Parkinson’s disease (PD), the second most prevalent neurodegenerative disorder, poses significant challenges to single-target therapeutic strategies due to its complex etiology. This has driven interest in multi-target approaches, particularly those leveraging natural compounds. Pingchan granules (PCG), a traditional Chinese medicine composed of plant- and animal-derived compounds, have shown efficacy in alleviating PD symptoms. Here, we identify 96 PCG-associated anti-PD targets, enriched in neuronal synaptic signaling and G protein-coupled receptor pathways. Through protein-protein interaction network analysis of anti-PD targets and random forest modeling of substantia nigra transcriptomic data from PD patients, SLC6A3 and SRC emerged as central hub targets, with Mendelian randomization further validating SRC as a potential therapeutic target. Molecular docking and single-cell sequencing reveal that dauricine, PCG’s principal active compound, binds strongly to SLC6A3 and SRC, modulating glucose metabolism pathways in dopaminergic neurons. These findings illuminate the molecular basis of PCG’s therapeutic effects, offer a foundation for future drug development, and underscore the potential of dauricine as a targeted treatment for PD.

Parkinson’s disease (PD) is a chronic neurodegenerative disorder marked by dopaminergic neuron degeneration in the substantia nigra. Emerging evidence suggests vitamin D3 (VD) plays a therapeutic role in PD, but its precise molecular mechanisms remain unclear. This study employed network pharmacology and bioinformatics to identify VD’s hub targets and related pathways. We identified 24 VD’s anti-PD targets, with estrogen receptor 1, estrogen receptor 2 (ESR2), sodium-dependent norepinephrine transporter, and insulin-like growth factor 1 receptor emerging as hub targets. Gene enrichment analysis elucidated that VD’s anti-PD mechanism is closely related to the estrogen signaling pathway. Additionally, two-sample Mendelian randomization suggested a positive causal relationship between 25-hydroxyvitamin D and estrogen levels in vivo. To verify the interaction between VD and the hub drug targets, we performed molecular docking and kinetic simulations, finding the strongest interaction between VD and ESR2. Further Mendelian randomization analysis of drug targets confirmed the significant effect of the ESR2 drug target on PD risk. Single-cell nuclear sequencing of dopaminergic neurons, coupled with GSEA analysis, indicated that ESR2 activation upregulates the neuroactive ligand-receptor interaction signaling pathway and downregulates the Parkinson’s disease pathway, thereby exerting a neuroprotective effect. In summary, our findings suggest that VD supplementation can not only elevate estradiol levels in humans but also directly activate ESR2, thereby modulating the estrogen signaling pathway in PD patients and providing neuroprotection. These predictive biological targets offer promising avenues for future clinical applications in Parkinson’s disease treatment.

Introduction Gene exchange between viruses and hosts plays an important role in driving virus-host coevolution, enabling adaptation of both viruses and hosts to environmental changes. However, the mechanisms and functional significance of virus-host gene exchanges over long-term scales remain largely unexplored. Objective The present study aimed to gain insights into the role of viruses in virus-host interactions and coevolution by monitoring virome dynamics along a millennium-long land reclamation chronosequence. Methods We collected 24 soil samples from 8 stages of a millennium-long land reclamation chronosequence, including non-reclamation, and reclamation periods of 10, 50, 100, 300, 500, 700, and 1000 years. We characterized their metagenomes, and identified DNA viruses within these metagenomes. Results Our findings reveal a significant shift in viral community composition after 50 years of land reclamation, but soil viral diversity reached a stable phase approximately 300 years after the initial reclamation. Analysis of the virus-host network showed a scale-free degree distribution and a reduction in complexity over time, with generalist viruses emerging as key facilitators of horizontal gene transfer. Conclusion These findings highlight the integral role of viruses, especially generalist types, in mediating gene exchanges between viruses and hosts, thereby influencing the coevolutionary dynamics in soil ecosystems over significant timescales. This study offers novel insights into long-term virus-host interactions, showing how the virome responds to environmental changes, driving shifts in various microbial functions in reclaimed land.

