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[...]mating and recombination of Cryptococcus have to occur in nature, as supported by population studies of environmental isolates [7], [8]. Besides fungi, inositol also plays a role in pathogenicity of other parasitic microorganisms [12].

A vast area in China is currently going through severe haze episodes with drastically elevated concentrations of PM2.5 in winter. Nitrate and sulfate are the main constituents of PM2.5, but their formations via NO2 and SO2 oxidation are still not comprehensively understood, especially under different pollution or atmospheric relative humidity (RH) conditions. To elucidate formation pathways of nitrate and sulfate in different polluted cases, hourly samples of PM2.5 were collected continuously in Beijing during the wintertime of 2016. Three serious pollution cases were identified reasonably during the sampling period, and the secondary formations of nitrate and sulfate were found to make a dominant contribution to atmospheric PM2.5 under the relatively high RH condition. The significant correlation between NOR, NOR = NO3-/(NO3-+NO2), and [NO2]2 × [O3] during the nighttime under the RH≥60 % condition indicated that the heterogeneous hydrolysis of N2O5 involving aerosol liquid water was responsible for the nocturnal formation of nitrate at the extremely high RH levels. The more often coincident trend of NOR and [HONO] × [DR] (direct radiation) × [NO2] compared to its occurrence with [Dust] × [NO2] during the daytime under the 30 % < RH < 60 % condition provided convincing evidence that the gas-phase reaction of NO2 with OH played a pivotal role in the diurnal formation of nitrate at moderate RH levels. The extremely high mean values of SOR, SOR = SO42-/(SO42-+SO2), during the whole day under the RH≥60 % condition could be ascribed to the evident contribution of SO2 aqueous-phase oxidation to the formation of sulfate during the severe pollution episodes. Based on the parameters measured in this study and the known sulfate production rate calculation method, the oxidation pathway of H2O2 rather than NO2 was found to contribute greatly to the aqueous-phase formation of sulfate.

Ubiquitin-proteasome mediated protein turnover is an important regulatory mechanism of cellular function in eukaryotes. Extensive studies have linked the ubiquitin-proteasome system (UPS) to human diseases, and an array of proteasome inhibitors have been successfully developed for cancer therapy. Although still an emerging field, research on UPS regulation of fungal development and virulence has been rapidly advancing and has generated considerable excitement in its potential as a target for novel drugs. In this review, we summarize UPS composition and regulatory function in pathogenic fungi, especially in stress responses, host adaption, and fungal pathogenesis. Emphasis will be given to UPS regulation of pathogenic factors that are important for fungal pathogenesis. We also discuss future potential therapeutic strategies for fungal infections based on targeting UPS pathways.

Inositol is an essential nutrient with important structural and signaling functions in eukaryotes. Its role in microbial pathogenesis has been reported in fungi, protozoans, and eubacteria. In a recent article, Porollo et al. [ mBio 5(6):e01834-14, 2014, doi:10.1128/mBio.01834-14] demonstrated the importance of inositol metabolism in the development and viability of Pneumocystis species—obligate fungal pathogens that remain unculturable in vitro . To understand their obligate nature, the authors used innovative comparative genomic approaches and discovered that Pneumocystis spp. are inositol auxotrophs due to the lack of inositol biosynthetic enzymes and that inositol insufficiency is a contributing factor preventing fungal growth in vitro . This work is in accord with other studies suggesting that inositol plays a conserved role in microbial pathogenesis. Inositol uptake and metabolism therefore may represent novel antimicrobial drug targets. Using comparative genomics to analyze metabolic pathways offers a powerful tool to gain new insights into nutrient utilization in microbes, especially obligate pathogens.

