BMC Biology最新文献

RNA velocity, as an extension of trajectory inference, is an effective method for understanding cell development using single-cell RNA sequencing (scRNA-seq) experiments. However, existing RNA velocity methods are limited by the batch effect because they cannot directly correct for batch effects in the input data, which comprises spliced and unspliced matrices in a proportional relationship. This limitation can lead to an incorrect velocity stream. This paper introduces VeloVGI, which addresses this issue innovatively in two key ways. Firstly, it employs an optimal transport (OT) and mutual nearest neighbor (MNN) approach to construct neighbors in batch data. This strategy overcomes the limitations of existing methods that are affected by the batch effect. Secondly, VeloVGI improves upon VeloVI's velocity estimation by incorporating the graph structure into the encoder for more effective feature extraction. The effectiveness of VeloVGI is demonstrated in various scenarios, including the mouse spinal cord and olfactory bulb tissue, as well as on several public datasets. The results show that VeloVGI outperformed other methods in terms of metric performance.

Background: The complete mitochondrial respiratory chain is a precondition for maintaining cellular energy supply, development, and metabolic balance. Due to the evolutionary differentiation of complexes and the semi-autonomy of mitochondria, respiratory chain subunits have become critical targets for crop improvement and fungal control. In fungi, mitochondrial complex I mediates growth and metabolism. However, the role of this complex in the pathogenesis of phytopathogenic fungi is largely unknown.

Results: In this study, we identified the NADH: ubiquinone oxidoreductase 24-kDa subunit (VdNuo1) of complex in vascular wilt pathogen, Verticillium dahliae, and examined its functional conservation in phytopathogenic fungi. Based on the treatments with respiratory chain inhibitors, the mitochondria-localized VdNuo1 was confirmed to regulate mitochondrial morphogenesis and homeostasis. VdNuo1 was induced during the different developmental stages in V. dahliae, including hyphal growth, conidiation, and melanized microsclerotia development. The VdNuo1 mutants displayed variable sensitivity to stress factors and decreased pathogenicity in multiple hosts, indicating that VdNuo1 is necessary in stress tolerance and full virulence. Comparative transcriptome analysis demonstrated that VdNuo1 mediates global transcriptional effects, including oxidation and reduction processes, fatty acid, sugar, and energy metabolism. These defects are partly attributed to impairments of mitochondrial morphological integrity, complex assembly, and related functions. Its homologue (CgNuo1) functions in the vegetative growth, melanin biosynthesis, and pathogenicity of Colletotrichum gloeosporioides; however, CgNuo1 does not restore the VdNuo1 mutant to normal phenotypes.

Conclusions: Our results revealed that VdNuo1 plays important roles in growth, metabolism, microsclerotia development, stress tolerance, and virulence of V. dahliae, sharing novel insight into the function of complex I and a potential fungicide target for pathogenic fungi.

Background: The mutualistic beneficial relationship between legume plants and rhizobia enables the growth of plants in nitrogen-limiting conditions. Rhizobia infect legumes through root hairs and trigger nodule organogenesis in the cortex. The plant hormone cytokinin plays a pivotal role in regulating both rhizobial infection and the initiation of nodule development. However, the mechanism used by the cytokinin output module to control symbiosis remains poorly documented.

Results: In this study, we identified a cytokinin signaling output component encoded by the Type-B RESPONSE REGULATOR (RRB) gene, LjRRB12, which is expressed in Lotus japonicus nodule primordia and young nodules. Disruption of LjRRB12 leads to a reduction in nodulation and to an increase in the number of infection threads. Overexpression of LjRRB12^D76E, an active form of the LjRRB12 protein, induces nodule-like structures in wild type and hit1 (hyperinfected 1/lotus histidine kinase 1) mutants but not in nin2 (nodule inception 2) mutants. Additionally, we utilized nCUT&Tag and EMSA to demonstrate that LjRRB12 can bind a CE (cytokinin response element) from the LjNIN promoter.

Conclusions: Our results provide a deeper understanding of nodule organogenesis by establishing a link between the cytokinin signal and the transcriptional regulation of LjNIN.

