Aridity shapes distinct biogeographic and assembly patterns of forest soil bacterial and fungal communities at the regional scale.

Climate change is exacerbating drought in arid and semi-arid forest ecosystems worldwide. Soil microorganisms play a key role in supporting forest ecosystem services, yet their response to changes in aridity remains poorly understood. We present results from a study of 84 forests at four south-to-north Loess Plateau sites to assess how increases in aridity level (1- precipitation/evapotranspiration) shapes soil bacterial and fungal diversity and community stability by influencing community assembly. We showed that soil bacterial diversity underwent a significant downward trend at aridity levels >0.39, while fungal diversity decreased significantly at aridity levels >0.62. In addition, the relative abundance of Actinobacteria and Ascomycota increased with higher aridity level, while the relative abundance of Acidobacteria and Basidiomycota showed the opposite trend. Bacterial communities also exhibited higher similarity-distance decay rates across geographic and environmental gradients than did fungal communities. Phylogenetic bin-based community assembly analysis revealed homogeneous selection and dispersal limitation as the two dominant processes in bacterial and fungal assembly. Dispersal limitation of bacterial communities monotonically increased with aridity levels, whereas homogeneous selection of fungal communities monotonically decreased. Importantly, aridity also increased the sensitivity of microbial communities to environmental disturbance and potentially decreased community stability, as evidenced by greater community similarity-environmental distance decay rates, narrower habitat niche breadth, and lower microbial network stability. Our study provides new insights into soil microbial drought response, with implications on the sustainability of ecosystems under environmental stress.

A small molecule blocking oncogenic protein EWS-FLI1 interaction with RNA helicase A inhibits growth of Ewing's sarcoma.

Many sarcomas and leukemias carry nonrandom chromosomal translocations encoding tumor-specific mutant fusion transcription factors that are essential to their molecular pathogenesis. Ewing's sarcoma family tumors (ESFTs) contain a characteristic t(11;22) translocation leading to expression of the oncogenic fusion protein EWS-FLI1. EWS-FLI1 is a disordered protein that precludes standard structure-based small-molecule inhibitor design. EWS-FLI1 binding to RNA helicase A (RHA) is important for its oncogenic function. We therefore used surface plasmon resonance screening to identify compounds that bind EWS-FLI1 and might block its interaction with RHA. YK-4-279, a derivative of the lead compound from the screen, blocks RHA binding to EWS-FLI1, induces apoptosis in ESFT cells and reduces the growth of ESFT orthotopic xenografts. These findings provide proof of principle that inhibiting the interaction of mutant cancer-specific transcription factors with the normal cellular binding partners required for their oncogenic activity provides a promising strategy for the development of uniquely effective, tumor-specific anticancer agents.

Magnesium, essential for base excision repair enzymes, inhibits substrate binding of N-methylpurine-DNA glycosylase.

N-Methylpurine-DNA glycosylase (MPG) initiates base excision repair in DNA by removing a wide variety of alkylated, deaminated, and lipid peroxidation-induced purine adducts. MPG activity and other DNA glycosylases do not have an absolute requirement for a cofactor. In contrast, all downstream activities of major base excision repair proteins, such as apurinic/apyrimidinic endonuclease, DNA polymerase beta, and ligases, require Mg(2+). Here we have demonstrated that Mg(2+) can be significantly inhibitory toward MPG activity depending on its concentration but independent of substrate type. The pre-steady-state kinetics suggests that Mg(2+) at high but physiologic concentrations decreases the amount of active enzyme concentrations. Steady-state inhibition kinetics showed that Mg(2+) affected K(m), but not V(max), and the inhibition could be reversed by EDTA but not by DNA. At low concentration, Mg(2+) stimulated the enzyme activity only with hypoxanthine but not ethenoadenine. Real-time binding experiments using surface plasmon resonance spectroscopy showed that the pronounced inhibition of activity was due to inhibition in substrate binding. Nonetheless, the glycosidic bond cleavage step was not affected. These results altogether suggest that Mg(2+) inhibits MPG activity by abrogating substrate binding. Because Mg(2+) is an absolute requirement for the downstream activities of the major base excision repair enzymes, it may act as a regulator for the base excision repair pathway for efficient and balanced repair of damaged bases, which are often less toxic and/or mutagenic than their subsequent repair product intermediates.