Graefes Arch Clin Exp Ophthalmol. 2024 Jun 6. doi: 10.1007/s00417-024-06538-2. Online ahead of print.

ABSTRACT

PURPOSE: To investigate the xenobiotic profiles of patients with neovascular age-related macular degeneration (nAMD) undergoing anti-vascular endothelial growth factor (anti-VEGF) intravitreal therapy (IVT) to identify biomarkers indicative of clinical phenotypes through advanced AI methodologies.

METHODS: In this cross-sectional observational study, we analyzed 156 peripheral blood xenobiotic features in a cohort of 46 nAMD patients stratified by choroidal neovascularization (CNV) control under anti-VEGF IVT. We employed Liquid Chromatography-Tandem Mass Spectrometry (LC-MS/MS) for measurement and leveraged an AI-driven iterative Random Forests (iRF) approach for robust pattern recognition and feature selection, aligning molecular profiles with clinical phenotypes.

RESULTS: AI-augmented iRF models effectively refined the metabolite spectrum by discarding non-predictive elements. Perfluorooctanesulfonate (PFOS) and Ethyl β-glucopyranoside were identified as significant biomarkers through this process, associated with various clinically relevant phenotypes. Unlike single metabolite classes, drug metabolites were distinctly correlated with subretinal fluid presence.

CONCLUSIONS: This study underscores the enhanced capability of AI, particularly iRF, in dissecting complex metabolomic data to elucidate the xenobiotic landscape of nAMD and environmental impact on the disease. The preliminary biomarkers discovered offer promising directions for personalized treatment strategies, although further validation in broader cohorts is essential for clinical application.

PMID:38842593 | DOI:10.1007/s00417-024-06538-2

J Cell Biol. 2024 Sep 2;223(9):e202405025. doi: 10.1083/jcb.202405025. Epub 2024 Jun 6.

ABSTRACT

Extracellular vesicles (EVs) are released by many cell types, including neurons, carrying cargoes involved in signaling and disease. It is unclear whether EVs promote intercellular signaling or serve primarily to dispose of unwanted materials. We show that loss of multivesicular endosome-generating endosomal sorting complex required for transport (ESCRT) machinery disrupts release of EV cargoes from Drosophila motor neurons. Surprisingly, ESCRT depletion does not affect the signaling activities of the EV cargo Synaptotagmin-4 (Syt4) and disrupts only some signaling activities of the EV cargo evenness interrupted (Evi). Thus, these cargoes may not require intercellular transfer via EVs, and instead may be conventionally secreted or function cell-autonomously in the neuron. We find that EVs are phagocytosed by glia and muscles, and that ESCRT disruption causes compensatory autophagy in presynaptic neurons, suggesting that EVs are one of several redundant mechanisms to remove cargoes from synapses. Our results suggest that synaptic EV release serves primarily as a proteostatic mechanism for certain cargoes.

PMID:38842573 | DOI:10.1083/jcb.202405025

Plant Cell. 2024 Jun 6:koae168. doi: 10.1093/plcell/koae168. Online ahead of print.

ABSTRACT

Organic carbon fixed in chloroplasts through the Calvin-Benson-Bassham Cycle can be diverted towards different metabolic fates, including cyoplasmic and mitochondrial respiration, gluconeogenesis, and synthesis of diverse plastid metabolites via the pyruvate hub. In plants, pyruvate is principally produced via cytoplasmic glycolysis, although a plastid-targeted lower glycolytic pathway is known to exist in non-photosynthetic tissue. Here, we characterized a lower plastid glycolysis-gluconeogenesis pathway enabling the direct interconversion of glyceraldehyde-3-phosphate and phospho-enol-pyruvate in diatoms, ecologically important marine algae distantly related to plants. We show that two reversible enzymes required to complete diatom plastid glycolysis-gluconeogenesis, Enolase and bis-phospho-glycerate mutase (PGAM), originated through duplications of mitochondria-targeted respiratory isoforms. Through CRISPR-Cas9 mutagenesis, integrative 'omic analyses, and measured kinetics of expressed enzymes in the diatom Phaeodactylum tricornutum, we present evidence that this pathway diverts plastid glyceraldehyde-3-phosphate into the pyruvate hub, and may also function in the gluconeogenic direction. Considering experimental data, we show that this pathway has different roles dependent in particular on day length and environmental temperature, and show that the cpEnolase and cpPGAM genes are expressed at elevated levels in high latitude oceans where diatoms are abundant. Our data provide evolutionary, meta-genomic and functional insights into a poorly understood yet evolutionarily recurrent plastid metabolic pathway.