Background: Microgenderome or arguably more accurately microsexome refers to studies on sexual dimorphism of human microbiomes aimed at investigating bidirectional interactions between human microbiomes, sex hormones, and immune systems. It is important because of its implications to disease susceptibility and therapy, in which men and women demonstrate divergence in many diseases especially autoimmune diseases. In a previous report [1], we presented analyses of several key ecological aspects of microgenderome by leveraging the large datasets of the HMP (human microbiome project) but failed to offer species-level composition differences such as sexually unique species (US) and enriched species (ES). Existing approaches, for such tasks, including differential species relative abundance analysis and differential network analysis, possess certain limitations given that virtually all rely on species abundance alone or are univariate, while ignoring species distribution information across samples. Obviously, it is both species abundance and distribution that shape/drive the structure and dynamics of human microbiomes, and both should be equally responsible for the universal heterogeneity of microbiomes including the sexual dimorphism.

Results: Here, we fill the gap by taking advantages of a recently developed computational algorithm, species specificity, and specificity diversity (SSD) framework (refer to the companion article) to reanalyze the HMP and complementary seminovaginal microbiome datasets. The SSD framework can randomly search and catalogue the sexually specific unique/enriched species with statistical rigor, guided by species specificity (a synthetic metric of abundance and distribution) and specificity diversity (SD). The SSD framework reveals that men seem to have more unique species than women in their gut and reproductive system microbiomes, but women seem to have more unique species than men in the airway, oral, and skin microbiomes, which is likely due to sexual dimorphism in the hormone and immune systems. We further investigate co-dependency and heterogeneity of those sexually unique/enriched species across 15 body sites, with core/periphery network analyses.

Conclusions: This study not only produced sexually unique/enriched species in the human microbiomes and analyzed their codependency and heterogeneity but also further validated the robustness of the SSD framework presented in the companion article, by performing all negative control tests based on the HMP gut microbiome samples.

Background: Differentiating the microbiome changes associated with diseases is challenging but critically important. Majority of existing efforts have been focused on a community level, but the discerning power of community or holistic metrics such as diversity analysis seems limited. This prompts many researchers to believe that the promise should be downward to species or even strain level-effectively and efficiently identifying unique or enriched species in diseased microbiomes with statistical rigor. Nevertheless, virtually, all species-level approaches such as differential abundance and differential network analysis methods exclusively rely on species abundances without considering species distribution information, while it can be said that distribution is equally, if not more, important than abundance in shaping the spatiotemporal heterogeneity of community compositions.

Results: Here, we fill the gap by developing a novel framework-species specificity and specificity diversity (SSD)-that synthesizes both abundance and distribution information to differentiate microbiomes, at both species and community scales, under different environmental gradients such as the healthy and diseased treatments. The proposed SSD framework consists of three essential elements. The first is species specificity (SS), a concept that reincarnates the traditional specialist-generalist continuum and is defined by Mariadassou et al. (Ecol Lett 18:974-82, 2015). The SS synthesizes a species' local prevalence (distribution) and global abundance information and attaches specificity measure to each species in a specific habitat (e.g., healthy or diseased treatment). The second element is a new concept to introduce here, the (species) specificity diversity (SD), which is inspired by traditional species (abundance) diversity in community ecology and measures the diversity of specificity (a proxy for metacommunity heterogeneity, essentially) with Renyi's entropy. The third element is a pair of statistical tests based on the principle of permutation tests.

Conclusions: The SSD framework can (i) identify and catalogue lists of unique species (US), significantly enriched species (ES) in each treatment based on SS and specificity permutation (SP) test and (ii) measure the holistic differences between assemblages (or treatments) based on SD and specificity diversity permutation (SDP) test. Both capacities can be enabling technologies for general comparative microbiome research including risk assessment, diagnosis, and treatment of microbiome-associated diseases.

Background: The expansion of CAG/CTG repeats in functionally unrelated genes is a causative factor in many inherited neurodegenerative disorders, including Huntington's disease (HD), spinocerebellar ataxias (SCAs), and myotonic dystrophy type 1 (DM1). Despite many years of research, the mechanism responsible for repeat instability is unknown, and recent findings indicate the key role of DNA repair in this process. The repair of DSBs induced by genome editing tools results in the shortening of long CAG/CTG repeats in yeast models. Understanding this mechanism is the first step in developing a therapeutic strategy based on the controlled shortening of repeats. The aim of this study was to characterize Cas9-induced DSB repair products at the endogenous HTT locus in human cells and to identify factors affecting the formation of specific types of sequences.

