Biology subjects

Liu, X.

Publications and source records attributed to Liu, X..

At least 343 records · Page 19Linked to original sources

bioRxiv2025

The Cortical Temporal Axis: MEG-Based Cross-Frequency Gradients with Biological Anchors

Neural oscillations have long been used to characterize the temporal dynamics of individual brain regions, yet a parsimonious, system-level representation that integrates multi-rhythmic activity has been lacking. Using source-localized resting-state magnetoencephalography (MEG) data, we computed regional power spectra and assessed spectral similarity, then applied diffusion map embedding to construct cross-frequency neurophysiological gradients that place whole-brain oscillations within a unified, low-dimensional coordinate system. We found the first three gradients accounted for over 40% of the variance, remained stable across individuals, and aligned with established functional, structural, and geometric cortical axes. Computational modeling showed that these gradients reflect local excitation-inhibition balance, while multimodal analyses revealed strong associations with neurotransmitter receptor distributions, cytoarchitecture, and cell-type-specific gene expression. Lifespan analyses further demonstrated systematic gradient reorganization, with distinct cognitive mappings onto functions such as language, memory, and multisensory integration. Clinically, Parkinsons disease patients displayed disrupted gradients, particularly in regions linked to language and social cognition. Finally, these gradient patterns exhibited high test-retest reliability. These findings establish MEG-derived neurophysiological gradients as robust, low-dimensional representations of cortical organization, offering a biologically grounded framework for studying brain aging and disease.

neuroscience↗

bioRxiv2025

Mus Musculus papillomavirus MmuPV1 resists restriction by human APOBEC3B

The single-stranded DNA deaminase APOBEC3B (A3B) is capable of potently restricting the replication of a range of viruses including retroviruses (cDNA) and herpesviruses (genomic DNA). However, these and likely other DNA virus families have evolved host species-specific counter-defenses that are equally potent and serve to protect viral DNA from restriction. Although high-risk human papillomavirus (HPV) infection triggers A3B upregulation, potentially as part of an antiviral response, the impact of this restriction factor on papillomavirus replication and pathogenesis has yet to be assessed. To study human A3B antiviral function in the absence of a species-specific counter-defense, here we ask whether human A3B is capable of restricting Mus musculus papillomavirus (MmuPV1) in cellulo and in vivo. First, we created human A3B and catalytic mutant A3B-E255A expressing FVB/N mice. Second, MmuPV1 gene expression and replication was quantified in primary keratinocytes from these animals and, surprisingly, enzymatically active human A3B caused no measurable impairment in viral transcript or DNA accumulation. Third, A3B, catalytic mutant A3B-E255A, and nontransgenic FVB/N animals were infected with MmuPV1 and similar pathologies were found regardless of A3B functionality. Thus, despite likely never being exposed to human A3B during evolution, MmuPV1 appears to be unaffected by this potent, primate-specific antiviral factor. These results suggest that MmuPV1 and perhaps papillomaviruses more broadly possess a conserved mechanism to efficiently escape restriction by human A3B and related DNA deaminases. IMPORTANCEHuman papillomaviruses (HPVs) are nearly ubiquitous, and persistent infection with high-risk types causes approximately 5% of cancers worldwide. Although HPV vaccination is effective for preventing infection, insufficient global coverage and a rising incidence of HPV-associated malignancies, such as oropharyngeal carcinoma, highlight the need to understand innate virus clearance mechanisms. APOBEC3 enzymes are a central component of the mammalian innate immune system and are hypothesized to restrict papillomavirus infection, particularly between species. Here, we establish mice that express the human antiviral enzyme APOBEC3B (A3B). Surprisingly, we find that human A3B is incapable of blocking the replication of a murine papillomavirus (Mus musculus papillomavirus 1, MmuPV1) in relevant primary cells from these animals or in infected tissues in vivo. These findings highlight the complexity of teasing apart host-pathogen interactions and suggest that papillomaviruses may have a general mechanism for escaping restriction by antiviral enzymes such as A3B.

microbiology↗

bioRxiv2025

Cross-Molecular Active Learning for the Discovery of Antimicrobial Polyacrylamides

