Biology subjects

Ma, Y.

Publications and source records attributed to Ma, Y..

At least 73 records · Page 4Linked to original sources

bioRxiv2026

HSC71 acetylation confers protection against Spiroplasma eriocheiris infection by inhibiting apoptosis and promoting ROS production in arthropods

Heat shock proteins (HSP) are increasingly recognized as pivotal regulators of host innate immunity. However, the role of HSP70 post-translational modifications in modulating the immunologic functions during pathogenic infection remains poorly understood. Here, we demonstrated that heat shock cognate 71 kDa protein (HSC71), a member of the HSP70 family, was deacetylated following infection with intracellular pathogen Spiroplasma eriocheiris. HSC71 deficiency exacerbated hemocyte apoptosis and increased host susceptibility to S. eriocheiris infection. Conversely, ectopic expression of hyperacetylation-mimetic HSC71(K579Q) in Drosophila S2 cells conferred robust protection against S. eriocheiris by suppressing apoptosis and augmenting reactive oxygen species (ROS) production. Mechanistically, carnitine O-acetyltransferase (Crat) was identified as the specific acetyltransferase for HSC71. Crat acetylated HSC71 at lysine 579 (K579), which in turn impeded its interaction with the E3 ubiquitin ligase CHIP, thereby stabilizing HSC71 by attenuating ubiquitin-mediated degradation. Crat deficiency induced apoptosis and reduced ROS levels in hemocytes, thereby exacerbating S. eriocheiris intracellular proliferation. Furthermore, acetylation of HSC71 at K579 weakened its binding to superoxide dismutase (SOD), resulting in impaired SOD activity and consequent accumulation of microbicidal ROS. Pharmacological inhibition of the deacetylase SIRT1 with EX-527 enhanced HSC71 acetylation and ROS production, conferring resistance to S. eriocheiris infection in crabs. Notably, EX-527 similarly enhanced the acetylation of Drosophila HSC71 homolog, HSPA8, which in turn impaired its interaction with SOD. This led to elevated ROS levels and restricted intracellular proliferation of S. eriocheiris in S2 cells, demonstrating evolutionary conservation of this mechanism among arthropods. Therefore, this study established the modulation of HSC71 acetylation as a promising strategy to enhance arthropod immunity. Author summaryMembers of the HSP70 family are indispensable components of host innate immunity, and their functions are finely tuned by post-translational modifications. This study investigated the mechanisms that underlie acetylation modification of HSC71 mediated resistance to S. eriocheiris infection in crab. Our results revealed that the acetyltransferase Crat and the antioxidant enzyme SOD directly interacted with HSC71. Mechanistically, Crat acetylated HSC71 at K579, which prevented its ubiquitination by promoting the disassociation of E3 ubiquitin ligase CHIP, thereby improving HSC71 stability. In HSC71-deficient or Crat-deficient crabs, hemocyte apoptosis was markedly enhanced, leading to higher host mortality upon S. eriocheiris challenge. Meanwhile, K579 acetylation on HSC71 weakened the interaction between HSC71 and SOD, resulting in the accumulation of intracellular ROS and thereby restricting S. eriocheiris propagation. Administration of the SIRT1 inhibitor EX-527 enhanced HSC71 acetylation, elevated ROS production and reduced host susceptibility to S. eriocheiris infection. These findings revealed a novel role for Crat-mediated acetylation of HSC71 in orchestrating host defense through two synergistic mechanisms: suppressing apoptosis and promoting ROS accumulation. Thus, targeting HSC71 acetylation may represent a promising avenue to combat S. eriocheiris infection.

immunology↗

bioRxiv2026

Evolutionary Divergence of Structure-Function Coupling between Human and Macaque: Spatial Patterns and Transcriptomic Basis

