Fertilization regulates global thresholds in soil bacteria.

Global patterns in soil microbiomes are driven by non-linear environmental thresholds. Fertilization is known to shape the soil microbiome of terrestrial ecosystems worldwide. Yet, whether fertilization influences global thresholds in soil microbiomes remains virtually unknown. Here, utilizing optimized machine learning models with Shapley additive explanations on a dataset of 10,907 soil samples from 24 countries, we discovered that the microbial community response to fertilization is highly dependent on environmental contexts. Furthermore, the interactions among nitrogen (N) addition, pH, and mean annual temperature contribute to non-linear patterns in soil bacterial diversity. Specifically, we observed positive responses within a soil pH range of 5.2-6.6, with the influence of higher temperature (>15°C) on bacterial diversity being positive within this pH range but reversed in more acidic or alkaline soils. Additionally, we revealed the threshold effect of soil organic carbon and total nitrogen, demonstrating how temperature and N addition amount interacted with microbial communities within specific edaphic concentration ranges. Our findings underscore how complex environmental interactions control soil bacterial diversity under fertilization.

Characterising global antimicrobial resistance research explains why One Health solutions are slow in development: An application of AI-based gap analysis.

The global health crisis posed by increasing antimicrobial resistance (AMR) implicitly requires solutions based a One Health approach, yet multisectoral, multidisciplinary research on AMR is rare and huge knowledge gaps exist to guide integrated action. This is partly because a comprehensive survey of past research activity has never performed due to the massive scale and diversity of published information. Here we compiled 254,738 articles on AMR using Artificial Intelligence (AI; i.e., Natural Language Processing, NLP) methods to create a database and information retrieval system for knowledge extraction on research perfomed over the last 20 years. Global maps were created that describe regional, methodological, and sectoral AMR research activities that confirm limited intersectoral research has been performed, which is key to guiding science-informed policy solutions to AMR, especially in low-income countries (LICs). Further, we show greater harmonisation in research methods across sectors and regions is urgently needed. For example, differences in analytical methods used among sectors in AMR research, such as employing culture-based versus genomic methods, results in poor communication between sectors and partially explains why One Health-based solutions are not ensuing. Therefore, our analysis suggest that performing culture-based and genomic AMR analysis in tandem in all sectors is crucial for data integration and holistic One Health solutions. Finally, increased investment in capacity development in LICs should be prioritised as they are places where the AMR burden is often greatest. Our open-access database and AI methodology can be used to further develop, disseminate, and create new tools and practices for AMR knowledge and information sharing.

Sanguinarine modulates microglial function via PPARγ activation and protects against CNS demyelination.

Microglia aggregate in regions of active inflammation and demyelination in the CNS of multiple sclerosis (MS) patients and are considered pivotal in the disease process. Targeting microglia is a promising therapeutic approach for myelin repair. Previously, we identified two candidates for microglial modulation and remyelination using a Connectivity Map (CMAP)-based screening strategy. Interestingly, with results that overlapped, sanguinarine (SAN) emerged as a potential drug candidate to modulate microglial polarization and promote remyelination. In the current study, we demonstrate the efficacy of SAN in mitigating the MS-like experimental autoimmune encephalomyelitis (EAE) in a dose-dependent manner. Meanwhile, prophylactic administration of a medium dose (2.5 mg/kg) significantly reduces disease incidence and ameliorates clinical signs in EAE mice. At the cellular level, SAN reduces the accumulation of microglia in the spinal cord. Morphological analyses and immunophenotyping reveal a less activated state of microglia following SAN administration, supported by decreased inflammatory cytokine production in the spinal cord. Mechanistically, SAN skews primary microglia towards an immunoregulatory state and mitigates proinflammatory response through PPARγ activation. This creates a favorable milieu for the differentiation of oligodendrocyte progenitor cells (OPCs) when OPCs are incubated with conditioned medium from SAN-treated microglia. We further extend our investigation into the cuprizone-induced demyelinating model, confirming that SAN treatment upregulates oligodendrocyte lineage genes and increases myelin content, further suggesting its pro-myelination effect. In conclusion, our data propose SAN as a promising candidate adding to the preclinical therapeutic arsenal for regulating microglial function and promoting myelin repair in CNS demyelinating diseases such as MS.