Antimicrobial resistance poses an urgent and increasing threat to global health. The development of new antimicrobials is crucial. Synthetic copolymers are attractive as a potential solution, because they can be produced at scale and designed to mimic antimicrobial peptides and act as broad-spectrum antimicrobials capable of evading resistance mechanisms. This work leverages a cross-molecular machine learning pipeline, trained on antimicrobial peptides, to develop potent antimicrobial polymers to combat Escherichia coli, which were then synthesized and validated experimentally. One candidate copolymer was further characterized and shown to permeabilize the bacterial membrane, which is associated with decreased resistance. Furthermore, this copolymer demonstrated remarkable synergy in eradicating biofilm-associated E. coli when combined with a first-line clinical drug regimen, reducing the amount needed to eradicate bacteria in biofilms by three orders of magnitude. These results demonstrate promise for potentiating antibacterial activity of currently available antibiotics, treating serious and complicated infections, and combatting antimicrobial resistance.

microbiology↗

bioRxiv2025

IGF-1 from bone marrow Adipoq-lineage cells stimulates endocortical bone formation in mature female mice

Insulin-like growth factor 1 (IGF-1) is an anabolic signal promoting growth, differentiation and function of both embryonic and postnatal tissues. Both endocrine and paracrine functions of IGF-1 have been documented to regulate bone growth and bone marrow hematopoiesis. Local production of IGF-1 from various cell types may contribute differently to the overall bioactivity of IGF-1 in bone, but relevant sources and mechanisms are yet to be fully elucidated. Here we report that the Adipoq+ stromal cells are a notable source of IGF-1 in the bone marrow of postnatal mice. Deletion of IGF-1 with Adipoq-Cre diminished endocortical bone formation and cortical bone mass in mature female mice. On the other hand, the trabecular bone parameters or hematopoietic properties were not affected in mutant mice of either sex. The study uncovers a local source of IGF-1 in the bone marrow microenvironment that contributes to bone anabolic regulation in a site-specific manner. Lay SummaryThe insulin-like growth factor 1 (IGF-1) is known to play important roles in promoting bone growth and in regulating blood stem or progenitor cells. The factor is available both through the blood circulation and from the local production by cells in the bone tissue, but the functional contribution of each source is not well understood. Here we discover the non-blood cells in the bone marrow (bone marrow stromal cells) as a notable source of IGF-1 which specifically stimulates bone formation in the bone shaft of the long bone.

developmental biology↗

bioRxiv2025

Integrated Proteomic and Epigenomic Analysis Reveals IGF2 as a Vulnerability in PRC2-Deficient Malignant Peripheral Nerve Sheath Tumors

Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive sarcomas with limited therapeutic options. Loss of the Polycomb repressive complex 2 (PRC2), via inactivating mutations in SUZ12 or EED, occurs frequently in MPNSTs and is associated with poor prognosis. However, the downstream chromatin and signaling consequences of these mutations remain incompletely understood. Here, we show that PRC2 deficiency in MPNST cells induces coordinated chromatin remodeling, characterized by loss of repressive H3K27me3 and gain of activating marks, including H3K27ac and H3K36me2. Integrative epigenomic, transcriptomic, and proteomic profiling revealed that this chromatin reprogramming activates a fetal-like growth signature centered on insulin-like growth factor 2 (IGF2) and its post-transcriptional regulators, Insulin-like Growth Factor 2 mRNA-Binding Protein (IGF2BP1-3). Functional studies demonstrate that PRC2-deficient cells are selectively dependent on IGF2 for proliferation, and that restoration of SUZ12 suppresses IGF2 expression and reduces growth. Analysis of human MPNST tumors confirms upregulation of the IGF2-IGF2BP axis in PRC2-deficient tumors, highlighting its clinical relevance. Together, these findings link PRC2 loss to activation of fetal growth factor-driven oncogenic signaling and identify IGF2 and its regulatory network as potential vulnerabilities in this aggressive tumor subtype.