BackgroundThe COVID-19 pandemic caused by SARS-CoV-2 has led to significant global morbidity and mortality, with potential neurological consequences, such as Parkinson's disease (PD). However, the underlying mechanisms remain elusive.MethodsTo address this critical question, we conducted an in-depth transcriptome analysis of dopaminergic (DA) neurons in both COVID-19 and PD patients. We identified common pathways and differentially expressed genes (DEGs), performed enrichment analysis, constructed protein‒protein interaction networks and gene regulatory networks, and employed machine learning methods to develop disease diagnosis and progression prediction models. To further substantiate our findings, we performed validation of hub genes using a single-cell sequencing dataset encompassing DA neurons from PD patients, as well as transcriptome sequencing of DA neurons from a mouse model of MPTP(1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine)-induced PD. Furthermore, a drug-protein interaction network was also created.ResultsWe gained detailed insights into biological functions and signaling pathways, including ion transport and synaptic signaling pathways. CD38 was identified as a potential key biomarker. Disease diagnosis and progression prediction models were specifically tailored for PD. Molecular docking simulations and molecular dynamics simulations were employed to predict potential therapeutic drugs, revealing that genistein holds significant promise for exerting dual therapeutic effects on both PD and COVID-19.ConclusionsOur study provides innovative strategies for advancing PD-related research and treatment in the context of the ongoing COVID-19 pandemic by elucidating the common pathogenesis between COVID-19 and PD in DA neurons.

Background Retrospective cohort and cross-sectional studies have indicated an association between ankylosing spondylitis (AS) and Parkinson's disease (PD). However, owing the multitude of limitations, a consistent conclusion has not been determined. Furthermore, whether a causal relationship exists between these two diseases remains unclear. Methods We conducted a two-way Mendelian randomization (MR) analysis using genome-wide association study data. For patients with PD, we utilised data from the ieu-b-7 database, whereas for patients with AS, we employed the three databases with the largest sample sizes for a combined analysis. These databases included ebi-a-GCST005529, finn-b-M13 ANKYLOSPON, and finn-b-M13 ANKYLOSPON STRICT. Our primary method of analysis was inverse variance weighting (IVW), supplemented by four other effective methods, to comprehensively infer a potential causal relationship between AS and PD. Additionally, we conduct various sensitivity analyses to assess the robustness of our estimates. Results Based on our IVW MR analysis, no significant causal relationship between AS and PD was observed (odds ratio [OR] = 1.01, 95% confidence interval [CI] = 0.99–1.03, P = 0.26). Additionally, our reverse MR analysis found no evidence supporting a significant causal relationship between PD and AS (OR = 0.93, 95% CI = 0.85–1.01, P = 0.068). These results were substantiated by comprehensive sensitivity analyses that indicated minimal bias in the causal estimates. Conclusion In contrast to numerous existing clinical studies, this study failed to provide evidence supporting a significant impact of AS on PD risk, or vice versa. Further investigations regarding the potential causal mechanisms linking AS and PD are warranted.

Viruses are crucial in shaping soil microbial functions and ecosystems. However, studies on soil viromes have been limited in both spatial scale and biome coverage. Here we present a comprehensive synthesis of soil virome biogeographic patterns using the Global Soil Virome dataset (GSV) wherein we analysed 1,824 soil metagenomes worldwide, uncovering 80,750 partial genomes of DNA viruses, 96.7% of which are taxonomically unassigned. The biogeography of soil viral diversity and community structure varies across different biomes. Interestingly, the diversity of viruses does not align with microbial diversity and contrasts with it by showing low diversity in forest and shrubland soils. Soil texture and moisture conditions are further corroborated as key factors affecting diversity by our predicted soil viral diversity atlas, revealing higher diversity in humid and subhumid regions. In addition, the binomial degree distribution pattern suggests a random co-occurrence pattern of soil viruses. These findings are essential for elucidating soil viral ecology and for the comprehensive incorporation of viruses into soil ecosystem models.

Cell size is a key morphological trait which is associated with microbial activity and nutrient acquisition. However, it is still unclear whether bacteria of different sizes have similar structural and functional properties. In this study, we sorted bacterial cells into five size classes (small, slightly small, medium, slightly large, large) using FACS and compared their structural and functional profiles in soils from deciduous and evergreen forests. The results showed that most (about 60%) of the bacterial cells fell under small or slightly small size classes. The five size classes harbored distinct bacterial communities in both types of forest soil. In spite of the lower relative abundance, slightly large and large bacterial cells had higher diversity compared to other size classes. Core communities of the five size classes in evergreen forest soil harbored more ubiquitous OTUs when compared with deciduous forest soil. Bacterial functional structures of the five size classes were significantly different in deciduous forest soil, while similar across size classes in evergreen forest soil. We conclude that cell size is an important factor that determines bacterial structure and function, and this relationship is depended on ecosystem or soil type. This study emphasizes cell size as a useful tool when assessing bacterial diversity and uncovers a direct relationship between microbial morphology and ecological traits.

