Communications Biology最新文献

Dendritic cell-targeting mRNA vaccines exhibit robust antitumor immune activation, however, their therapeutic efficacy remains unsatisfactory due to multiple delivery challenges, including carrier complexity, biomaterial toxicity, nucleic acid instability, and endosomal entrapment, which collectively compromise both safety and treatment outcomes. Here, we report the construction of poly T-modified poly (lactic-co-glycolic acid) (PLGA) nanoparticles to condense an HCC-specific GPC3 mRNA with a unique poly(A) tail via hydrogen bonding interactions between A-T base pairs, affording P-(H)-m that further undergoes endoplasmic reticulum membrane camouflage to produce the target biomimetic vaccine, P-(H)-m@EMLN. The endoplasmic reticulum membrane enables P-(H)-m@EMLN with simultaneously enhanced endosomal escape properties and immunogenicity, which leads to a high tumor inhibition ratio (TIR) of 98.8% and long-term immunity activation in a Hepa1-6 tumor-bearing mouse model. Overall, this study reports the mRNA vaccine, P-(H)-m@EMLN via hydrogen bonding interactions between the poly T sequence of polymeric carrier and poly A tail of mRNA for robust immunotherapy of hepatocellular carcinoma.

How does the brain turn a physical signal like speech into meaning? It draws on two key sources: linguistic structure (e.g., phonemes, syntax) and statistical regularities from experience. Yet how these jointly shape neural representations of language remains unclear. We used MEG to track phonemic and acoustic encoding during spoken language comprehension in native Dutch, Mandarin-Chinese, and Turkish speakers. Phoneme-level encoding is stronger during sentence comprehension than in word lists, and more robust within words than random syllables. Surprisingly, similar encoding emerges even in an uncomprehended language but only with prior exposure. In contrast, acoustic edges are briefly suppressed early in comprehension. This suggests that the brain's alignment to speech (in phase and power) is robustly tuned by structure and by learned statistical patterns. Our findings show how structured knowledge and experience-based learning interact to shape neural responses to language, offering insight into how the brain processes complex, meaningful signals.

Postoperative cognitive dysfunction (POCD) is common in older surgical patients, yet its mechanistic underpinnings remain incompletely defined. Building on the premise that immune-cell metabolism shapes inflammatory signaling, we investigated whether microglia export metabolic instructions through extracellular vesicles (EVs) to remodel astrocytic function. We show that plasma EVs from POCD patients and EVs from activated microglia are enriched for ATP citrate lyase (ACLY) and are efficiently taken up by astrocytes. EV-delivered ACLY increases acetyl-CoA availability and enhances NF-κB p65 acetylation, which in turn suppresses the astrocytic glutamate transporter EAAT1 (SLC1A3). This program diminishes glutamate clearance, leading to synaptic dysfunction and cognitive impairment. In aged mice, systemic or hippocampal EV administration recapitulated microgliosis/astrogliosis, dendritic spine loss, impaired long-term potentiation, and deficits in the Morris water maze and novel object recognition. Chromatin immunoprecipitation confirmed acetyl-p65 occupancy at the SLC1A3 promoter, linking ACLY activity to direct transcriptional repression of EAAT1. Interventions that blocked EV biogenesis/uptake or reduced ACLY (genetically or pharmacologically) attenuated p65 acetylation, restored EAAT1 expression and glutamate uptake, and improved synaptic and behavioral outcomes. These findings identify a microglia-to-astrocyte ACLY-p65-EAAT1 axis that couples immunometabolism to excitatory neurotransmitter dysregulation and cognitive decline in POCD, highlighting ACLY and EV pathways as actionable therapeutic targets.

Domestic cattle (Bos taurus and Bos indicus) underpin food security and livelihoods worldwide but face intensifying pressures from climate change, infectious disease, and inconsistent feed supplies. African and European indigenous cattle provide a natural comparative framework spanning gradients of climate, pathogen burden, and husbandry, and possess genomic mosaics comprising African taurine, European taurine, and indicine ancestry. We analyzed whole-genome sequences from 519 cattle across 24 African and European indigenous populations and 117 publicly available genomes from Africa, Asia, Europe, and the Americas. This dataset reveals admixture mosaics among major lineages and identifies 36 candidate genes exhibiting adaptive retention of ancestral alleles associated with response to heat stress (e.g., HSPA12B, DDIT3), immunity (IRAK3), productivity (ACSF3), and reproductivity (SSMEM1, SPEF1). Our study suggests that historical admixture introduced variation shaped by local ecological selection, clarifying how environmental heterogeneity drives the retention of advantageous alleles and informing sustainable breeding and diversity conservation.

The karst ecosystem in southwestern China is a global hotspot for cavefish diversity research, yet the origins and evolutionary history of this diversity remain poorly understood. To elucidate their evolutionary origins and history, we analyzed 183 cavefish species and their close relatives from ten clades. Our findings indicate that freshwater fishes began colonizing caves ~44 million years ago (Ma). Speciation was driven by in situ diversification, starting around 43.2 Ma, increasing sharply by ~35 Ma and 18 Ma, and peaking at ~8.3 Ma, 2.5 Ma, and 1.5 Ma. Distinct hydrological basins exhibited divergent diversification patterns. Dispersal between the Pearl and Yangtze River basins began by ~24.1 Ma, accelerated around 21 Ma, 13 Ma, and 9.6 Ma, and peaked at ~13 Ma, 5 Ma, and 2 Ma. We propose that river drainages in southwestern China developed stepwise from the late Eocene to early Pleistocene, with connectivity between the Pearl and Yangtze basins established by the late Oligocene ( ~ 26 Ma). The origin and diversification of cavefishes are closely linked to the evolution of karst landscapes, shaped by orogeny and monsoon-driven climate changes since the late Eocene. These insights are crucial for informing conservation strategies for these unique habitats under ongoing climate change.