cancer biology↗

bioRxiv2025

A multi-tissue atlas of genetic regulatory effects in sheep

Characterizing the impact of genomic variants on genome function and ultimately complex traits in livestock is essential for the development of sustainable precision agriculture and comparative genomics. Here, as part of the Farm animal Genotype-Tissue Expression (FarmGTEx) project, we present the pilot phase of the SheepGTEx resource through analyzing 6,761 RNA-sequencing samples of 51 primary tissues in a multi-breed population of sheep. We identify millions of regulatory variants associated with seven types of molecular phenotypes, and fine-map 322,468 primary and 114,017 non-primary effects, revealing a high degree of regulatory allelic heterogeneity. We systematically characterize the pleiotropic effects of these variants on molecular phenotypes, assess their context-specific regulatory patterns across tissues, breeds, sexes, and developmental stages, as well as explore their evolutionary constraints across mammals. Finally, we demonstrate the substantial potential of the SheepGTEx resource (https://sheepgtex.farmgtex.org), by providing examples of regulatory mechanisms underpinning 34 complex traits, population divergence between European and Asian breeds, and adaptive evolution in sheep over the past ten millennia.

genomics↗

bioRxiv2025

Multimerin1, not Galectin-8, Promotes Gastric Chief Cell Differentiation by Tempering WNT Signaling

Galectins are a family of proteins that bind galactose-containing glycans. One member, galectin-8, preferentially binds galactose that contains a terminal sulfate. Aberrant expression and secretion of sulfated glycosylation epitopes, such as 3-Sulfo-LeA/C, is a feature of high-risk human foregut metaplasias. In addition, recent work has demonstrated that 3-Sulfo-LeC is a marker of mature murine zymogenic chief cells of the stomach and that 3-Sulfo-LeC epitope is secreted via cathartocytosis during the cellular transition to a metaplastic state. Based on those findings, we used Lgals8-/-mice, to determine whether galectin-8 might play a role in chief cell homeostasis. We observed delayed gastric differentiation in the Lgals8-/-mice and discovered that this phenotype was due to an unappreciated deletion of Mmrn1 and Snca in the Lgals8-/- line. We show that multimerin-1 tempers WNT stimulation of the gastric corpus at an early age, as evidenced by nuclear beta-catenin staining and proliferation throughout the gland. Because multimerin-1 is synthesized and secreted from endothelial cells and not from the epithelial compartment, these data uncover a role for mesodermal cells in epithelial developmental and maturation of the mouse stomach. As prior studies have suggested galectin-8 and multimerin-1 have overlapping functions albeit, divergent with respect to bone, future studies using pure knockouts are necessary to refine these phenotypes.

developmental biology↗

bioRxiv2025

Bio-synthesis of 15N-Labeled G-Quadruplexes to Investigate the Structure and Interactions in the Cell Lysate using Nuclear Magnetic Resonance

G-quadruplexes (G4) play key roles in biology, making it critical to understand their structure and ligand-binding behavior in cellular environments for advancing G4-targeted therapeutics. While in-cell nuclear magnetic resonance (NMR) is a powerful technique for studying G4 in situ, its application is limited by the challenge of producing isotope-labeled single-stranded DNA (ssDNA). Here, we introduce Restriction Endonuclease Digestion (RED), a simple and cost-effective method to generate 15N-labeled ssDNA. This approach combines molecular cloning and enzymatic design processing by propagating plasmids in E. coli cultured with 15NH4Cl, followed by double restriction digestion and isolation target 15N-ssDNA. Using RED, we produced milligram-scale quantities of 96%-enriched 15N-labeled human telomeric G4 ssDNA (wtTel23c, CTAGGG(TTAGGG)3), ideal for NMR analysis. The NMR spectra revealed that wtTel23c adopts G4 topology and undergoes multiple conformations of wtTel23c in potassium-containing solutions and in Xenopus laevis cell lysate. Interaction studies with the ligand TMPyP4 showed distinct binding profiles in cellular and dilute environments. In dilute solution, TMPyP4 binds to the top tetrad of wtTel23c, while it binds to the loop in cellular environments. The RED method offers an efficient strategy for producing stable isotope-labeled ssDNA, opening new avenues for studying G4 structures and their ligand interactions in complex biological contexts.

biochemistry↗

bioRxiv2025

Structural and functional insights into QueC-family protein in QatABCD anti-phage system