PMID:38842420 | DOI:10.1093/plcell/koae168

OMICS. 2024 Jun 6. doi: 10.1089/omi.2024.0111. Online ahead of print.

ABSTRACT

Systems biology and multiomics research expand the prospects of planetary health innovations. In this context, this mini-review unpacks the twin scholarships of glycomedicine and precision medicine in the current era of single-cell multiomics. A significant growth in glycan research has been observed over the past decade, unveiling and establishing co- and post-translational modifications as dynamic indicators of both pathological and physiological conditions. Systems biology technologies have enabled large-scale and high-throughput glycoprofiling and access to data-intensive biological repositories for global research. These advancements have established glycans as a pivotal third code of life, alongside nucleic acids and amino acids. However, challenges persist, particularly in the simultaneous analysis of the glycome and transcriptome in single cells owing to technical limitations. In addition, holistic views of the complex molecular interactions between glycomics and other omics types remain elusive. We underscore and call for a paradigm shift toward the exploration of integrative glycan platforms and analysis methods for single-cell multiomics research and precision medicine biomarker discovery. The integration of multiple datasets from various single-cell omics levels represents a crucial application of systems biology in understanding complex cellular processes and is essential for advancing the twin scholarships of glycomedicine and precision medicine.

PMID:38841897 | DOI:10.1089/omi.2024.0111

Microbiome Res Rep. 2024 Feb 22;3(2):18. doi: 10.20517/mrr.2023.79. eCollection 2024.

ABSTRACT

Background: The gut and its microbiome have a major impact on many aspects of health and are therefore also an attractive target for drug- or food-based therapies. Here, we report on the added value of combining a microbiome screening model, the i-screen, with fresh intestinal tissue explants in a microfluidic gut-on-a-chip model, the Intestinal Explant Barrier Chip (IEBC). Methods: Adult human gut microbiome (fecal pool of 6 healthy donors) was cultured anaerobically in the i-screen platform for 24 h, without and with exposure to 4 mg/mL inulin. The i-screen cell-free culture supernatant was subsequently applied to the luminal side of adult human colon tissue explants (n = 3 donors), fixed in the IEBC, for 24 h and effects were evaluated. Results: The supplementation of the media with inulin promoted the growth of Anaerostipes, Bifidobacterium, Blautia, and Collinsella in the in vitro i-screen, and triggered an elevated production of butyrate by the microbiota. Human colon tissue exposed to inulin-treated i-screen cell-free culture supernatant or control i-screen cell-free culture supernatant with added short-chain fatty acids (SCFAs) showed improved tissue barrier integrity measured by a 28.2%-34.2% reduction in FITC-dextran 4000 (FD4) leakage and 1.3 times lower transport of antipyrine. Furthermore, the release of pro-inflammatory cytokines IL-1β, IL-6, IL-8, and TNF-α was reduced under these circumstances. Gene expression profiles confirmed these findings, but showed more profound effects for inulin-treated supernatant compared to SCFA-supplemented supernatant. Conclusion: The combination of i-screen and IEBC facilitates the study of complex intestinal processes such as host-microbial metabolite interaction and gut health.

PMID:38841408 | PMC:PMC11149092 | DOI:10.20517/mrr.2023.79

Microbiome Res Rep. 2024 Jan 18;3(2):14. doi: 10.20517/mrr.2023.65. eCollection 2024.