A fundamental feature of the visual system is its ability to detect image contrast. The contrast processing starts in the first synapse of the retina where parallel pathways are established to compute contrast to bright (ON pathway) and dark (OFF pathway) objects, separately transferred to morphologically identified ON and OFF cells throughout the visual system. Here, we found that response polarity in ON and OFF neurons is not fixed but rather switches dynamically to the opposite polarity. The switch was not observed in rod-knockout mice, indicating that rods generate the polarity switch. We determined that neither horizontal cells nor rod-signaling pathways were responsible for the switch. Instead, we discovered that EAAT5 glutamate transporters located at photoreceptor terminals were required to produce the polarity switch. Our findings exhibit the plasticity of ON-OFF coding in retinal interneurons and their ability to encode contrast across the visual dynamic range.

Human immunodeficiency virus (HIV) can invade the central nervous system during the initial stages of infection and contribute to HIV-associated neurocognitive disorder, affecting up to 50% of people living with HIV (PLWH). To investigate HIV-1-induced immunometabolic changes in the brain, we used a three-dimensional microglia-embedded human neural organoid model. Transcriptomic analysis and genome-scale metabolic modeling revealed that HIV-1 infection led to more pronounced transcriptional changes in the presence of microglia, including upregulation of pro-inflammatory pathways. We identified CCR6, important for HIV-1 permissiveness, to be significantly upregulated upon infection. Metabolic analysis showed increased expression in metabolite transport-related genes, including solute carrier (SLC) genes and altered amino acid metabolism, particularly involving arginine, proline, and tyrosine. These microglia-driven immunometabolic changes may contribute to neuronal dysregulation and, subsequently, neurological complications, which are often observed in PLWH. Early detection of these alterations could support timely therapeutic intervention to improve HIV-related neurologic insult.

Fatal interactions with wind turbines are a major threat to bat populations worldwide. Yet, the ultimate causes for bats colliding with wind turbines remain elusive. Using an extensive acoustic data set recorded at nacelle height in different parts of Germany, we show that feeding and social activity occur at all studied wind turbines. At least seven bat species (accounting for 95% of German bat fatalities) perform song flight at wind turbines, a behavior related to mating and courtship, indicating that males may find wind turbines attractive for establishing mating territories. Male songs broadcast over considerable distances and could function as acoustic beacons attracting females to turbine sites. Analysis of 3D thermal detection shows that bat density is higher in the rotor swept zone than in the free air space surrounding turbines. This strongly suggests that bats actively approach turbines, possibly in search of mating, roosting and/or foraging opportunities.

Acetylcholine differentially modulates anterior cingulate (ACC) and lateral prefrontal (LPFC) cortices for cognitive-emotional integration, but cell-specific expression and function of muscarinic receptors (mAChR) and corresponding CHRM1-4 genes in these areas of the primate brain are largely unknown. Our single-nucleus RNA sequencing and mRNA-protein histology in macaques revealed CHRM3 as the most enriched mAChR gene in neurons, while m1 predominates at the protein level, likely due to nuclear retention of CHRM3 and cytoplasmic trafficking of CHRM1. CHRM3 and CHRM1 showed strong co-expression and functional overlap, and were transcriptomically-distinct from CHRM2, which was uniquely enriched in deep layer excitatory and PVALB+ inhibitory neurons. Between-region comparisons showed that CHRM3 is enriched in LPFC relative to ACC excitatory neurons. Further, CHRM1-3+ neurons showed region-specific transcriptomic signatures, with upregulation of synaptic plasticity genes in ACC relative to LPFC. Functional in vitro experiments confirmed a robust cholinergic-mediated decrease in excitatory and increase in inhibitory synaptic tone specific to ACC neurons, accompanied by changes in spine morphology. In contrast, cholinergic stimulation reduced inhibitory current amplitude in LPFC, shifting the microcircuit towards a stronger excitatory tone. These findings highlight region-specific acetylcholine signaling essential for flexible processing, learning and memory, which may underlie neurochemical circuit imbalance in neuropsychiatric disorders.

Dynamic regulation of lipid membrane composition is fundamental to living cells; however, synthetic analogs capable of such regulation remain scarce. Here, we present an artificial cell platform in which riboswitch-mediated expression of phospholipase D (PLD) enables stimulus-responsive lipid remodeling within lipid vesicles. In this system, chemically induced activation of a fluoride-responsive riboswitch triggers cell-free synthesis of PLD, which hydrolyzes phosphatidylcholine (PC) to phosphatidic acid (PA) in the inner leaflet of the vesicles. This enzymatic reaction generates a negatively charged asymmetric membrane, enabling functionalization with mechanosensitive channels such as the mechanosensitive channel of large conductance (MscL). We characterized the kinetics of asymmetry generation by varying plasmid DNA and fluoride concentrations, and evaluated membrane behavior using lipid compositions with or without cholesterol. Our platform demonstrates a strategy for coupling gene expression to dynamic membrane remodeling and underscores the potential of riboswitch-regulated lipid transitions in building environment-responsive artificial cells with programmable functions.