QatABCD is a widespread prokaryotic anti-phage defense system comprising four protein components, out of which QatC, a QueC-family protein is the signature component. QueC family proteins are nucleoside biosynthesis enzymes involved in the biosynthesis of queuosine, a 7-deazaguanine derivative. Recently, QueC-family proteins were shown to catalyze a deazaguanylation protein-nucleobase conjugation reaction in type IV CBASS antiphage defense. However, the mechanism of QatABCD, even the function of QatC in this system, remains unknown. Here, we demonstrate that QatBCD forms a complex in which QatD is highly flexible. Crystal structures of the QatBC complex in apo and ATP-bound form support a shared role for QueC-family proteins in targeting protein substrates for N-terminal modification as in type IV CBASS. We show that the QatB N-terminal loop, its binding with QatC and QatC catalytic site are essential for QatABCD defense in vivo, suggesting a modification might occur analogous to CBASS. These findings provide structural and functional insights into QueC-family protein in QatABCD system, suggesting the conserved mechanisms and critical roles of QueC-family in prokaryotic immunity.

biochemistry↗

bioRxiv2025

A single-component optogenetic toolkit for programmable control of microtubule

Microtubules (MTs) form dynamic cytoskeletal scaffolds essential for intracellular transport, organelle positioning, and spatial organization of signaling. Their architecture and function are continuously remodeled through the concerted actions of microtubule-associated proteins (MAPs), post-translational modifications (PTMs), and molecular motors. To precisely interrogate these processes in living systems, we developed a genetically encoded optogenetic toolkit for spatiotemporal control of MT organization and dynamics. By replacing native multimerization motifs with a blue light-responsive oligoermization domain, we have engineered single-component probes, OptoMT and OptoTIP, that reversibly label MT polymers or track plus-ends with tunable kinetics from seconds to minutes. When coupled to enzymatic effectors, these modules enable localized tubulin acetylation or detyrosination, directly linking PTMs to MT stability. We further engineered OptoMotor, a light-activatable kinesin platform that reconstitutes tail-dependent cargo transport along MTs, and OptoSAW, a light-triggered severing actuator for controlled MT disassembly. Using these tools, we reveal how local MT integrity governs lysosomal trafficking and ER-associated signaling dynamics. Collectively, this versatile single-component toolkit bridges molecular design with cytoskeletal function, offering new avenues to illuminate how dynamic cytoskeletal architectures coordinate intracellular organization, transport, and signaling.

cell biology↗

bioRxiv2025

Discrete cytokine signaling networks instruct distinctsynovial pathotypes in inflammatory arthritis

Patients with rheumatoid arthritis (RA) display distinct patterns of synovitis. To define the inflammatory mechanisms driving this heterogeneity, we analyzed the inflamed synovium of wild-type (WT), Il6ra-/-, and Il27ra-/- mice with antigen-induced arthritis (AIA). Remarkably, each strain developed a joint pathology mirroring a major RA synovial pathotype: myeloid-rich (WT), fibroblast-rich/pauci-immune (Il6ra-/-), and lymphoid-rich (Il27ra-/-) synovitis. Histology confirmed minimal immune infiltration in Il6ra-/- joints, while WT and Il27ra-/- mice exhibited prominent immune involvement, including organized synovial lymphoid-like aggregates in Il27ra-/- mice. Transcriptomic and epigenomic profiling revealed both shared and distinct regulatory programs among genotypes. Il6ra-/- mice showed increased WNT, DKK, and AMPK signaling associated with fibroblast, chondrocyte, and osteoclast activation (e.g., Adamts19, Dkk1, Ecm1). Consistent with synovial ectopic lymphoid-like structures, Il27ra-/- mice showed enrichment of lymphocyte activation (e.g., Il17a, Il22, Bhlhe40). WT mice exhibited hallmarks of MAP kinase activation. These molecular signatures parallel those of fibroblast-, lymphoid-, and myeloid-rich synovitis in RA. Defining a STAT1-STAT3 regulatory interplay influencing transcriptional decisions in WT and Il27ra-/- mice, our findings offer insights into cytokine-driven disease heterogeneity. Together, these results establish a framework for mechanism-based classification of synovitis and introduce new mouse models to study the molecular drivers of synovial pathotypes and treatment response.