ABSTRACT

The intestinal microbiota and its metabolites are known to influence host metabolic health. However, little is known about the role of specific microbes. In this work, we used the minimal consortium Oligo-Mouse-Microbiota (OMM12) to study the function of Coriobacteriia under defined conditions in gnotobiotic mice. OMM12 mice with or without the addition of the dominant gut bacterium Eggerthella lenta (E. lenta) were fed with diets varying in fat content and primary bile acids. E. lenta stably colonised the mouse caecum at high relative abundances (median: 27.5%). This was accompanied by decreased occurrence of Akkermansia muciniphila and Enterococcus faecalis, but results did not reach statistical significance in all groups depending on diet and inter-individual differences. Changes in host parameters (anthropometry, blood glucose, and cholesterol) and liver proteomes were primarily due to diet. In contrast, metabolomes in colon content differed significantly between the colonisation groups. The presence of E. lenta was associated with elevated levels of latifolicinin C acid and decreased creatine, sarcosine, N,N-dimethylarginine, and N-Acetyl-DL-methionine. In conclusion, E. lenta altered specific metabolites in the colon but did not have significant effects on the mice or liver proteomes under the conditions tested due to marked inter-individual differences.

PMID:38841406 | PMC:PMC11149096 | DOI:10.20517/mrr.2023.65

Microbiome Res Rep. 2024 Apr 3;3(2):26. doi: 10.20517/mrr.2023.57. eCollection 2024.

ABSTRACT

Aim: Our gut microbiome has its own functionalities which can be modulated by various xenobiotic and biotic components. The development and application of a high-throughput functional screening approach of individual gut microbiomes accelerates drug discovery and our understanding of microbiome-drug interactions. We previously developed the rapid assay of individual microbiome (RapidAIM), which combined an optimized culturing model with metaproteomics to study gut microbiome responses to xenobiotics. In this study, we aim to incorporate automation and multiplexing techniques into RapidAIM to develop a high-throughput protocol. Methods: To develop a 2.0 version of RapidAIM, we automated the protein analysis protocol, and introduced a tandem mass tag (TMT) multiplexing technique. To demonstrate the typical outcome of the protocol, we used RapidAIM 2.0 to evaluate the effect of prebiotic kestose on ex vivo individual human gut microbiomes biobanked with five different workflows. Results: We describe the protocol of RapidAIM 2.0 with extensive details on stool sample collection, biobanking, in vitro culturing and stimulation, sample processing, metaproteomics measurement, and data analysis. The analysis depth of 5,014 ± 142 protein groups per multiplexed sample was achieved. A test on five biobanking methods using RapidAIM 2.0 showed the minimal effect of sample processing on live microbiota functional responses to kestose. Conclusions: Depth and reproducibility of RapidAIM 2.0 are comparable to previous manual label-free metaproteomic analyses. In the meantime, the protocol realizes culturing and sample preparation of 320 samples in six days, opening the door to extensively understanding the effects of xenobiotic and biotic factors on our internal ecology.

PMID:38841404 | PMC:PMC11149095 | DOI:10.20517/mrr.2023.57

Front Plant Sci. 2024 May 22;15:1420938. doi: 10.3389/fpls.2024.1420938. eCollection 2024.

NO ABSTRACT

PMID:38841285 | PMC:PMC11150839 | DOI:10.3389/fpls.2024.1420938

Front Cell Neurosci. 2024 May 22;18:1373557. doi: 10.3389/fncel.2024.1373557. eCollection 2024.