Structural-functional coupling (SFC) provides critical insights into how the brains structural architecture constrains functional organization for supporting higher-order cognition. Investigating evolutionary differences in SFC between humans and macaques may provide new insights into the neural basis of unique human cognitive abilities. In this study, we analyzed multimodal magnetic resonance imaging data from anesthetized and awake adult rhesus macaques and adult humans to examine cross-species divergences in SFC. Moreover, we integrated transcriptomic data to elucidate the molecular mechanisms underlying evolutionary differences in SFC patterns. We find that humans and macaques exhibit distinct SFC patterns: the human brain shows high SFC in the lateral and medial prefrontal cortex, whereas macaques show high SFC in the sensorimotor cortex. Notably, language-related regions in the human lateral temporal cortex exhibit relatively low SFC. Furthermore, the human whole-brain SFC pattern and the evolutionary differences in SFC between humans and macaques are negatively correlated with cortical evolutionary expansion. By integrating human and macaque transcriptomes, we reveal that the macaque SFC specifically associated genes are primarily involved in basic physiological functions, whereas the human SFC specifically associated genes exhibit evolutionary adaptations in synaptic function, neurotransmitter secretion, and other molecular processes. Moreover, the human-specific genes showing significant overlap with Human Accelerated Regions genes were mainly enriched in cell types of astrocyte and oligodendrocyte and in diseases of schizophrenia and Alzheimers diseases. Overall, these findings advance our understanding of the intricate relationships of SFC in human and macaque brains and provide novel insights in understanding evolutionary conservation and species specificity in cognitive function and gene regulation.

evolutionary biology↗

bioRxiv2026

Metabolic control of mitochondrial plasticity and extracellular vesicle biology drives Cryptococcus neoformans virulence

Metabolic adaptation to nutrient stress is a key but poorly understood driver of fungal virulence. Here, we show that a dominant East Asian lineage of Cryptococcus neoformans (VNIa-5), which disproportionately infects immunocompetent hosts, has undergone lineage-specific rewiring of glucose-responsive stress pathways. Integrating population genomics, transcriptomics, and experimental infection models, we demonstrate that VNIa-5s clinical dominance is not explained by environmental prevalence. Instead, selective activation of Snf1 signalling links glucose limitation to mitochondrial tubularisation, extracellular vesicle remodelling, and enhanced melanization. Under low-glucose conditions, VNIa-5 exhibits marked mitochondrial plasticity and extracellular vesicle compositional shifts resembling hypervirulent outbreak lineages of Cryptococcus gattii. Following experimental induction of dormancy, VNIa-5 shows significantly increased virulence in vivo compared with the closely related but clinically rare VNIa-31 subclade, with host survival tightly correlated with mitochondrial morphology. These findings identify metabolic stress integration as a central mechanism shaping cryptococcal virulence and disease in immunocompetent human hosts.

microbiology↗

bioRxiv2026

Transforming Histology into Virtual Multiplex Immunofluorescence to Decode Prognostic Spatial Immunity in Hepatocellular Carcinoma

The spatial organization of the tumor immune microenvironment (TIME) drives hepatocellular carcinoma (HCC) prognosis but remains unquantifiable on routine H&E slides. Here, we present HCCExplorer, a deep learning framework that translates H&E into virtual multiplex immunofluorescence (mIF) and uses multi-modal graph learning to decode spatial survival signals. Trained on 30 H&E-mIF slide pairs, HCCExplorer evaluated a 1,813-slide multi-center cohort. It achieved superior overall survival stratification over clinical indices and state-of-the-art pathology and protein foundation models, yielding a concordance index of 0.71 and a Hazard Ratio (HR) of 15.46 (P < 0.001), maintaining stability across three external cohorts. Beyond risk stratification, interpretation of model features identified M1 macrophage infiltration as a protective determinant (HR=0.40, P < 0.05). Furthermore, it uncovered a protective "Containment Niche" at the invasion frontier (HR=0.02, P < 0.01), featuring macrophages co-localizing with Foxp3+ Tregs and CD4+ T cells. Ultimately, HCCExplorer provides actionable, spatially-resolved biomarkers from conventional histology for precision HCC management.

pathology↗

bioRxiv2026

Development and characterization of mouse-adapted recombinant SARS-CoV-2 expressing reporter genes