pathology↗

bioRxiv2025

Effects of carbon dioxide enrichment and environmental factors on photosynthesis, growth and yield and their interaction in cucumber: a meta-analysis

Despite the ongoing increase in atmospheric carbon dioxide concentrations, these levels remain well below the optimal threshold for cucumber growth and development. In addressing the challenges posed by climate change to agricultural production, the use of carbon dioxide enrichment (eCO2) has become increasingly widespread in order to meet global demand for cucumbers. Nevertheless, the impact of eCO2 and environmental factors on cucumber growth remains to be elucidated. In this study, we conducted a meta-analysis of 73 research papers on eCO2 in cucumbers was conducted, and their photosynthesis, growth, and yield were analysed. In summary, under conditions of elevated CO2 levels, the net photosynthetic rate, biomass, and yield of cucumbers exhibited a marked increase of 56.31%, 27.75%, and 21.98%, respectively. Concurrently, stomatal conductance and transpiration rate exhibited a decline of 36.07% and 30.42%, respectively. In the context of the implementation of eCO2 at varying levels within a production environment, the prevailing recommendation pertains to the range of 800-1200 ppm. It is advised that this be integrated with elevated light intensity, augmented temperature, suitable humidity levels, and a sufficient supply of fertiliser to achieve a synergistic effect. The findings of this study contribute to enhancement of environmental control in the context of greenhouse cultivation of cucumber in response to climate change, as well as promoting the green and sustainable development of the cucumber industry.

plant biology↗

bioRxiv2025

Unbounded Cell Growth and Proteome Imbalance in Doxorubicin-Induced Senescent RPE-1 Cells

Cellular senescence is traditionally viewed as a terminal state of cell-cycle arrest accompanied by widespread molecular remodeling, yet its underlying regulatory logic and progression remain poorly understood. Here, we combined quantitative phase microscopy and normalized Raman imaging with quantitative proteomic and phosphoproteomic profiling to examine human RPE1 cells undergoing doxorubicin-induced senescence. Senescent cells did not reach a steady state but instead exhibited sustained, unbounded growth over a 12 day period, marked by a continuous rise in dry mass and volume coupled with declining mass density. Time resolved proteomics revealed extensive and asynchronous remodeling across organelles, with lysosomal, ER, and Golgi proteins increasing in abundance, whereas nuclear and mitochondrial proteins declined, indicating large scale reorganization of cellular composition. Phosphoproteomic inference linked these structural shifts to regulatory signaling, confirming the expected downregulation of CDK activity while revealing coordinated activation of stress and DNA damage responsive kinases such as CAMK2D, DNAPK, and MARK family members. Together, these integrated data depict senescence as a dynamic, actively regulated state, maintained through coordinated remodeling of proteome composition and signaling activity rather than passive arrest. Our findings highlight how combining quantitative biophysical measurements with multi-layered molecular profiling exposes the regulatory architecture that sustains the senescent phenotype and its loss of internal homeostasis.

cell biology↗

bioRxiv2025

The roles of Transposable Elements and Gene Family Dynamics in Shaping Diversity and Evolution in Diatoms

Diatoms are key players in aquatic ecosystems, having evolved through secondary endosymbiosis. Using long-read sequencing, we investigated how transposable elements (TEs) and gene family dynamics have shaped diatom diversification from inter-lineage to intra-species scales. Across diatom lineages, we identified ecological adaptation-linked expansions, including polyamine synthesis genes for silicification and glutathione S-transferases for oxidative stress resistance. Centric diatoms showed lineage-specific expansion of flotation-associated microtubule genes, while pennate diatoms expanded motility-related actin and myosin genes. At the intra-species level, distinct Phaeodactylum tricornutum strains revealed genomic adaptations correlated with their unique features, including strain-specific expansion and contraction in the cruciform strains morphological genes and the Baltic Sea isolates amine metabolism genes. Our estimates of major lineage divergence times in diatoms ([~]202 Ma and [~]173 Ma) were highly consistent with the two deep WGD events ([~]200 Ma and [~]170 Ma). At these evolutionary nodes, gene families showed extensive lineage-specific expansions and contractions, likely linking ancient polyploidy to subsequent gene content evolution. Substantial TE expansions occurred more recently (0.5-5 Ma), with most diatoms showing recent bursts of Long Terminal Repeat Retrotransposons (LTR-RTs) and araphid pennate diatoms displaying more ancient TE insertion peaks. This likely reflects the progressive loss of ancient TE copies, leaving only recent TE insertions detectable. Our findings provide genomic evidence for the adaptive evolution of diatoms, highlighting the crucial roles of TEs and gene family dynamics in shaping their morphological diversity and environmental adaptations, and suggesting a potential connection between WGDs, gene family dynamics, and TE insertions in genome evolution.