Nitrogen (N) is a vital nutrient essential for both soil microbiota and plant growth. The intersection of climate change and human activities has increased N inputs, leading to notable N losses that have concerning effects on human health. It is widely recognized that soils can retain large amounts of N. Therefore, understanding the global patterns of N cycling, influenced by regional environmental variations, is crucial for estimating soils' N retention abilities. In this paper, we analyzed 2,039 soil metagenomic samples to map out N cycling processes worldwide and revealed significant differences in N cycling among various ecosystems. Remarkably, natural ecosystems, especially grasslands, showed a much higher potential to retain soil N than agricultural lands. Moreover, natural ecosystems provided more consistent predictions of potential N retention relative to total soil N than agricultural systems. This divergence might be due to disruptions caused by intensive farming, which can lead to ecological imbalance in cultivated areas. These insights highlight the urgent need for global sustainable farming practices, aligning agricultural goals with ecosystem health.

Antibiotic overuse and the subsequent environmental contamination of residual antibiotics poses a public health crisis via an acceleration in the spread of antibiotic resistance genes (ARGs) through horizontal gene transfer. Although the occurrence, distribution, and driving factors of ARGs in soils have been widely investigated, little is known about the antibiotic resistance of soilborne pathogens at a global scale. To explore this gap, contigs from 1643 globally sourced metagnomes are assembled, yielding 407 ARG-carrying pathogens (APs) with at least one ARG; APs are detected in 1443 samples (sample detection rate of 87.8%). The richness of APs is greater in agricultural soils (with a median of 20) than in non-agricultural ecosystems. Agricultural soils possess a high prevalence of clinical APs affiliated with Escherichia, Enterobacter, Streptococcus, and Enterococcus. The APs detected in agricultural soils tend to coexist with multidrug resistance genes and bacA. A global map of soil AP richness is generated, where anthropogenic and climatic factors explained AP hot spots in East Asia, South Asia, and the eastern United States. The results herein advance this understanding of the global distribution of soil APs and determine regions prioritized to control soilborne APs worldwide.

Soil harbors a vast expanse of unidentified microbes, termed as microbial dark matter, presenting an untapped reservoir of microbial biodiversity and genetic resources, but has yet to be fully explored. In this study, we conduct a large-scale excavation of soil microbial dark matter by reconstructing 40,039 metagenome-assembled genome bins (the SMAG catalogue) from 3304 soil metagenomes. We identify 16,530 of 21,077 species-level genome bins (SGBs) as unknown SGBs (uSGBs), which expand archaeal and bacterial diversity across the tree of life. We also illustrate the pivotal role of uSGBs in augmenting soil microbiome’s functional landscape and intra-species genome diversity, providing large proportions of the 43,169 biosynthetic gene clusters and 8545 CRISPR-Cas genes. Additionally, we determine that uSGBs contributed 84.6% of previously unexplored viral-host associations from the SMAG catalogue. The SMAG catalogue provides an useful genomic resource for further studies investigating soil microbial biodiversity and genetic resources.

RNA base editing is a promising tool in precise molecular therapy. Currently, there are two widely used RNA base editors, REPAIR and RESCUE. REPAIR only facilitates A-to-I conversions, while RESCUE performs both A-to-I and C-to-U conversions. Thus, RESCUE can generate twice the number of mutations compared to REPAIR. However, transcription-wide impact due to RESCUE-induced off-target single-nucleotide variants (SNVs) is not fully appreciated. Therefore, to determine the off-target effects of RESCUE-mediated editing, we employed transcription-wide sequencing on cells edited by RESCUE. The SNVs showed different off-target effects on mRNA, circRNA, lncRNA, and miRNA expression patterns and their interacting networks. Our results illustrate the transcription-wide impact of RESCUE-induced off-target SNVs and highlight the need for careful characterization of the off-target impact by this editing platform.