Transgenic K18-hACE2 mice are a standard model for Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), albeit with limitations. A mouse-adapted 30 (MA30) SARS-CoV-2 has been developed to allow infection of wild-type (WT) mice strains. However, SARS-CoV-2 MA30 cannot be easily tracked in vitro, ex vivo, or in vivo. To address the problem, we developed a recombinant (r)SARS-CoV-2 based on the MA30 strain expressing fluorescent (mCherry) and luciferase (nanoluciferase, Nluc) reporter genes, alone or in combination, that enable tracking of viral infection in WT C57BL/6 and BALB/c mice. Insertion of the reporter genes resulted in minor viral attenuation in vitro, with [~]0.5-1.0-log lower titers than rSARS-CoV-2 MA30 WT in A549 hACE2 cells, while maintain similar plaque morphology and replication kinetics in Vero AT cells. In vivo, reporter-expressing rSARS-CoV-2 MA30 caused transient weight loss, contrasting with lethal rSARS-CoV-2 MA30 WT infection. Bioluminescence imaging of rSARS-CoV-2 MA30 Nluc in C57BL/6 and BALB/c mice revealed peak pulmonary replication at 2 days post-infection, with resolution by day 4, and correlated with tissue viral loads. Our results demonstrate the feasibility of using rSARS-CoV-2 MA30 expressing reporter genes to track viral infection in vitro, ex vivo, and in vivo without a need for secondary approaches to monitor viral infection as are required for rSARS-CoV-2 MA30 WT. Our system is highly suitable to evaluate prophylactic vaccines and therapeutic antibodies or antiviral approaches in WT or transgenic C57BL/6 and BALB/c mice without the shortcomings of K18-hACE2 mice and with the added advantage of non-invasive monitoring of treatment efficacy. ImportanceThe K18-hACE2 transgenic mouse model limits the capability to study SARS-CoV-2. While a mouse adapted 30 (MA30) has been developed to study SARS-CoV-2 in wild-type (WT) mice, it does not allow non-invasive tracking of viral infections. Recombinant viruses expressing reporter genes enable real-time monitoring of infection dynamics, opening an avenue to study viral tropism and easily evaluate prophylactic and therapeutic approaches. They furthermore support longitudinal studies, which reduces the number of research animals required. Here, we show that a recombinant (r)SARS-CoV-2 expressing fluorescent (mCherry) and nanoluciferase (Nluc) reporter genes, alone or in combination, can be used to track viral infections in vitro, ex vivo, and in vivo without the need for secondary approaches that are required to detect SARS-CoV-2 MA30 in WT mice. These reporter-expressing rSARS-CoV-2 MA30 may accelerate vaccine development and antiviral drug discovery in WT or transgenic mice bypassing the need for hACE2 overexpression in K18-hACE2 transgenic mice.

microbiology↗

bioRxiv2026

Large-scale quantum computing framework enhances drug discovery in multiple stages

Coherent Ising machines (CIMs) excel at solving large-scale combinational optimization problems (COPs), but their insufficient long-term stability has hindered their applications in compute-intensive tasks like computer-aided drug discovery (CADD). By improving fiber vibration isolation and temperature control system, we have implemented a 2000-node CIM named QBoson-CPQC-3Gen achieving stable solutions over one hour on large-scale COPs. Graph-based encoding schemes were further introduced to realize a CIM-based CADD workflow including allosteric site detection, protein-peptide docking and intermolecular similarity calculation. CIM-based methods demonstrated superior speed and accuracy than heuristic algorithms. Especially, QBoson-CPQC-3Gen identified 2 novel druggable sites and bioactive compounds for 6 targets, which were further validated in vitro, in-cell and by crystal structures. Our contributions established a quantum-computing framework for multi-stage drug discovery, representing a significant advancement in both quantum computing applications and pharmaceutical research.

bioinformatics↗

bioRxiv2026

WUSCHEL modulates jasmonate signaling to control the balance between growth and defense in the shoot apical meristem

The growth-defense trade-off is an essential survival strategy for plants under environmental stress. However, how this balance is maintained at the meristematic level remains unclear. Here, we show that wounding of rosette leaves systemically inhibits inflorescence stem growth, associated with reduced cell proliferation in the inner cell layers of the shoot apical meristem (SAM), but not in the apical stem cell domain. Mechanistically, this selective cell behavior is dependent on the interplay between the growth-repressing jasmonate (JA) signaling and the growth-promoting stem cell regulator WUSCHEL (WUS). WUS mitigates wounding-induced growth inhibition by repressing JA-responsive gene expression via promoting the accumulation of JASMONATE-ZIM DOMAIN 3 (JAZ3), which encodes a JA signaling repressor. WUS on the one hand induces JAZ3 mRNA accumulation and on the other hand directly competes with the JA receptor CORONATINE INSENSITIVE1 (COI1) for JAZ3 binding, thereby inhibiting JAZ3 protein degradation. Our findings identify a WUS-JAZ3-COI1 regulatory module that coordinates the growth-defense balance in the SAM upon systemic wounding, revealing a cell-type-specific mechanism for sustaining developmental robustness of the meristem during stress response.

