases, such as obesity, Colorectal Cancer (CRC), Myalgic Encephalomyelitis (ME) and Inflammatory Bowel Disease (IBD). Nonetheless, the CC-associated dysbiosis seems to be unique, presenting features observed in both obesity (reduced proportion of Mucoromycota) and CRC/ME/IBD (increased proportions of Sordariomycetes, Saccharomycetaceae and Malassezia). One species of Mucoromycota (Rhyzopus oryzae) stands out as a promising probiotic candidate in adjuvant therapies, aimed at treating and/or preventing the development of CC. Competing Interest Statement The authors have declared no competing interest. Footnotes * https://osf.io/5fxgn * https://www.ncbi.nlm.nih.gov/sra

Lysolecithin might increase ruminal and intestinal emulsification, leading to increased digestibility, but there is minimum information about which is the most appropriate phase to start supplementation and its impacts on feedlot performance and muscle fatty acid profile. Two experiments were conducted to evaluate the effects of phase-feeding of Lysoforte™ eXtend (LYSO). In the first experiment, 1,760 predominantly Bos indicus bullocks (initial body weight of 400 ± 0.561 kg) were allocated in a complete randomized block design. LYSO was supplemented at 1 g/1% of ether extract from the diet. Treatments were no LYSO supplementation (NON); LYSO starting during the growing period and continuing during the finishing period; LYSO starting during the finishing period (FIN); and LYSO during adaptation, growing, and finishing periods (ALL). In the second experiment, the same treatments were evaluated with 96 bullocks (64 Nellore and 32½ Nellore × ½ Angus) in a 4 × 2 factorial arrangement (treatments × genotype). For both studies, intake and average daily gain were accessed; carcass characteristics were evaluated in the first experiment, while digestibility of nutrients and profile of muscle fatty acids were measured in the second experiment. In the first experiment, LYSO increased final body weight ( P < 0.022) and average daily gain (GRO and FIN; P < 0.05). In the second study, a treatment × breed × feeding phase interaction was observed with Nellore having a greater average daily gain ( P < 0.05) than crossbreds in every feeding phase that LYSO was introduced to the diet. A treatment × feeding phase interaction was observed for digestibility, such that LYSO increased total dry matter ( P = 0.004), crude protein ( P = 0.043), and NDF ( P = 0.001) digestibility during the finishing period. A treatment × breed × day classification was observed ( P < 0.05). During the finishing phase, crossbreds treated with LYSO had greater DMI ( P < 0.05) on very hot days than NON. Also, animals treated with LYSO presented a greater C18:3 n3 concentration ( P = 0.047) in the longissimus . Overall, feeding LYSO during GRO and FIN enhanced feedlot performance and should lead to higher intakes during very hot days of the finishing feeding period.