Results: The location of the cleavage site and the surrounding sequence influence the outcome of DNA repair. DSBs within CAG repeats result in shortening of the repeats in frame in ~ 90% of products. The mechanism of this contraction involves MRE11-CTIP and RAD51 activity and DNA end resection. We demonstrated that a DSB located upstream of CAG repeats induces polymerase theta-mediated end joining, resulting in deletion of the entire CAG tract. Furthermore, using proteomic analysis, we identified novel factors that may be involved in CAG sequence repair.

Conclusions: Our study provides new insights into the complex mechanisms of CRISPR/Cas9-induced shortening of CAG repeats in human cells.

Background: In trypanosomatids, a group of unicellular eukaryotes that includes numerous important human parasites, cis-splicing has been previously reported for only two genes: a poly(A) polymerase and an RNA helicase. Conversely, trans-splicing, which involves the attachment of a spliced leader sequence, is observed for nearly every protein-coding transcript. So far, our understanding of splicing in this protistan group has stemmed from the analysis of only a few medically relevant species. In this study, we used an extensive dataset encompassing all described trypanosomatid genera to investigate the distribution of intron-containing genes and the evolution of splice sites.

Results: We identified a new conserved intron-containing gene encoding an RNA-binding protein that is universally present in Kinetoplastea. We show that Perkinsela sp., a kinetoplastid endosymbiont of Amoebozoa, represents the first eukaryote completely devoid of cis-splicing, yet still preserving trans-splicing. We also provided evidence for reverse transcriptase-mediated intron loss in Kinetoplastea, extensive conservation of 5' splice sites, and the presence of non-coding RNAs within a subset of retained trypanosomatid introns.

Conclusions: All three intron-containing genes identified in Kinetoplastea encode RNA-interacting proteins, with a potential to fine-tune the expression of multiple genes, thus challenging the perception of cis-splicing in these protists as a mere evolutionary relic. We suggest that there is a selective pressure to retain cis-splicing in trypanosomatids and that this is likely associated with overall control of mRNA processing. Our study provides new insights into the evolution of introns and, consequently, the regulation of gene expression in eukaryotes.

Eukaryotic microorganisms, or "protists," while often inconspicuous, play fundamental roles in the Earth ecosystem, ranging from primary production and nutrient cycling to interactions with human health and society. In the backdrop of accelerating climate dysregulation, alongside anthropogenic disruption of natural ecosystems, understanding changes to protist functional and ecological diversity is of critical importance. In this review, we outline why protists matter to our understanding of the global ecosystem and challenges of predicting protist species resilience and fragility to climate change. Finally, we reflect on how protistology may adapt and evolve in a present and future characterized by rapid ecological change.

Background: Inflammatory bowel disease (IBD), a persistent gastrointestinal disease, is featured with impaired gut immunity. Previous studies have demonstrated that tuft cells can regulate the intestinal type 2 immune response by activating downstream ILC2 and Th2 cells and repair gut barrier upon invasion of parasitic helminths, bacteria, protozoans, and enteritis through different chemo-sensing receptors, such as bitter taste receptors. Berberine is a widely used in the treatment of diarrhea in clinic, however the mechanism underlying this effect is not clear. In this study, we aim to explore the relationship between berberine and tuft cells in dextran sulfate sodium (DSS) -induced colitis.

Results: Our data showed that berberine significantly ameliorated DSS-induced colitis and regulating type 2 innate immune lymphocytes (ILC2) and Th2 immune cells via tuft cells in the gut. Furthermore, the effect of berberine on colitis was partially abolished by U73122, a bitter taste receptor inhibitor, suggesting that bitter taste signalling pathway played an important role in the effect of berberine on relieving colitis.

Conclusions: Berberine ameliorates dextran sulfate sodium -induced colitis through tuft cells and bitter taste signalling. Our study reveals the unique pharmacological mechanisms of berberine in the context of colitis, laying the foundation for further clinical applications of this compound.