plant biology↗

bioRxiv2026

A Bear-Specific Coding Exon in TMEM41B Is Associated with Cold Adaptation

AbstractBears exhibit an unusual form of hibernation in which core body temperature remains relatively high despite profound suppression of whole-body metabolism. How such a warm yet hypometabolic state is achieved remains poorly understood. Here, through integrative analysis of 238 RNA-seq datasets spanning seven species, we identify transmembrane protein 41B (TMEM41B) as an evolutionarily conserved factor associated with thermogenic capacity. Loss of Tmem41b in mice and Drosophila results in severe cold intolerance, whereas its overexpression enhances thermogenic performance, supporting a conserved role in heat production. Comparative genomic analyses reveal a bear-specific 51-amino acid N-terminal extension in TMEM41B, arising from a 5' untranslated region mutation that converts a premature stop codon into coding sequence. Interactome profiling indicates that this bear-specific isoform differs from the canonical TMEM41B in its protein interaction landscape, including reduced association with components of mitochondria-associated endoplasmic reticulum membranes such as voltage-dependent anion-selective channel protein 1 (VDAC1). Consistent with this altered interaction profile, the extended isoform is associated with reduced mitochondrial oxidative activity. Functional analyses further suggest that the 51- amino acid extension modulates multiple cellular programs, including suppression of oxidative phosphorylation and myogenic differentiation alongside activation of osteogenic pathways, collectively biasing cells toward a hypometabolic state. Notably, expression of the polar bear TMEM41B isoform in mice induces a torpor-like phenotype under fasting conditions. Together, these findings identify TMEM41B as a conserved regulator of thermogenic capacity and suggest that evolutionary modification of its N terminus may contribute to metabolic suppression and energy conservation during bear hibernation.

evolutionary biology↗

bioRxiv2026

Sequential evolution of antidote and toxin links genetic incompatibility with immune responses

Toxin-antidote (TA) systems are selfish genetic elements that promote their own inheritance by selectively eliminating offspring lacking the module, thereby establishing post-zygotic genetic incompatibilities between individuals and populations. Although these systems are widespread across species, their evolutionary origins remain poorly understood. Here, we report the discovery of a novel TA gene pair in the nematode Caenorhabditis nigoni. The antidote gene, Cni-shls-2, is a species-specific F-box gene that arose through recent tandem duplications. Its absence results in embryonic lethality in both C. nigoni and its hybrids with the sister species C. briggsae. This lethality is caused by a maternally deposited toxin, Cni-hlix-1, a chimeric gene formed through the fusion of host and bacterial sequences. Phylogenetic and genomic analyses reveal a sequential evolution of the TA system, in which the antidote evolved prior to the toxin. The stepwise evolution of TA and the potential microbial origin of the toxin support the hypothesis that the antidote initially evolved in response to pathogen exposure, followed by the domestication of the toxin, thereby elucidating the origins of TA formation. These findings highlight the central role of host-pathogen conflict as a driving force in the emergence of genetic incompatibilities and the evolution of reproductive barriers.

evolutionary biology↗

bioRxiv2026

Plasmid transfer and loss probabilities interactively determine antibiotic resistance spread in surface-associated bacterial biomass

Plasmid transfer among bacteria is an evolutionary driver of the spread of antibiotic resistance. Surface-associated bacterial biomass is a hotspot for plasmid transfer due to the dense spatial packing of cells. Compared to plasmid dynamics within a single biomass unit, the determinants of plasmid transfer between discrete units are less understood. Yet, discrete units routinely physically collide with each other as they grow, such as in sparse biofilms. Here, we used individual-based modelling to quantitatively predict how the probabilities of plasmid transfer and loss affect plasmid spread between discrete bacterial colonies as they grow and physically collide into each other. We found that these factors have interactive effects on the extent of plasmid transfer and the subsequent proliferation of transconjugants. We further found that these effects are controlled by the spatial distance between the colliding colonies and the spatial positioning of plasmid-carrying cells along the collision boundary. We then experimentally tested our modelling predictions using strains of Pseudomonas stutzeri and Escherichia coli that can exchange an antibiotic resistance-encoding plasmid. Our study reveals that plasmid transfer between colliding biomass units is determined by the complex interplay between plasmid transfer, plasmid loss, and spatial constraints, expanding our understanding of plasmid dynamics.