Invasive fungal infections kill more than 1.5 million people each year, with limited treatment options. There is no vaccine available in clinical use to prevent and control fungal infections. Our recent studies showed that a mutant of the F-box protein Fbp1, a subunit of the SCF(Fbp1) E3 ligase in Cryptococcus neoformans , elicited superior protective Th1 host immunity. Here, we demonstrate that the heat-killed fbp1 Δ cells (HK-fbp1) can be harnessed to confer protection against a challenge by the virulent parental strain, even in animals depleted of CD4 + T cells. This finding is particularly important in the context of HIV/AIDS-induced immune deficiency. Moreover, we observed that HK-fbp1 vaccination induces significant cross-protection against challenge with diverse invasive fungal pathogens. Thus, our data suggest that HK-fbp1 has the potential to be a broad-spectrum vaccine candidate against invasive fungal infections in both immunocompetent and immunocompromised populations. Cryptococcus neoformans is a fungal pathogen that infects the lungs and then often disseminates to the central nervous system, causing meningitis. How Cryptococcus is able to suppress host immunity and escape the antifungal activity of macrophages remains incompletely understood. We reported that the F-box protein Fbp1, a subunit of the SCF(Fbp1) E3 ligase, promotes Cryptococcus virulence by regulating host- Cryptococcus interactions. Our recent studies demonstrated that the fbp1 Δ mutant elicited superior protective Th1 host immunity in the lungs and that the enhanced immunogenicity of heat-killed fbp1 Δ yeast cells can be harnessed to confer protection against a subsequent infection with the virulent parental strain. We therefore examined the use of heat-killed fbp1 Δ cells in several vaccination strategies. Interestingly, the vaccine protection remains effective even in mice depleted of CD4 + T cells. This finding is particularly important in the context of HIV/AIDS-induced immune deficiency. Moreover, we observed that vaccinating mice with heat-killed fbp1 Δ induces significant cross-protection against challenge with diverse invasive fungal pathogens, including C. neoformans , C. gattii , and Aspergillus fumigatus , as well as partial protection against Candida albicans . Thus, our data suggest that the heat-killed fbp1Δ strain has the potential to be a suitable vaccine candidate against cryptococcosis and other invasive fungal infections in both immunocompetent and immunocompromised populations. IMPORTANCE Invasive fungal infections kill more than 1.5 million people each year, with limited treatment options. There is no vaccine available in clinical use to prevent and control fungal infections. Our recent studies showed that a mutant of the F-box protein Fbp1, a subunit of the SCF(Fbp1) E3 ligase in Cryptococcus neoformans , elicited superior protective Th1 host immunity. Here, we demonstrate that the heat-killed fbp1 Δ cells (HK-fbp1) can be harnessed to confer protection against a challenge by the virulent parental strain, even in animals depleted of CD4 + T cells. This finding is particularly important in the context of HIV/AIDS-induced immune deficiency. Moreover, we observed that HK-fbp1 vaccination induces significant cross-protection against challenge with diverse invasive fungal pathogens. Thus, our data suggest that HK-fbp1 has the potential to be a broad-spectrum vaccine candidate against invasive fungal infections in both immunocompetent and immunocompromised populations.

Echinocandins show fungicidal activity against common invasive mycoses but are ineffective against cryptococcosis. The underlying mechanism for echinocandin resistance in remains poorly understood but has been shown to involve Cdc50, the regulatory subunit of lipid flippase. In a forward genetic screen for Δ suppressor mutations that are caspofungin resistant, we identified Crm1 ( aspofungin esistant utation ), a homolog of mechanosensitive channel proteins, and showed that Δ restored caspofungin resistance in Δ cells. Caspofungin-treated Δ cells exhibited abnormally high intracellular calcium levels ([Ca ]c) and heightened activation of the calcineurin pathway. Deletion of in the Δ background normalized the abnormally high [Ca ]c. Cdc50 interacts with Crm1 to maintain cellular calcium homeostasis. Analysis of chitin/chitosan content showed that deleting reversed the decreased chitosan production of Δ cells. Together, these results demonstrate that Cdc50 and Crm1 regulation of the calcineurin pathway and cytoplasmic calcium homeostasis may underlie caspofungin resistance in is the leading cause of fungal meningitis, accounting for ∼15% of HIV/AIDS-related deaths, but treatment options for cryptococcosis are limited. Echinocandins are the newest fungicidal drug class introduced but are ineffective in treating cryptococcosis. Our previous study identified the lipid flippase subunit Cdc50 as a contributor to echinocandin resistance in Here, we further elucidated the mechanism of Cdc50-mediated caspofungin drug resistance. We discovered that Cdc50 interacts with the mechanosensitive calcium channel protein Crm1 to regulate calcium homeostasis and caspofungin resistance via calcium/calcineurin signaling. These results provide novel insights into echinocandin resistance in this pathogen, which may lead to new treatment options, as well as inform echinocandin resistance mechanisms in other fungal organisms and, hence, advance our understanding of modes of antifungal drug susceptibility and resistance.

G protein-coupled receptors (GPCRs) represent the largest family of transmembrane receptors and are responsible for transducing extracellular signals into intracellular responses that involve complex intracellular-signaling networks. This review highlights recent research advances in fungal GPCRs, including classification, extracellular sensing, and G protein-signaling regulation. The involvement of GPCRs in pheromone and nutrient sensing has been studied extensively over the past decade. Following recent advances in fungal genome sequencing projects, a panoply of GPCR candidates has been revealed and some have been documented to play key roles sensing diverse extracellular signals, such as pheromones, sugars, amino acids, nitrogen sources, and even photons. Identification and deorphanization of additional putative GPCRs may require the development of new research tools. Here, we compare research on GPCRs in fungi with information derived from mammalian systems to provide a useful road map on how to better understand ligand-GPCR-G protein interactions in general. We also emphasize the utility of yeast as a discovery tool for systemic studies of GPCRs from other organisms.

