Communications Biology最新文献

The continued spread and regular outbreaks of African swine fever (ASF) have severely threatened the pig-related industries, causing economic losses. African swine fever virus (ASFV) encoded more than 150 different proteins, but the biological characteristics of the majority of these proteins remain unknown. In this study, we leveraged the Phage ImmunoPrecipitation Sequencing (PhIp-Seq) platform to perform an exhaustive serological analysis of ASFV to characterize the specific reactivities of serum anti-ASFV IgG antibodies against the ASFV proteome at peptide resolution. High-resolution epitope mapping of the ASFV antigens was conducted, and a total of 29 ASFV antigens with high immunogenicity were identified, 14 of which, to the best of our knowledge, have not been previously identified as serological antigens. The immunogenicity of these 29 antigens was evaluated, and their conservation was statistically analyzed across 169 ASFV strains. We found that the uncharacterized protein DP238L is a conserved antigen that is widely hit within the population. The immunogenicity of DP238L and multi-epitope recombinant proteins was validated by immunoblotting and animal immunization trials, confirming the immunogenicity of the identified antigens and the reliability of the PhIp-Seq based epitope mapping strategy. These findings provide insights into the structures and functions of antigen proteins and identify crucial targets for ASFV detection and vaccine development.

We previously identified Stromalin, a cohesin complex subunit, as a learning suppressor in Drosophila melanogaster that acts by limiting synaptic vesicle numbers in dopamine neurons. However, the mechanism by which Stromalin modulates synaptic vesicles remains unclear. We hypothesized that this occurred through the cohesin complex's function in developmental gene regulation. Through dopamine neuron-specific RNA-sequencing followed by RNAi screening, we identified Neprilysin 1 (Nep1), a zinc-dependent metallopeptidase, to be positively regulated by the cohesin complex and a key downstream effector of Stromalin. Nep1 knockdown phenocopies Stromalin knockdown effects, enhancing learning and memory and increasing synaptic vesicle markers in dopamine neurons. Like Stromalin, Nep1 suppresses synaptic strength between dopamine and mushroom body neurons. Finally, we show Nep1 overexpression rescues both memory and synaptic vesicle phenotypes caused by Stromalin reduction. Interestingly, while cohesin complex appears to set the expression levels for Nep1 during development, Nep1 function in adult flies supports its learning effects.

Liver cancer treatment with cisplatin is often hindered by drug resistance. This study aimed to identify key genes associated with cisplatin resistance in liver cancer and develop targeted inhibitors. Using genome-wide CRISPR-Cas9 screening, ATOX1 was identified as a critical gene for cisplatin resistance. ATOX1 was highly expressed in liver cancer tissues and associated with poor prognosis. Knockdown of ATOX1 in liver cancer cells enhanced cisplatin sensitivity in vitro and in vivo. Molecular dynamics simulation and virtual screening identified compound 8 as a potent ATOX1 inhibitor with high affinity (Kd = 12.5 μM) and exhibited synergistic effects with cisplatin on liver cancer cell growth. Mechanistically, compound 8 inhibits the activity of ATOX1, leading to intracellular copper accumulation. The elevated copper levels subsequently promote increased DNA methylation at the NOTCH1 promoter, resulting in suppression of the NOTCH1/HES1 signaling pathway and enhancing the sensitivity of liver cancer cells to cisplatin. In conclusion, ATOX1 is crucial for cisplatin resistance in liver cancer and linked to poor prognosis. Targeting ATOX1 with compound 8 may be a novel therapeutic strategy for overcoming cisplatin resistance.

Methamphetamine (Meth) abuse leads to cognitive impairment, with the hippocampus being severely affected. However, the precise cellular mechanisms underlying Meth-induced hippocampal damage remain unclear. This study utilizes single-nucleus RNA sequencing (snRNA-seq) to investigate the transcriptional changes in mouse hippocampal neurons after acute Meth exposure. We analyze 36,376 nuclei isolated from the hippocampus of acute Meth-treated and control mice, revealing significant alterations in excitatory neuron transcriptomes. Notably, oxidative phosphorylation (OXPHOS) and peroxisome pathways were prominently activated. Five distinct excitatory neuron subtypes were identified across different hippocampal regions, with the dorsal-ventral (DG) region exhibiting the most pronounced changes in gene expression, inflammatory response, reactive oxygen species (ROS) signaling, and OXPHOS activity. High-dimensional weighted correlation network analysis (hdWGCNA) reveals five modules endowed with functional roles in recognizing-associated pathways. Furthermore, it provides insights into intercellular communication and transcriptional regulation patterns within the hippocampus after Meth exposure. In conclusion, this study offers a comprehensive understanding of Meth's impact on hippocampal transcriptomes and may guide the development of therapeutic strategies for acute Meth-induced neurotoxicity.