microbiology↗

bioRxiv2026

ToolsGenie 2.0: A Scalable and Extensible Multi-Agent System for Bioinformatics Automation

The rapid expansion of biomedical data necessitates efficient bioinformatics tools, yet conventional workflows rely heavily on manual dependencies, hindering scalability and broader adoption. Building on the foundation of ToolsGenie 1.0, we introduce ToolsGenie 2.0, a multi-agent AI framework that automates bioinformatics analyses through natural language queries and file inputs. ToolsGenie 2.0 addresses the growing need for customizable analyses by offering extensibility, reproducibility, improved accuracy, and ease of use. It incorporates a ReAct-based architecture with dual-layer extensibility for sub-agents and specialized tools, along with dynamic Docker image selection for automated, sandboxed, and secure environment management. Rigorous benchmarking shows that ToolsGenie 2.0 achieves 68.6% accuracy on an in-house dataset and 48.3% accuracy on BixBench, demonstrating competitive performance across diverse evaluation settings. These innovations position ToolsGenie 2.0 as a versatile platform for broadening access to bioinformatics in both research and clinical contexts. ToolsGenie 2.0 is available on the PromptBio platform (platform.promptbio.ai).

bioinformatics↗

bioRxiv2026

System-wide profiling reveals metabolic alterations in a G2019S LRRK2 knockin mouse model of Parkinson's disease: systemic depletion of pyrimidine nucleosides

G2019S LRRK2 is the most common cause of familial Parkinsons disease (PD) and is associated with sporadic PD, arising from the interplay of genetic predisposition, environmental exposure and aging. Metabolic syndrome is implicated as a risk factor for PD, but the interaction between G2019S LRRK2 and metabolic stress in disease pathogenesis remains unclear. We employed high-fat diet (HFD) feeding to induce metabolic syndrome in aged mutant LRRK2 mice, followed by system-wide characterization, including metabolomic or proteomic profiling, and bulk or single-nucleus RNA sequencing. We find that thymidine and deoxyuridine levels are consistently reduced across tissues in G2019S LRRK2 knockin mice accompanied by increased hepatic expression of thymidine phosphorylase. HFD exposure further unmasks disruptions in purine and energy metabolism in brain and lung of G2019S LRRK2 knockin mice, with midbrain astrocytes and oligodendrocytes exhibiting the most pronounced impairment in oxidative phosphorylation transcriptional pathways. Our findings demonstrate that pre-existing metabolic syndrome unmasks widespread disruptions in systemic nucleotide and energy metabolism and exacerbates mitochondrial dysfunction in G2019S LRRK2 knockin mice. This conditional "two-hit" phenotype underscores the critical role of environmental factors, such as diet, in revealing metabolic vulnerabilities associated with PD-linked genetic backgrounds, and provides potential metabolic targets for therapeutic intervention in PD.

neuroscience↗

bioRxiv2025

Tryptophan-substitution antimicrobial peptide temporin-1CEb: in vitro and in vivo antibacterial activity against clinically isolated multidrug-resistant Klebsiella pneumoniae

Tryptophan (Trp)-substitution antimicrobial peptides (AMPs) exhibit enhanced interactions with bacterial cell membranes, potentially improving their antimicrobial efficacy. K. pneumoniae (20.59% of 2054 ICU isolates) is resistant to multiple clinically used antibiotics and presents significant treatment challenges. In the present study, three Trp-modified peptides (I4W, L12W, and I1WL5W) were generated by substituting Ile or Leu residues in temporin-1CEb, a peptide derived from frog skin, with Trp at various sites to assess their antibacterial effects and mechanisms against K. pneumoniae. Compared with L12W, both I4W and I1WL5W displayed superior antimicrobial activity and lower cytotoxicity. Mechanistic studies revealed that the AMPs exerted antibacterial and bactericidal effects through bacterial surface charge neutralization, insertion into bacterial cell membranes, increased permeability of both the inner and outer membranes, and disruption of membrane integrity. Notably, I1WL5W exhibited the most potent membrane-disrupting activity. Assessment of the impact of Trp-containing peptides on bacterial biofilms revealed that these peptides not only inhibited exopolysaccharide production and biofilm formation but also degraded preformed biofilms. A murine lung infection model was established to investigate the therapeutic efficacy of I1WL5W against MDRKP 1203-induced lung infection in mice. Compared with the control treatment, treatment with I1WL5W resulted in reduced bacterial counts and levels of IL-6 and TNF- in both the blood and lung tissues of MDRKP 1203-infected mice, and treatment with I1WL5W improved lung tissue structure. The present study provides valuable insights for designing Trp-containing peptides with potent antimicrobial properties by facilitating their penetration across bacterial membranes.

