AP2XII-1 and AP2XI-2 Suppress Schizogony Gene Expression in Toxoplasma gondii.

Toxoplasma gondii is an intracellular parasite that is important in medicine and veterinary science and undergoes distinct developmental transitions in its intermediate and definitive hosts. The switch between stages of T. gondii is meticulously regulated by a variety of factors. Previous studies have explored the role of the microrchidia (MORC) protein complex as a transcriptional suppressor of sexual commitment. By utilizing immunoprecipitation and mass spectrometry, constituents of this protein complex have been identified, including MORC, Histone Deacetylase 3 (HDAC3), and several ApiAP2 transcription factors. Conditional knockout of MORC or inhibition of HDAC3 results in upregulation of a set of genes associated with schizogony and sexual stages in T. gondii tachyzoites. Here, our focus extends to two primary ApiAP2s (AP2XII-1 and AP2XI-2), demonstrating their significant impact on the fitness of asexual tachyzoites and their target genes. Notably, the targeted disruption of AP2XII-1 and AP2XI-2 resulted in a profound alteration in merozoite-specific genes targeted by the MORC-HDAC3 complex. Additionally, considerable overlap was observed in downstream gene profiles between AP2XII-1 and AP2XI-2, with AP2XII-1 specifically binding to a subset of ApiAP2 transcription factors, including AP2XI-2. These findings reveal an intricate cascade of ApiAP2 regulatory networks involved in T. gondii schizogony development, orchestrated by AP2XII-1 and AP2XI-2. This study provides valuable insights into the transcriptional regulation of T. gondii growth and development, shedding light on the intricate life cycle of this parasitic pathogen.

Mitochondrial dysfunction induced by bedaquiline as an anti-Toxoplasma alternative.

Toxoplasma gondii is a zoonotic parasite that infects one-third of the world's population and nearly all warm-blooded animals. Due to the complexity of T. gondii's life cycle, available treatment options have limited efficacy. Thus, there is an urgent need to develop new compounds or repurpose existing drugs with potent anti-Toxoplasma activity. This study demonstrates that bedaquiline (BDQ), an FDA-approved diarylquinoline antimycobacterial drug for the treatment of tuberculosis, potently inhibits the tachyzoites of T. gondii. At a safe concentration, BDQ displayed a dose-dependent inhibition on T. gondii growth with a half-maximal effective concentration (EC50) of 4.95 µM. Treatment with BDQ significantly suppressed the proliferation of T. gondii tachyzoites in the host cell, while the invasion ability of the parasite was not affected. BDQ incubation shrunk the mitochondrial structure and decreased the mitochondrial membrane potential and ATP level of T. gondii parasites. In addition, BDQ induced elevated ROS and led to autophagy in the parasite. By transcriptomic analysis, we found that oxidative phosphorylation pathway genes were significantly disturbed by BDQ-treated parasites. More importantly, BDQ significantly reduces brain cysts for the chronically infected mice. These results suggest that BDQ has potent anti-T. gondii activity and may impair its mitochondrial function by affecting proton transport. This study provides bedaquiline as a potential alternative drug for the treatment of toxoplasmosis, and our findings may facilitate the development of new effective drugs for the treatment of toxoplasmosis.

Controls and variability of soil respiration temperature sensitivity across China.

Understanding the temperature sensitivity (Q10) of soil respiration is critical for benchmarking the potential intensity of regional and global terrestrial soil carbon fluxes-climate feedbacks. Although field observations have demonstrated the strong spatial heterogeneity of Q10, a significant knowledge gap still exists regarding to the factors driving spatial and temporal variabilities of Q10 at regional scales. Therefore, we used a machine learning approach to predict Q10 from 1994 to 2016 with a spatial resolution of 1 km across China from 515 field observations at 5 cm soil depth using climate, soil and vegetation variables. Predicted Q10 varied from 1.54 to 4.17, with an area-weighted average of 2.52. There was no significant temporal trend for Q10 (p = 0.32), but annual vegetation production (indicated by normalized difference vegetation index, NDVI) was positively correlated to it (p < 0.01). Spatially, soil organic carbon (SOC) was the most important driving factor in 62 % of the land area across China, and varied greatly, demonstrating soil controls on the spatial pattern of Q10. These findings highlighted different environmental controls on the spatial and temporal pattern of soil respiration Q10, which should be considered to improve global biogeochemical models used to predict the spatial and temporal patterns of soil carbon fluxes to ongoing climate change.

The anti-Toxoplasma activity of the plant natural phenolic compound piceatannol.