ABSTRACT

Protein kinase C (PKC) plays a key role in modulating the activities of the innate immune cells of the central nervous system (CNS). A delicate balance between pro-inflammatory and regenerative activities by microglia and CNS-associated macrophages is necessary for the proper functioning of the CNS. Thus, a maladaptive activation of these CNS innate immune cells results in neurodegeneration and demyelination associated with various neurologic disorders, such as multiple sclerosis (MS) and Alzheimer's disease. Prior studies have demonstrated that modulation of PKC activity by bryostatin-1 (bryo-1) and its analogs (bryologs) attenuates the pro-inflammatory processes by microglia/CNS macrophages and alleviates the neurologic symptoms in experimental autoimmune encephalomyelitis (EAE), an MS animal model. Here, we demonstrate that (2S,5S)-(E,E)-8-(5-(4-(trifluoromethyl)phenyl)-2,4-pentadienoylamino)benzolactam (TPPB), a structurally distinct PKC modulator, has a similar effect to bryo-1 on CNS innate immune cells both in vitro and in vivo, attenuating neuroinflammation and resulting in CNS regeneration and repair. This study identifies a new structural class of PKC modulators, which can therapeutically target CNS innate immunity as a strategy to treat neuroinflammatory and neurodegenerative disorders.

PMID:38841204 | PMC:PMC11150779 | DOI:10.3389/fncel.2024.1373557

Med Genet. 2023 Aug 16;35(3):163-171. doi: 10.1515/medgen-2023-2036. eCollection 2023 Sep.

ABSTRACT

Critical genetic and hormonal switches characterize fetal sex development in humans. They are decisive for gonadal sex determination and subsequent differentiation of the genital and somatic sex phenotype. Only at the first glace these switches seem to behave like the dual 0 and 1 system in computer sciences and lead invariably to either typically male or female phenotypes. More recent data indicate that this model is insufficient. In addition, in case of distinct mutations, many of these switches may act variably, causing a functional continuum of alterations of gene functions and -dosages, enzymatic activities, sex hormone levels, and sex hormone sensitivity, giving rise to a broad clinical spectrum of biological differences of sex development (DSD) and potentially diversity of genital and somatic sex phenotypes. The gonadal anlage is initially a bipotential organ that can develop either into a testis or an ovary. Sex-determining region Y (SRY) is the most important upstream switch of gonadal sex determination inducing SOX9 further downstream, leading to testicular Sertoli cell differentiation and the repression of ovarian pathways. If SRY is absent (virtually "switched off"), e. g., in 46,XX females, RSPO1, WNT4, FOXL2, and other factors repress the male pathway and promote ovarian development. Testosterone and its more potent derivative, dihydrotestosterone (DHT) as well as AMH, are the most important upstream hormonal switches in phenotypic sex differentiation. Masculinization of the genitalia, i. e., external genital midline fusion forming the scrotum, growth of the genital tubercle, and Wolffian duct development, occurs in response to testosterone synthesized by steroidogenic cells in the testis. Müllerian ducts will not develop into a uterus and fallopian tubes in males due to Anti-Müllerian-Hormone (AMH) produced by the Sertoli cells. The functionality of these two hormone-dependent switches is ensured by their corresponding receptors, the intracellular androgen receptor (AR) and the transmembrane AMH type II receptor. The absence of high testosterone and high AMH is crucial for anatomically female genital development during fetal life. Recent technological advances, including single-cell and spatial transcriptomics, will likely shed more light on the nature of these molecular switches.

PMID:38840820 | PMC:PMC10842585 | DOI:10.1515/medgen-2023-2036

Free Radic Biol Med. 2024 Jun 3:S0891-5849(24)00510-0. doi: 10.1016/j.freeradbiomed.2024.06.001. Online ahead of print.

ABSTRACT

Fibrosis is the tissue scarring characterized by excess deposition of extracellular matrix (ECM) proteins, mainly collagens. A fibrotic response can take place in any tissue of the body and is the result of an imbalanced reaction to inflammation and wound healing. Metabolism has emerged as a major driver of fibrotic diseases. While glycolytic shifts appear to be a key metabolic switch in activated stromal ECM-producing cells, several other cell types such as immune cells, whose functions are intricately connected to their metabolic characteristics, form a complex network of pro-fibrotic cellular crosstalk. This review purports to clarify shared and particular cellular responses and mechanisms across organs and etiologies. We discuss the impact of the cell-type specific metabolic reprogramming in fibrotic diseases in both experimental and human pathology settings, providing a rationale for new therapeutic interventions based on metabolism-targeted antifibrotic agents.