pharmacology and toxicology↗

bioRxiv2025

Activation of the medial entorhinal cortex drives memory-guided navigation behavior

The cognitive map in the medial entorhinal cortex (MEC) is essential for spatial memory and exhibits experience-dependent changes. Yet, it remains unclear whether MEC activation is sufficient to bias the network toward memory-guided navigation, precluding a causal link between the MEC and spatial memory. To address this gap, we examined and optogenetically manipulated MEC activity as mice navigated a virtual track for a water reward based on memory. During learning, spatial activity in the pre-reward region showed the highest consistency along the track and closely paralleled improvements in reward-predictive behaviors. This elevated pre-reward consistency was widespread across MEC neurons, rather than confined to a particular cell type, indicating a network-level representation supporting reward prediction. Strikingly, optogenetic activation of MEC at non-reward locations biased reward-predictive behaviors toward stimulation sites, but only when stimulation patterns were spatially consistent. Consistent stimulation also induced anticipatory reward-seeking before stimulation onset and this behavior gradually developed with repeated stimulation, reflecting memory formation for stimulation locations. Moreover, in animals that failed to learn the track well, consistent pre-reward activation, alone or combined with landmark activation, significantly enhanced their reward prediction. Thus, spatially consistent MEC activation underlies memory-guided reward prediction, supporting a causal role for the MEC in spatial memory.

neuroscience↗

bioRxiv2025

MAGNET: an all-in-one foundation model for cross-modal and cross-dimensional microscopic image restoration

The application of emerging Foundation models in current microscopy has remained limited due to task-specific model designs, strong modality dependence and insufficient robustness under complex degradations. Here, we introduce MAGNET (Microscopic All-in-one General fouNdation model for imagE resToration), the first end-to-end All-in-One foundation model designed for universal microscopic image restoration. MAGNET integrates multi-task, cross-modal and cross-dimensional (2D + 3D) image restoration capabilities within a single unified architecture, and it is specifically designed to handle composite degradations in practical imaging systems. The framework comprises three components: (i) a task-aware, prompt-guided feature enhancement module for adaptive learning across diverse degradations; (ii) an LIIF-based reconstruction module enabling continuous, resolution-adaptive restoration; and (iii) a dimension-compatible triple-plane projection module supporting both 2D and 3D data. Trained on large-scale datasets spanning 5 major microscopy modalities (structured illumination, confocal, light-sheet, wide-field and two-photon) and 8 representative restoration tasks, MAGNET achieves state-of-the-art performance across super-resolution, denoising, deblurring, background suppression, isotropic reconstruction, aberration correction, de-scattering and virtual staining. Beyond supervised training, MAGNET supports direct inference on unseen systems, efficient few-shot fine-tuning and self-supervised test-time optimization, enabling robust performance across diverse data and imaging conditions. MAGNET serves as a unified, generalizable, and scalable computational framework for microscopy, enabling more efficient and reliable downstream analyses in cell biology, neuroscience, and pathology.

cell biology↗

bioRxiv2025

Pulmonary mRNA-LNP Vaccines for Rapid and Durable Protection Against Bacterial Infection