Catharanthine can be coupled with vindoline to synthesize vinblastine and vincristine, which have been used clinically as potent anticancer drugs. However, the structural complexity and low abundance in nature hamper bulk chemical synthesis and plant extraction, leading to a limited supply and a high cost of this plant natural product. Here, we engineer the methylotrophic yeast Pichia pastoris for complete biosynthesis of catharanthine from simple carbon sources. Through the selection of stable integration sites, screening of biosynthetic pathway enzymes with higher activity and/or specificity, amplification of flux-limiting enzyme encoding genes, rewiring of cellular metabolism and process optimization, we achieve de novo biosynthesis of catharanthine with a titre as high as 2.57 mg l −1 , which also represents the most complicated molecule heterologously synthesized in a non-model microorganism. Our study establishes P. pastoris as a cell factory for producing plant natural products with complex biosynthetic pathways.

Peripheral immune cells play a vital role in the development of Parkinson’s disease (PD). However, their cytokine and chemokine secretion functions remain unclear. Therefore, we aimed to explore the cytokine and chemokine secretion functions of specific immune cell subtypes in drug-naïve patients with PD at different ages of onset. We included 10 early-onset and 10 late-onset patients with PD and age-matched healthy controls (HCs). We used mass cytometry to select specific immune cell subsets and evaluate intracellular cytokine and chemokine expression. Statistical tests included t -tests, analysis of variance, bivariate correlation analysis, and linear regression analysis. Compared with HCs, patients with PD exhibited significantly decreased intracellular pro-inflammatory cytokines and chemokines in selected clusters (e.g., tumor necrosis factor (TNF)-α, interleukin (IL)−8, IL-1β, and CC-chemokine ligand (CCL)17). Specific cytokines and cell clusters were associated with clinical symptoms. TNF-α played an important role in cognitive impairment. Intracellular TNF-α levels in the naïve CD8 + T-cell cluster C16 (CD57 − naïve CD8 + T) and natural killer (NK) cell cluster C32 (CD57 − CD28 − NK) were negatively correlated with Montreal Cognitive Assessment scores. The C16 cluster affected cognitive function and motor symptoms. Increased TNF-α and decreased interferon-γ expression in C16 correlated with increased Unified Parkinson’s Disease Rating Scale III scores in patients with PD. In summary, we developed a more detailed cytokine and chemokine map of peripheral specific CD8 + T cell and NK cell subsets, which revealed disrupted secretory function in patients with PD and provided unique clues for further mechanistic exploration.

The phyllosphere provides a habitat for a large sum of microorganisms which are modulated by numerous biotic and abiotic factors. While it is logical that host lineage must have some effect on the phyllosphere habitat, it is unclear if phyllospheres harbor similar microbial core communities across multiple ecosystems at the continental-scale. Here we collected 287 phyllosphere bacterial communities from seven ecosystems (including paddy field, dryland, urban area, protected agricultural land, forest, wetland, and grassland) in east-China to identify the regional core community and to characterize the importance of such communities in maintaining phyllosphere bacterial community structure and function. Despite significantly different bacterial richness and structure, the seven studied ecosystems contained a similar regional core community of 29 OTUs that comprised 44.9 % of the total bacterial abundance. The regional core community was less affected by environmental variables and less connected in the co-occurrence network compared with other non-core OTUs (the whole minus regional core community). Furthermore, the regional core community also had a large proportion (>50 %) of a constrained set of nutrient metabolism related functional potentials and less functional redundancy. This study suggests there is a robust regional core phyllosphere community regardless of ecosystem or spatial and environmental heterogeneity, and supports the argument that core communities are pivotal in maintaining microbial community structure and function.

This work revealed the profile of viral communities in paddy soils with different levels of arsenic (As) contamination during the flooded period. The structure of viral communities differed significantly in highly and moderately As-contaminated soils. The diversity of soil viral communities under high As contamination decreased. Siphoviridae, Podoviridae, Myoviridae, and Microviridae were the dominant viral families in all samples, and the relative abundances of five of the top 20 viral genera were significantly different between highly and moderately As-contaminated groups. Seventeen dissimilatory As(V)-reducing bacteria were predicted to host 161 viral operational taxonomic units (vOTUs), mainly affiliated with the genera of Sulfurospirillum, Deferribacter, Bacillus and Fusibacter. Among them, 28 vOTUs were also associated with Fe(III)-reducing bacteria, which belonged to different species of the genus Shewanella. Procrustes analysis showed that the community structure of soil viruses was strongly correlated with both prokaryotic community structure and geochemical properties. Random forest analyses revealed that the Total-Fe, DCB-Fe and oxalate-Fe were the most significant variables on viral community richness, while the total-As concentration was an important factor on the Shannon index. Furthermore, As resistance genes (ArsC, ArsR and ArsD), As methylation genes (arsM) and As transporter genes (Pst and Pit) were identified among the auxiliary metabolic genes (AMGs) of the virome. This work revealed that the viruses might influence microbial adaptation in response to As-induced stress, and provided a perspective on the potential virus-mediated biogeochemical cycling of As.