PMID:38838921 | DOI:10.1016/j.freeradbiomed.2024.06.001

Curr Opin Plant Biol. 2024 Jun 4;81:102570. doi: 10.1016/j.pbi.2024.102570. Online ahead of print.

ABSTRACT

Meiosis is a conserved eukaryotic cell division that produces spores required for sexual reproduction. During meiosis, chromosomes pair and undergo programmed DNA double-strand breaks, followed by homologous repair that can result in reciprocal crossovers. Crossover formation is highly regulated with typically few events per homolog pair. Crossovers additionally show wider spacing than expected from uniformly random placement - defining the phenomenon of interference. In plants, the conserved HEI10 E3 ligase is initially loaded along meiotic chromosomes, before maturing into a small number of foci, corresponding to crossover locations. We review the coarsening model that explains these dynamics as a diffusion and aggregation process, resulting in approximately evenly spaced HEI10 foci. We review how underlying chromatin states, and the presence of interhomolog polymorphisms, shape the meiotic recombination landscape, in light of the coarsening model. Finally, we consider future directions to understand the control of meiotic recombination in plant genomes.

PMID:38838583 | DOI:10.1016/j.pbi.2024.102570

Environ Microbiol. 2024 Jun;26(6):e16662. doi: 10.1111/1462-2920.16662.

ABSTRACT

Our study delved into the relationship between root-associated fungi, gene expression and plant morphology in Norway spruce cuttings derived from both slow-and fast-growing trees. We found no clear link between the gene expression patterns of adventitious roots and the growth phenotype, suggesting no fundamental differences in the receptiveness to fungal symbionts between the phenotypes. Interestingly, saplings from slow-growing parental trees exhibited a higher richness of ectomycorrhizal species and larger roots. Some ectomycorrhizal species, typically found on mature spruces, were more prevalent on saplings from slow-growing spruces. The ericoid mycorrhizal fungus, Hyaloscypha hepaticola, showed a stronger association with saplings from fast-growing spruces. Moreover, saplings from slow-growing spruces had a greater number of Ascomycete taxa and free-living saprotrophic fungi. Aboveground sapling stems displayed some phenotypic variation; saplings from fast-growing phenotypes had longer branches but fewer whorls in their stems compared to those from the slow-growing group. In conclusion, the observed root-associated fungi and phenotypic characteristics in young Norway spruces may play a role in their long-term growth rate. This suggests that the early interactions between spruces and fungi could potentially influence their growth trajectory.

PMID:38840258 | DOI:10.1111/1462-2920.16662

Nat Cell Biol. 2024 Jun 5. doi: 10.1038/s41556-024-01436-5. Online ahead of print.

ABSTRACT

The lysosomal degradation of macromolecules produces diverse small metabolites exported by specific transporters for reuse in biosynthetic pathways. Here we deorphanized the major facilitator superfamily domain containing 1 (MFSD1) protein, which forms a tight complex with the glycosylated lysosomal membrane protein (GLMP) in the lysosomal membrane. Untargeted metabolomics analysis of MFSD1-deficient mouse lysosomes revealed an increase in cationic dipeptides. Purified MFSD1 selectively bound diverse dipeptides, while electrophysiological, isotope tracer and fluorescence-based studies in Xenopus oocytes and proteoliposomes showed that MFSD1-GLMP acts as a uniporter for cationic, neutral and anionic dipeptides. Cryoelectron microscopy structure of the dipeptide-bound MFSD1-GLMP complex in outward-open conformation characterized the heterodimer interface and, in combination with molecular dynamics simulations, provided a structural basis for its selectivity towards diverse dipeptides. Together, our data identify MFSD1 as a general lysosomal dipeptide uniporter, providing an alternative route to recycle lysosomal proteolysis products when lysosomal amino acid exporters are overloaded.