genomics↗

bioRxiv2025

Integrative k-mer and Transcriptomic Analysis Reveals Putative Sex-Determining Genes in Spinacia turkestanica

Deciphering the regulation of sex-determining gene/s in dioecious crops is crucial for molecular breeding. However, the identification of sex-determining gene/s in Spinacia is challenging due to incomplete genome assemblies, high genomic similarity between males and females, and the limitations of transcriptome-only analyses, which may miss unannotated or novel genes in poorly assembled or absent genomic regions. To overcome these limitations, we employed a reference-genome-free k-mer approach to identify candidate sex-determining genes in Spinacia turkestanica, the closest evolutionary relative of cultivated spinach (S. oleracea). Male-specific reads were de novo assembled into contigs, revealing 21.5 Mb of the sex-determining region (SDR). Using the MAKER pipeline, which integrates transcriptomic and proteomic evidence, we predicted 226 protein-coding genes within the SDR, including nine previously unannotated. Transcriptomic profiling combined with weighted gene co-expression network analysis identified eight SDR DEGs, including two newly annotated genes, co-expressing during early male flower development. qPCR validation confirmed three SDR genes as candidate sex-determining factors, including TU_SDR00087 (bZIP domain), TU_SDR000168 (RNA-binding splicing factor domain), and TU_SDR000174 (MYB domain). Together, these findings provide a foundation for functional characterization of sex determination in Spinacia. HighlightA k-mer based analysis uncovered male-specific regions and candidate sex-determining genes in Spinacia turkestanica, advancing understanding of sex regulation and spinach breeding.

genetics↗

bioRxiv2025

Benchmarking Perturbation Tools for the Noncoding Genome

Deciphering the functionality of the noncoding genome which includes important cis-regulatory elements (CREs) and transcribed noncoding RNA genes remains technically challenging. Here, using massively parallel genetic screening, we systematically benchmark the performance of five representative loss-of-function perturbation tools, including single guide RNA (gRNA) mediated SpCas9 cleavage or CRISPR interference, and paired gRNA (pgRNA) involved dual-SpCas9, Big Papi (paired SpCas9 and SaCas9) or dual-enAsCas12a fragment deletion methods, in decoding the roles of the noncoding genome. For targeting CREs such as enhancer, dual-SpCas9 outperforms other methods with superior efficiency of destroying functional genomic regions. For perturbing noncoding RNA genes, in addition to dual-SpCas9, other RNA-targeting methods such as RNA interference are recommended to discriminate transcript-dependent or -independent roles. A deep learning model DeepDC with associated web server is built to facilitate optimal dual-SpCas9 pgRNA design for efficiently deleting a genomic fragment. Together, our work provides practical guidance on selecting appropriate loss-of-function tools to resolve the functional complexity of the noncoding genome.

genetics↗

bioRxiv2025

Co-administration of intranasal parainfluenza virus vaccines expressing antigenically distinct SARS-CoV-2 S antigens elicits broad and durable immunity in hamsters