Soil contains a vast number of unidentified microbes, known as soil microbial dark matter. This is an important source of microbial biodiversity and genetic resources, but has yet to be fully explored. In this study, we conducted the first large-scale excavation of soil microbial dark matter by reconstructing 40,039 metagenome-assembled genome bins (the SMAG catalog) from 2,990 soil metagenomes. We identified 16,530 of 21,077 species-level genome bins (SGBs) as unknown SGBs (uSGBs), which greatly expand archaeal and bacterial diversity across the tree of life. The uSGBs identified substantially increased the functional landscape and intra-species genome diversity of the soil microbiome, and provided large proportions of the 43,169 biosynthetic gene clusters and 8,544 CRISPR-Cas genes mined from the SMAG catalog. This suggests their potential for genetic resource exploitation. In addition, we determined that uSGBs contributed 84.6% of novel viral-host associations identified from the SMAG catalog. Our results demonstrate the richness of microbial dark matter in soil and highlight its potential in inspiring new avenues of research in the field of soil microbiology. We believe that the SMAG catalog will be of great value and interest to the broad readership, and will serve as a valuable genomic database to drive significant advances in understanding soil microbial biodiversity and exploiting novel genetic resources.

Soil microbial community rhythms are a foundational mechanism that underpins soil microbial ecological processes, but evidence of endogenous circadian rhythms in these communities which are regulated by microbial molecular oscillations is lacking. In this study we used soil total and potentially active microbial communities to explore endogenous circadian rhythms excluded diurnal environmental fluctuations. Even though the communities were sampled from constantly dark, flooded paddy soil conditions, the potentially active microbial community structures were significantly different between the surface soil's ‘day’ and ‘night’. Seven taxa were identified as circadian indicators from the presence of circadian clock genes. The circadian indicators contributed to endogenous circadian rhythms by regulating community diversity, species interactions, and community assembly. These findings emphasize the importance of diurnal-scale perspective in understanding microbial ecological processes and, more practically, in the design of microbial ecology experiments.

Background : Co-occurrence pattern provides vital insight into complex microbial interactions of microbiomes. Although network analysis offers useful tools for describing microbial co-occurrence pattern, evolution of co-occurrence networks remains largely uncharacterized. Here, we simulated the evolution of the Earth microbial co-occurrence network and estimated topological fitness of its nodes based on the degree growth exponent. Results : We showed that the Earth microbial co-occurrence network evolved following Bianconi-Barabasi model. The Earth microbial co-occurrence network had reached to a stable status with around 500 nodes. Degree growth exponent was the major determinant of accumulated degree of taxa. The positive correlation between topological fitness and gene numbers in corresponding genomes suggests the intrinsic feature of topological fitness. The gamma distribution of topological fitness suggests the extinction of taxa with low topological fitness. We then examined the impact of node extinction and decay, finding that the link acquisition of hub nodes was not affected. Conclusions : This study glimpses the evolution feature of Earth microbial co-occurrence network and provides a framework for predicting potential hubs in the evolving network in future.

Cereal crop production is severely affected by seed-borne bacterial diseases across the world. Locally occurring disease resistance in various crops remains elusive. Here, we have observed that rice plants of the same cultivar can be differentiated into disease-resistant and susceptible phenotypes under the same pathogen pressure. Following the identification of a seed-endophytic bacterium as the resistance-conferring agent, integration of high-throughput data, gene mutagenesis and molecular interaction assays facilitated the discovery of the underlying mode of action. Sphingomonas melonis that is accumulated and transmitted across generations in disease-resistant rice seeds confers resistance to disease-susceptible phenotypes by producing anthranilic acid. Without affecting cell growth, anthranilic acid interferes with the sigma factor RpoS of the seed-borne pathogen Burkholderia plantarii, probably leading to impairment of upstream cascades that are required for virulence factor biosynthesis. The overall findings highlight the hidden role of seed endophytes in the phytopathology paradigm of 'disease triangles', which encompass the plant, pathogens and environmental conditions. These insights are potentially exploitable for modern crop cultivation threatened by globally widespread bacterial diseases.