Pulmonary bacterial infections remain a major clinical challenge. Although vaccination reduces infection rates and mortality, the vulnerable post-vaccination immunity gap can still result in infection and vaccine failure. In addition, effective vaccines are unavailable for many clinically important bacterial pathogens. Here, we report a pulmonary mRNA-lipid nanoparticle (mRNA-LNP) vaccine incorporating a novel ionizable lipid engineered for localized high-level expression, which elicits both rapid and durable protections against bacterial lung infections, effectively bridging this critical window of vulnerability. Intratracheal delivery of mRNA-LNP rapidly primes lung neutrophils and macrophages into a transcriptionally pre-activated state, enhancing their phagocytic activity and enabling rapid, antigen-independent bacterial clearance during the early post-vaccination period (approximately 1-7 days). Subsequently, vaccination induces potent antigen-specific adaptive responses, conferring sustained protection against both laboratory and clinical drug-resistant Pseudomonas aeruginosa strains. Single-cell transcriptomics and immune profiling reveal coordinated activation of innate and adaptive immune programs. This dual-phase immune response exemplifies a paradigm-shifting vaccine design that integrates innate and adaptive immunity to confer both immediate and long-term protection. Our findings establish a mechanistic basis for rapid antibacterial defense and highlight pulmonary mRNA-LNP vaccination as a promising strategy for combating respiratory infections.

bioengineering↗

bioRxiv2025

Proteasome activator Blm10 maintains cellular proteostatic balance and gamete quality in budding yeast

The proteasome is responsible for regulated protein degradation in eukaryotic cells. Its best characterized substrates are ubiquitinated proteins that are targeted to the 26S proteasome complex, consisting of a 19S regulatory particle (RP) capping the barrel-shaped 20S core peptidase (CP). The CP can interact with other caps, including Blm10/PA200, a nearly 250 kDa protein whose biological function is not well understood. Blm10 is upregulated during gametogenesis in budding yeast, suggestive of a natural stage-specific modulation of proteasome composition. Here, we investigate the function of Blm10 during yeast gametogenesis, identifying it as a weak activator of the proteasome that can displace the 19S RP from the CP. Due to this competition for the CP, overexpression of Blm10 can lead to attenuation of ubiquitin-dependent degradation and proteostatic defects. Cells lacking Blm10 also display markers of proteostatic stress, including Hsp104 foci and heat sensitivity, suggesting that Blm10 safeguards normal proteostatic balance. We find that Blm10 is important for producing fit gametes and ensuring full rejuvenation of aged cells following gametogenesis. Furthermore, we observe direct association of aggregate-prone proteins and protein-folding factors with immunoprecipitated Blm10-proteasomes. Finally, we discovered that 14-3-3 proteins Bmh1/2 are novel cofactors of Blm-10 bound proteasomes and describe how Blm10 controls CP gate configuration. Overall, our data suggest a role for Blm10-proteasomes in maintaining gamete proteostasis through fine-tuning of proteasome activity and prevention of protein aggregation.

molecular biology↗

bioRxiv2025

Identification of the protein precursor for thyroid hormone synthesis in the basal chordate ascidian Styela clava

Thyroid hormones (THs) play crucial roles in development, growth, and metabolism across the animal kingdom1,2. Although the mechanism of TH synthesis in vertebrates has been well described, it remains elusive in invertebrates due to the lack of identified orthologs of the thyroglobulin (TG), the protein precursor for TH synthesis3,4. Here, we identified a functional TG protein encompassing multiple TG type 1 (Tg1)-domains, encoded by the ScTg-like gene in proto-vertebrate ascidian Styela clava based on the immunoprecipitation-mass spectrometry combined with phylogenetic and expression pattern analyses. In vitro iodination experiments demonstrated that ScTG-like has the capacity to provide hormonogenic sites for TH synthesis. Furthermore, in vivo gene knockdown of ScTg-like revealed that the larval metamorphosis was significantly inhibited as a consequence of diminished TH levels, indicating that ScTg-like is responsible for the production of endogenous TH. Additionally, an invaginated follicle-like structure was first discovered at the central anterior of the larval trunk where both ScTG-like protein and THs were deposited, suggesting that this structure serves as the location for THs synthesis and storage, functionally similar to vertebrate thyroid follicles. Moreover, we analyzed the structural features of ScTG-like protein and detected the similarly organized Tg1-containing proteins in multiple bilaterian phyla, suggesting that endogenous TH synthesis may be an ancestral, possibly synapomorphic, trait of bilaterians. Our study is the first to identify the TH protein precursor outside vertebrates by providing the direct evidence of endogenous de novo TH synthesis, which offers insights into the evolution of TG protein and the emergence of a major vertebrate endocrine system.

evolutionary biology↗