Toxoplasma gondii is an obligate intracellular protozoan that infects the nucleated cells of warm-blooded animals and causes life-threatening disease in immunocompromised patients. Due to the limited effectiveness and prominent side effects of existing drugs, there is an urgent need to develop new therapeutic options against T. gondii. Piceatannol is a natural plant compound with multiple functions such as antibacterial, antileukemic and antiparasitic activities. In the present study, the anti-T. gondii activity of piceatannol was evaluated. Piceatannol potently inhibited Toxoplasma with a half-maximal effective concentration (EC50) of 28.10 µM. Piceatannol showed a significant inhibitory effect on intracellular proliferation, inhibiting intracellular parasites at a rate of 98.9% when treatment with 100 µM piceatannol. However, the invasion ability of tachyzoites was not affected by piceatannol. By immunofluorescence assay, we noted that the parasite showed abnormalities in cell division after exposure to piceatannol. To determine the in vivo effect of piceatannol on acute infection, a model was established by infecting BALB/c mice with the virulent RH strain of T. gondii. Mice infected with 500 tachyzoites showed a significant therapeutic effect when treated with 15 mg/kg of piceatannol. These results suggest that piceatannol is a promising drug for the treatment of T. gondii.

Evaluation of the Combined Effect of Artemisinin and Ferroptosis Inducer RSL3 against Toxoplasma gondii.

Toxoplasma gondii is a widespread intracellular pathogen that infects humans and a variety of animals. Dihydroartemisinin (DHA), an effective anti-malarial drug, has potential anti-T. gondii activity that induces ferroptosis in tumor cells, but the mechanism by which it kills T. gondii is not fully understood. In this study, the mechanism of DHA inhibiting T. gondii growth and its possible drug combinations are described. DHA potently inhibited T. gondii with a half-maximal effective concentration (EC50) of 0.22 µM. DHA significantly increased the ROS level of parasites and decreased the mitochondrial membrane potential, which could be reversed by ferroptosis inhibitors (DFO). Moreover, the ferroptosis inducer RSL3 inhibited T. gondii with an EC50 of 0.75 µM. In addition, RSL3 enhanced the DHA-induced ROS level, and the combination of DHA and RSL3 significantly increased the anti-Toxoplasma effect as compared to DHA alone. In summary, we found that DHA-induced ROS accumulation in tachyzoites may be an important cause of T. gondii growth inhibition. Furthermore, we found that the combination of DHA and RSL3 may be an alternative to toxoplasmosis. These results will provide a new strategy for anti-Toxoplasma drug screening and clinical medication guidance.

A decreasing carbon allocation to belowground autotrophic respiration in global forest ecosystems.

Belowground autotrophic respiration (RAsoil) depends on carbohydrates from photosynthesis flowing to roots and rhizospheres, and is one of the most important but least understood components in forest carbon cycling. Carbon allocation plays an important role in forest carbon cycling and reflects forest adaptation to changing environmental conditions. However, carbon allocation to RAsoil has not been fully examined at the global scale. To fill this knowledge gap, we first used a Random Forest algorithm to predict the spatio-temporal patterns of RAsoil from 1981 to 2017 based on the most updated Global Soil Respiration Database (v5) with global environmental variables; calculated carbon allocation from photosynthesis to RAsoil (CAB) as a fraction of gross primary production; and assessed its temporal and spatial patterns in global forest ecosystems. Globally, mean RAsoil from forests was 8.9 ± 0.08 Pg C yr-1 (mean ± standard deviation) from 1981 to 2017 and increased significantly at a rate of 0.006 Pg C yr-2, paralleling broader soil respiration changes and suggesting increasing carbon respired by roots. Mean CAB was 0.243 ± 0.016 and decreased over time. The temporal trend of CAB varied greatly in space, reflecting uneven responses of CAB to environmental changes. Combined with carbon use efficiency, our CAB results offer a completely independent approach to quantify global aboveground autotropic respiration spatially and temporally, and could provide crucial insights into carbon flux partitioning and global carbon cycling under climate change.

[Allelopathic effects of secalonic acid F produced by Aspergillus japonicus on Zea mays].

Aspergillus japonicus Saito is a common soil-borne fungus, and exists on the surface of some cereal crop seeds. Secalonic acid F (SAF) is the main allelochemical from the fungus. Bioassays showed that SAF significantly stimulated the seedling growth of corn (Zea mays L.) at a concentration of 0.0375 mmol.L-1. The root length, root numbers and root oxidation activities increased by 31.7%, 13.2%, and 373%, respectively. Secalonic acid F also increased the nutrient absorption of P, K, Ca, Mg, and S at the same concentration. However, SAF inhibited the seedling growth of corn at concentrations of 0.3 mmol.L-1 and 0.6 mmol.L-1. The root length, root dry weight, and shoot length were inhibited by 27.7%, 39.1% and 35.8% by 0.3 mmol.L-1 of SAF, and root activities were inhibited by 72.1% and 100% by 0.3 mmol.L-1 and 0.6 mmol.L-1 of SAF, respectively. The nutrient absorption of N, P, K, Ca, Mg and Fe was reduced when the corn seedlings were treated with 0.3 mmol.L-1 SAF. Transmission electron microscope, observations showed that the corn treated with 0.3 mmol.L-1 of SAF had a swelling and disorderly arrangement chloroplast, and the stratiform structure of chloroplast became unconspicuous.