PMID:38839979 | DOI:10.1038/s41556-024-01436-5

Nat Plants. 2024 Jun 5. doi: 10.1038/s41477-024-01732-w. Online ahead of print.

NO ABSTRACT

PMID:38839947 | DOI:10.1038/s41477-024-01732-w

Cancer Gene Ther. 2024 Jun 5. doi: 10.1038/s41417-024-00790-8. Online ahead of print.

ABSTRACT

Systems biology has been applied at the multi-scale level within the cancer field, improving cancer prevention, diagnosis and enabling precision medicine approaches. While systems biology can expand the knowledge and skills for oncological treatment, it also represents a challenging expedition due to cancer complexity, heterogeneity and diversity not only between different cancer indications, but also in its evolution process through space and time. Here, by characterizing the transcriptional perturbations of the tumor microenvironment induced by oncolytic, we aimed to rationally design a novel armed oncolytic herpes virus. We found that intratumor oncovirotherapy with HSV-1 induces T-cell activation signatures and transcriptionally activates several costimulatory molecules. We identified differentially expressed costimulatory receptors and binding partners, where inducible co-stimulators (ICOS) resulted in the potentially most beneficial targeted therapy. Through an ex-vivo transcriptomic analysis, we explored the potential of arming an oncolytic virus as a combination therapy strategy; in particular, we engineered a targeted herpes virus encoding ICOSL (THV_ICOSL), which resulted in a significant improvement in tumor size control compared to unarmed parental virus. Also, combination with a PD-1 inhibitor enhanced antitumor efficacy as predictable by upregulation of PD-1 and ligands pair (PD-L1/PD-L2) upon oncolytic virus injection. Generation of the human version of this virus encoding hICOSL orthologue effectively and specifically activated human T cells by triggering the ICOS pathway. Our data support the data-driven generation of armed oncolytic viruses as combination immunotherapeutic with checkpoint inhibitors.

PMID:38839891 | DOI:10.1038/s41417-024-00790-8

J Sci Med Sport. 2024 May 22:S1440-2440(24)00181-6. doi: 10.1016/j.jsams.2024.05.009. Online ahead of print.

ABSTRACT

We quantified and compared the mechanical force demands relative to the maximum dynamic force (MDF) of 11 cyclists when pedaling at different intensities (ventilatory threshold, maximum lactate steady state, respiratory compensation point, and maximal aerobic power), cadences (free, 40, 60 and 80 rpm), and all-out resisted sprints. Relative force demands (expressed as %MDF) progressively increased with higher intensities (p < 0.001) and lower cadences (p < 0.001). Notwithstanding, relative force demands were low (<54 % MDF) for all conditions, even during the so-called 'torque training'. These results might be useful when programming on-bike resistance training to improve torque production capacity.

PMID:38839539 | DOI:10.1016/j.jsams.2024.05.009

Sci Adv. 2024 Jun 7;10(23):eadk2693. doi: 10.1126/sciadv.adk2693. Epub 2024 Jun 5.

ABSTRACT

T helper 1 (TH1) cell identity is defined by the expression of the lineage-specifying transcription factor T-bet. Here, we examine the influence of T-bet expression heterogeneity on subset plasticity by leveraging cell sorting of distinct in vivo-differentiated TH1 cells based on their quantitative expression of T-bet and interferon-γ. Heterogeneous T-bet expression states were regulated by virus-induced type I interferons and were stably maintained even after secondary viral infection. Exposed to alternative differentiation signals, the sorted subpopulations exhibited graded levels of plasticity, particularly toward the TH2 lineage: T-bet quantities were inversely correlated with the ability to express the TH2 lineage-specifying transcription factor GATA-3 and TH2 cytokines. Reprogramed TH1 cells acquired graded mixed TH1 + TH2 phenotypes with a hybrid epigenetic landscape. Continuous presence of T-bet in differentiated TH1 cells was essential to ensure TH1 cell stability. Thus, innate cytokine signals regulate TH1 cell plasticity via an individual cell-intrinsic rheostat to enable T cell subset adaptation to subsequent challenges.