We compare Community Multiscale Air Quality (CMAQ) model predictions with measured nitrous acid (HONO) concentrations in Beijing, China, for December 2015. The model with the existing HONO chemistry in CMAQ severely underestimates the observed HONO concentrations with a normalized mean bias of −97 %. We revise the HONO chemistry in the model by implementing six additional heterogeneous reactions in the model: the reaction of nitrogen dioxide (NO2) on ground surfaces, the reaction of NO2 on aerosol surfaces, the reaction of NO2 on soot surfaces, the photolysis of aerosol nitrate, the nitric acid displacement reaction, and the hydrochloric acid displacement reaction. The model with the revised chemistry substantially increases HONO predictions and improves the comparison with observed data with a normalized mean bias of −5 %. The photolysis of HONO enhances daytime hydroxyl radical by almost a factor of 2. The enhanced hydroxyl radical concentrations compare favorably with observed data and produce additional sulfate via the reaction with sulfur dioxide, aerosol nitrate via the reaction with nitrogen dioxide, and secondary organic aerosols via the reactions with volatile organic compounds. The additional sulfate stemming from revised HONO chemistry improves the comparison with observed concentration; however, it does not close the gap between model prediction and the observation during polluted days.

Macrophages are key cellular components of innate immunity, acting as the first line of defense against pathogens to modulate homeostatic and inflammatory responses. They help clear pathogens and shape the T-cell response through the production of cytokines and chemokines. The facultative intracellular fungal pathogen Cryptococcus neoformans has developed a unique ability to interact with and manipulate host macrophages. These interactions dictate how Cryptococcus infection can remain latent or how dissemination within the host is achieved. In addition, differences in the activities of macrophages have been correlated with differential susceptibilities of hosts to Cryptococcus infection, highlighting the importance of macrophages in determining disease outcomes. There is now abundant information on the interaction between Cryptococcus and macrophages. In this review we discuss recent advances regarding macrophage origin, polarization, activation, and effector functions during Cryptococcus infection. The importance of these strategies in pathogenesis and the potential of immunotherapy for cryptococcosis treatment is also discussed.

In the summer of 2018, a comprehensive field campaign, with measurements on HONO and related parameters, was conducted at the foot (150 m a.s.l.) and the summit of Mt. Tai (1534 m a.s.l.) in the central North China Plain (NCP). With the implementation of a 0-D box model, the HONO budget with six additional sources and its role in radical chemistry at the foot station were explored. We found that the model default source, NO + OH, could only reproduce 13 % of the observed HONO, leading to a strong unknown source strength of up to 3 ppbv h−1. Among the additional sources, the NO2 uptake on the ground surface dominated (∼ 70 %) nighttime HONO formation, and its photo-enhanced reaction dominated (∼ 80 %) daytime HONO formation. Their contributions were sensitive to the mixing layer height (MLH) used for the parameterizations, highlighting the importance of a reasonable MLH for exploring ground-level HONO formation in 0-D models and the necessity of gradient measurements. A ΔHONO/ΔNOx ratio of 0.7 % for direct emissions from vehicle exhaust was inferred, and a new method to quantify its contribution to the observations was proposed and discussed. Aerosol-derived sources, including the NO2 uptake on the aerosol surface and the particulate nitrate photolysis, did not lead to significant HONO formation, with their contributions lower than NO + OH. HONO photolysis in the early morning initialized the daytime photochemistry at the foot station. It was also a substantial radical source throughout the daytime, with contributions higher than O3 photolysis to OH initiation. Moreover, we found that OH dominated the atmospheric oxidizing capacity in the daytime, while modeled NO3 appeared to be significant at night. Peaks of modeled NO3 time series and average diurnal variation reached 22 and 9 pptv, respectively. NO3-induced reactions contribute 18 % of nitrate formation potential (P(HNO3)) and 11 % of the isoprene (C5H8) oxidation throughout the whole day. At night, NO3 chemistry led to 51 % and 44 % of P(HNO3) or the C5H8 oxidation, respectively, implying that NO3 chemistry could significantly affect nighttime secondary organic and inorganic aerosol formation in this high-O3 region. Considering the severe O3 pollution in the NCP and the very limited NO3 measurements, we suggest that besides direct measurements of HOx and primary HOx precursors (O3, HONO, alkenes, etc.), NO3 measurements should be conducted to understand the atmospheric oxidizing capacity and air pollution formation in this and similar regions.