Pathogens and hosts require rapid modulation of virulence and defense mechanisms at the infection axis, but monitoring such modulations is challenging. In studying the human fungal pathogen Cryptococcus neoformans , mouse and rabbit infection models are often employed to shed light on the disease mechanisms but that may not be clinically relevant. In this study, we developed an animal infection model using the non-human primate cynomolgus monkey Macaca fascicularis . In addition, we systematically profiled and compared transcriptional responses between the infected mice and the cynomolgus monkey, using simultaneous or dual RNA next-generation sequencing. We demonstrated that there are shared but distinct transcriptional profiles between the two models following C . neoformans infection. Specifically, genes involved in immune and inflammatory responses are all upregulated. Osteoclastogenesis and insulin signaling are also significantly co-regulated in both models and disrupting an osteoclastogenesis-associated gene (OC-STAMP) or the insulin-signaling process significantly altered the host tolerance to C . neoformans . Moreover, C . neoformans was shown to activate metal sequestration, dampen the sugar metabolism, and control cell morphology during infection. Taking together, we described the development of a non-human primate model of cryptococcosis that allowed us to perform an in-depth analysis and comparison of transcriptome profiles during infections of two animal models and conceptually identify host genes important in disease responses. This study provides new insights in understanding fungal pathogenesis mechanisms that potentially facilitate the identification of novel drug targets for the treatment of cryptococcal infection.
Lysine acetylation is critical in regulating important biological processes in many organisms, yet little is known about acetylome evolution and its contribution to phenotypic diversity. Here, we compare the acetylomes of baker’s yeast and the three deadliest human fungal pathogens, Cryptococcus neoformans , Candida albicans , and Aspergillus fumigatus . Using mass spectrometry enriched for acetylated peptides together with public data from Saccharomyces cerevisiae , we show that fungal acetylomes are characterized by dramatic evolutionary dynamics and limited conservation in core biological processes. Notably, the levels of protein acetylation in pathogenic fungi correlate with their pathogenicity. Using gene knockouts and pathogenicity assays in mice, we identify deacetylases with critical roles in virulence and protein translation elongation. Finally, through mutational analysis of deactylation motifs we find evidence of positive selection at specific acetylation motifs in fungal pathogens. These results shed new light on the pathogenicity regulation mechanisms underlying the evolution of fungal acetylomes.
Although the causal relationship between Alzheimer’s disease (AD) and iron overload remains unclear, iron dyshomeostasis or improper transport mechanisms are speculated to lead to the accumulation of this neurotoxic metal in the hippocampal formation and other cerebral areas related to neurodegenerative diseases, resulting in the formation of reactive oxygen species (ROS) and, ultimately, cell death. In this study, exposure to high dietary iron (HDI) revealed no significant difference in the number of iron-positive cells and iron content in the cortex and hippocampal region between wild-type (WT) and APP/PS1 mice; however, compared with the control mice, the HDI-treated mice exhibited upregulated divalent metal transporter 1 (DMT1) and ferroportin (Fpn) expression, and downregulated transferrin receptor (TFR) expression. Importantly, we confirmed that there were significantly fewer NeuN-positive neurons in both APP/PS1 and WT mice given HDI, than in the respective controls. Moreover, this iron-induced neuron loss may involve increased ROS and oxidative mitochondria dysfunction, decreased DNA repair, and exacerbated apoptosis and autophagy. Although HDI administration might trigger protective antioxidant, anti-apoptosis, and autophagy signaling, especially in pathological conditions, these data clearly indicate that chronic iron exposure results in neuronal loss due to apoptosis, autophagy, and ferroptosis, hence increasing the risk for developing AD.
Near-infrared (NIR) emitting persistent phosphors of Cr3+-doped zinc gallogermanate have emerged for in vivo bioimaging with the advantage of no need for in situ excitation. However, it is challenging to synthesize well-dispersed and uniform spherical particles with high brightness, high resolution, and distinguished NIR long afterglow. In this work, Zn3Ga2Ge2O10:Cr3+ (ZGGC) monospheres were directly synthesized by a facile hydrothermal method with the assistance of citric anions (Cit3–), which emit an NIR emission at ∼696 nm and exhibit excellent NIR-persistent luminescence with rechargeability. Controlled experiments indicated that the shape evolution of the ZGGC product is significantly affected by Cit3–, solution pH, and the duration and temperature of hydrothermal reaction. Furthermore, compositional influence on the crystal structure, bandgap, trap depth, and luminescence characteristics of Zn y Ga2Ge2O10−δ:Cr3+ (y = 2.8, 3.0, 3.2) were investigated in detail, which allows us to construct an energy level diagram of the ZGGC host, Cr3+ ions, and electron traps. It was found that the bandgap and conduction-band minimum (CBM) are significantly affected by the Zn content, while the valence-band maximum (VBM) is not. The y = 3.0 sample exhibited the best persistent luminescence, owing to its deepest defects. The ZGGC-NH2 prepared through surface functionalization of ZGGC spheres showed distinguished NIR long afterglow, low toxicity, and great potential for in vitro cell imaging and in vivo bioimaging in the absence of excitation. Moreover, the persistent luminescence signal from the ZGGC-NH2 can be repeated in vivo through in situ recharge with external excitation of a red LED lamp, indicating that the ZGGC-NH2 is suitable for applications in long-term in vivo imaging.
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