PMID:38838155 | DOI:10.1126/sciadv.adk2693

PLoS Comput Biol. 2024 Jun 5;20(6):e1012103. doi: 10.1371/journal.pcbi.1012103. Online ahead of print.

ABSTRACT

Long non-coding RNAs (lncRNAs) have received attention in recent years for their regulatory roles in diverse biological contexts including cancer, yet large gaps remain in our understanding of their mechanisms and global maps of their targets. In this work, we investigated a basic unanswered question of lncRNA systems biology: to what extent can gene expression variation across individuals be attributed to lncRNA-driven regulation? To answer this, we analyzed RNA-seq data from a cohort of breast cancer patients, explaining each gene's expression variation using a small set of automatically selected lncRNA regulators. A key aspect of this analysis is that it accounts for confounding effects of transcription factors (TFs) as common regulators of a lncRNA-mRNA pair, to enrich the explained gene expression for lncRNA-mediated regulation. We found that for 16% of analyzed genes, lncRNAs can explain more than 20% of expression variation. We observed 25-50% of the putative regulator lncRNAs to be in 'cis' to, i.e., overlapping or located proximally to the target gene. This led us to quantify the global regulatory impact of such cis-located lncRNAs, which was found to be substantially greater than that of trans-located lncRNAs. Additionally, by including statistical interaction terms involving lncRNA-protein pairs as predictors in our regression models, we identified cases where a lncRNA's regulatory effect depends on the presence of a TF or RNA-binding protein. Finally, we created a high-confidence lncRNA-gene regulatory network whose edges are supported by co-expression as well as a plausible mechanism such as cis-action, protein scaffolding or competing endogenous RNAs. Our work is a first attempt to quantify the extent of gene expression control exerted globally by lncRNAs, especially those located proximally to their regulatory targets, in a specific biological (breast cancer) context. It also marks a first step towards systematic reconstruction of lncRNA regulatory networks, going beyond the current paradigm of co-expression networks, going beyond the current paradigm of co-expression networks, and motivates future analyses assessing the generalizability of our findings to additional biological contexts.

PMID:38838009 | DOI:10.1371/journal.pcbi.1012103

Insect Sci. 2024 Jun 4. doi: 10.1111/1744-7917.13384. Online ahead of print.

ABSTRACT

A systems biology approach was employed to gain insight into tick biology and interactions between vectors and pathogens. Haemaphysalis longicornis serves as one of the primary vectors of Babesia microti, significantly impacting human and animal health. Obtaining more information about their relationship is crucial for a comprehensive understanding of tick and pathogen biology, pathogen transmission dynamics, and potential control strategies. RNA sequencing of uninfected and B. microti-infected ticks resulted in the identification of 15 056 unigenes. Among these, 1 051 were found to be differentially expressed, with 796 being upregulated and 255 downregulated (P < 0.05). Integrated transcriptomics datasets revealed the pivotal role of immune-related pathways, including the Toll, Janus kinase/signal transducer and activator of transcription (JAK-STAT), immunodeficiency, and RNA interference (RNAi) pathways, in response to infection. Consequently, 3 genes encoding critical transcriptional factor Dorsal, Relish, and STAT were selected for RNAi experiments. The knockdown of Dorsal, Relish, and STAT resulted in a substantial increase in Babesia infection levels compared to the respective controls. These findings significantly advanced our understanding of tick-Babesia molecular interactions and proposed novel tick antigens as potential vaccine targets against tick infestations and pathogen transmission.

PMID:38837613 | DOI:10.1111/1744-7917.13384