Intranasal COVID-19 vaccines with the ability to induce broad and durable mucosal and systemic immunity would be useful as stand-alone vaccines or in combination with injectable vaccines. Here, we evaluated in the hamster model the immunogenicity, breadth of immunity, and durability of protection elicited by co-administration of two live-attenuated bovine/human parainfluenza virus type 3 (B/HPIV3) vectors expressing antigenically distinct prefusion stabilized S proteins of the ancestral SARS-CoV-2 isolate (B/HPIV3/S-6P) or the Omicron/BA.5 variant (B/HPIV3/S-BA.5-2P). These vectors are being developed as bivalent pediatric vaccines against HPIV3 and SARS-CoV-2 and are based on bovine PIV3 with the fusion (F) and hemagglutinin-neuraminidase (HN) glycoproteins replaced by those of human PIV3. To broaden the S-specific antibody response, we evaluated co-administration of these B/HPIV3 S-expressing vectors. Each B/HPIV3 S-expressing vector induced robust serum anti-S IgG and IgA antibody levels to the antigen-matched S protein that were sustained for at least five months. Co-administration increased the breadth of the S-specific antibody response, spanning the antigenic breadths of the response elicited by each B/HPIV3 S-expressing vector individually. Animals that had received the mixture of vectors developed neutralizing antibodies to ancestral as well as recently circulating SARS-CoV-2 strains. Hamsters immunized intranasally were protected against Omicron/BA.5 challenge 5 months after immunization, with no weight loss, SARS-CoV-2 challenge virus replication, or increase in host inflammatory cytokines in the upper and lower airways detectable after the challenge, indicating durable protection. Thus, intranasal co-administration of live-attenuated B/HPIV3 expressing antigenically distinct S proteins induced broad and durable antibody responses and long-term protection against Omicron/BA.5 challenge. This approach warrants further development and may better protect against emerging SARS-CoV-2 variants. Author summaryCurrent SARS-CoV-2 vaccines protect against severe disease but are less efficient at blocking infection. Intranasal SARS-CoV-2 vaccines, however, have been shown to induce local immunity that better blocks infection at the nasal portal of entry and have been proposed as booster vaccines to induce better protection against SARS-CoV-2 variants. In the present study, we evaluated in hamsters an intranasal live-attenuated chimeric bovine/human parainfluenza virus type 3 (B/HPIV3) as a bivalent pediatric vaccine against PIV3 and SARS-CoV-2. Co-administration in a single intranasal dose of two B/HPIV3 vectors, one expressing the spike protein S from the antigenically distinct ancestral Wuhan-Hu-1 strain and one expressing S of Omicron/BA.5, induced broad and durable serum anti-S IgG and IgA antibody responses that remained strong for at least five months. Hamsters challenged with the Omicron/BA.5 strain five months after immunization were protected from weight loss, inflammatory responses, and challenge virus replication in the upper and lower airways after challenge. Thus, in the hamster model, intranasal immunization with live-attenuated B/HPIV3 expressing SARS-CoV-2 S can provide durable protection for several months, and combining two antigenically distinct B/HPIV3 S-expressing vectors substantially broadens the antibody response. This mucosal immunization approach may better protect against infection from emerging SARS-CoV-2 variants.

microbiology↗

bioRxiv2025

Inhibition of CGRP receptor ameliorates AD pathology by reprogramming lipid metabolism through HDAC11/LXRβ/ABCA1 signaling

The Calcitonin gene-related peptide (CGRP) receptor has gained attention in Alzheimers Disease (AD) research due to its involvement in regulating neuroinflammation. However, its role and mechanism in AD pathology remain unclear. Here, we demonstrate that CALCRL, a core component of the CGRP receptor, is upregulated in the hippocampus of AD dementia patients and 5xFAD mice. Knockout of the CGRP receptor ligand Calca or pharmacological blockade using Rimegepant (Rim), reduces soluble A{beta}1-42 oligomer-induced neuronal death and glial inflammation. Rim treatment also rescues neurobehavioral impairments, neurodegeneration, and lipid metabolism dysfunction in 5xFAD mice. Mechanistically, these effects are mediated through HDAC11 inhibition, which enhances LXR{beta} acetylation and ABCA1 expression, promoting the reprogramming of neuronal lipid metabolism. Importantly, this CALCRL/HDAC11/LXR{beta}/ABCA1 axis is conserved across both humans and mice. Our findings uncover a novel mechanism underlying AD pathogenesis and highlight the therapeutic potential of targeting CGRP signaling in AD. HIGHLIGHTSInhibition of CGRP receptor ameliorates disease pathology in models of AD HDAC11 mediates CGRP receptor function in AD HDAC11 is a pivotal regulator in lipid metabolism by LXR{beta}/ABCA1 signaling The HDAC11/LXR{beta}/ABCA1 axis is conserved in AD humans and mice

neuroscience↗