Our thoughts fluctuate dynamically, driven either by external stimuli and tasks (on-task thoughts) or drifting to task-unrelated contents (off-task thoughts or mind wandering). Although research has identified neural markers distinguishing different thought types, the temporal signature (dynamics) of on- and off-task thoughts remains poorly understood. This EEG study investigated different neurodynamical features-autocorrelation window (ACW), Lempel-Ziv complexity (LZC), power-law exponent (PLE), and median frequency (MF)-to differentiate these thoughts in their underlying dynamics during a signal-response task. Off-task thoughts exhibited prolonged ACW, reduced LZC, increased PLE, and smaller MF compared to on-task thoughts, establishing a distinct neurodynamic signature. Through statistical modeling, we identified a hierarchical background-foreground structure among these measures that unfolds along a temporal continuum, transitioning from longer block-level (17-second) to shorter trial-level (3-second) timescale. Notably, the longer background (block-level ACW) and shorter foreground (trial-level ACW and LZC) layers are tightly coupled during the "faster and shorter" on-task thoughts whereas they are more loosely related during "slower and longer" off-task thoughts. These findings, replicated in an independent dataset, demonstrate how the organization of our brain's dynamics, along a temporal continuum of longer background durations to shorter foreground durations, shapes on-task and off-task thoughts thereby yielding their distinct signatures.

Addressing whether antisense oligonucleotides (ASOs)-based targeting of genes embedded with intronic noncoding RNAs (ncRNAs) affects the expression and function of intronic ncRNAs is crucial to the success of ASOs in clinical trials. While studying zebrafish posterior pituitary development-an important neuroendocrine interface-we found that an ASO targeting the slit3 splice site, but not the translation start site, disrupts pituitary axonal morphogenesis. In addition to altered slit3 splicing, we observed increased expression of slit3, its intron-embedded microRNA mir-218a-1, its longest intron, and the paralogous slit2 gene. The ASO-induced phenotype does not occur when mature mir-218a-1 is blocked by an ASO or in mir-218a-1^-/- mutants, or when the splicing of the exon immediately upstream of the mir-218a-1 embedded intron is blocked by an ASO. The axonal phenotype also phenocopies in samples injected with mir-218a mimic in a dose-dependent manner. Our results indicate that despite the ASO-induced genetic compensation response, intron-retained transcripts can escape the nonsense-mediated decay (NMD) machinery, become stabilized, and lead to increased intronic primary microRNA expression and function. As prematurely terminated intron-retained transcripts can translocate to axons and affect neuronal function, our study warrants further validation for other classes of ncRNAs. Moreover, the idiosyncratic phenotypes observed with translation- versus splice-blocking ASOs can serve as markers to identify the role of intronic microRNAs.

Medication-related osteonecrosis of the jaw (MRONJ) is a severe complication associated with antiresorptive therapy, characterized by compromised bone and soft tissue integrity. However, the underlying tissue-level mechanisms remain poorly understood. To uncover cell functions and spatial organization surrounding ONJ lesions, imaging mass cytometry is used to profile lesions at single-cell resolution across epithelial, stromal, and vascular regions. Widespread immune infiltration is observed, with regulatory T cells, M2-like macrophages, exhausted T cells, and natural killer cells shifting from dispersed to clustered spatial patterns, indicating altered immune organization. Epithelial regions show reduced epithelial marker expression and disrupted architecture despite elevated proliferation-related markers, while fibroblasts and endothelial cells display signs of activation. Functional profiling reveals concurrent proliferative, apoptotic, and stress-associated signatures across multiple cell populations. This comprehensive spatial and functional atlas provides insights into the pathophysiology of MRONJ and may inform future therapeutic strategies aimed at restoring tissue homeostasis and promoting effective healing.

Motor learning induces widespread brain changes, yet the microstructural mechanisms underlying human white matter (WM) plasticity remain poorly understood. Animal studies have identified roles for neurites, glia, and myelin, but in vivo human evidence has been limited by measurement specificity. Here, we combine multi-contrast quantitative MRI (qMRI), tractometry, and a novel multivariate analysis framework to investigate the microstructural basis of WM plasticity during motor skill learning. In a longitudinal within-subject study, 24 healthy adults completed 4 weeks of balance training following a baseline control period without training. We mapped changes across tractography-defined WM pathways using complementary qMRI markers related to tissue density, myelin, neurite architecture, and iron. Multivariate analysis revealed biologically plausible, behaviorally relevant plasticity in distributed pathways-including the cortico-ponto-cerebello-thalamo-cortical loop, anterior thalamic radiation, and corticospinal tracts-with important contributions from myelin-related metrics. Notably, we observed changes consistent with training-related modulation of the aggregate g-ratio in humans. These spatially distributed effects converged into a single latent dimension predicting neocortical plasticity, suggesting a coordinated, cross-tissue mechanism of brain adaptation. This biologically interpretable framework offers a powerful new approach for investigating WM microstructure in the contexts of plasticity, development, aging, disease, and rehabilitation.

Toxoplasma gondii is a protozoan parasite able to infect and survive in diverse host environments. However, its sexual reproduction, culminating in infectious oocysts, occurs exclusively in feline intestines. Recent studies identified the transcription factors AP2XII-1 and AP2XI-2 as crucial for pre-sexual development. Their depletion enabled merozoite formation in human fibroblasts, but progression to sexual stages appeared to require additional cues. Host-specific factors governing this process are suspected but remain elusive. Here, we describe a robust continuous feline intestinal organoid culture system without feeder cells to investigate whether the feline cellular and metabolic environment promotes sexual development of in vitro-generated merozoites. Using ultrastructural and transcriptional analyses, we found elevated levels of sexual stage-specific transcripts. While advanced sexual stage formation could not yet be observed, our feline intestinal organoid model provides a controlled and reproducible experimental system to systematically uncover the feline host factors and molecular mechanisms of T. gondii's sexual development.