Biology subjects

Shi, Y.

Publications and source records attributed to Shi, Y..

At least 145 records · Page 8Linked to original sources

bioRxiv2025

Allosteric Modulation of MIF-2 Structure, Catalysis, and Biological Signaling via Cysteine Residues and a Small Molecule, Ebselen

The macrophage migration inhibitory factor (MIF) family of cytokines comprised of the MIF and D-dopachrome tautomerase (or MIF-2) paralogs share identical tertiary and quaternary structures that contribute to their overlapping enzymatic and signaling activities. Recent investigations of MIF and MIF-2 have shown them to possess N-to-C-terminal allosteric crosstalk, but despite the similarity of this "allosteric pathway," its regulation of MIF and MIF-2 is not identical. Thus, structure alone does not preserve the precise allosteric mechanism and additional residues that modulate MIF and MIF-2 allosteric function must be characterized. Cysteines have been identified as allosteric switches for the same biochemical functions of MIF and small molecules targeting its N-terminal enzymatic site have affected the structure of three proximal cysteines. Ebselen is a compound that forms covalent selenylsulfide bonds with MIF cysteines and is hypothesized to destabilize and dissociate the MIF trimer into monomers. Ebselen-bound MIF also displays little-to-no catalysis or biological signaling. However, it is unclear whether Ebselen similarly affects the MIF-2 paralog, despite MIF-2 containing two related cysteines (MIF contains three). We used mutagenesis, nuclear magnetic resonance (NMR), molecular dynamics (MD) simulations, in vitro and in vivo biochemistry to investigate the mechanism of Ebselen as an allosteric modulator of MIF-2 via its cysteines. Our findings suggest that Ebselen partially disrupts the MIF-2 homotrimer, though the overall population of such a structure is <35%, even on the timescale of many hours. Ebselen does attenuate the biological functions of MIF-2 and solution structural biology captures the conformational transitions preceding the destabilized MIF-2 trimer. Significance StatementThe nearly identical MIF and MIF-2 structures have been recently shown to contain an N-to-C-terminal crosstalk between non-overlapping functional sites in vitro and in vivo. Small molecule inhibitors designed as therapeutics for the MIF superfamily have primarily targeted the N-terminal active site, while very few allosteric molecules have been reported. Ebselen, however, destabilizes MIF by covalently modifying its distal Cys80 residue and disrupting its obligate trimeric assembly. This unique mechanism has never been evaluated in the MIF-2 paralog, and this study reports the structural, dynamic, and functional impact of Ebselen on MIF-2. We define the essential structural hallmarks preceding trimer dissociation and reveal that Ebselen inhibits MIF-2 function before trimer disruption, leading to destabilized monomer-monomer interfaces that slowly degrade the quaternary assembly.

biophysics↗

bioRxiv2025

Bridging 3D Molecular Structures and Artificial Intelligence by a Conformation Description Language

Artificial intelligence, particularly language models (LMs), is reshaping research paradigms across scientific domains. In the fields of chemistry and pharmacy, chemical language models (CLMs) have achieved remarkable success in two-dimensional (2D) molecular modeling tasks by leveraging one-dimensional (1D) representations of molecules, such as SMILES and SELFIES. However, extending these successes to three-dimensional (3D) molecular modeling remains a significant challenge, largely due to the absence of effective 1D representations for capturing 3D molecular structures. To address this gap, we introduce ConfSeq, a novel molecular conformation description language that integrates SMILES with internal coordinates including dihedral angles, bond angles, and pseudo-chirality. This design naturally ensures SE(3) invariance, while preserving the human readability and conciseness characteristic of SMILES. ConfSeq enables the reformulation of a range of 3D molecular modeling tasks, such as molecular conformation prediction, 3D molecular generation, and 3D molecular representation, into sequence modeling problems. Then, by simply employing a standard Transformer architecture, we achieve state-of-the-art performance on various benchmark sets. Furthermore, compared to widely used diffusion-based approaches in 3D molecular modeling, the ConfSeq-based method offers unique advantages in inference efficiency, generation controllability, and enables scoring of generated molecules. We believe that ConfSeq can serve as a foundational tool, advancing the development of sequence-based 3D molecular modeling methods.

bioinformatics↗

bioRxiv2025

Cover crop root channels promote bacterial adaptation to drought in the maize rhizosphere

BackgroundIncreasing drought frequency poses a significant threat to agricultural productivity. A promising strategy to enhance crop resilience against drought is the utilisation of root channels left by winter cover crops, which can improve access to subsoil water and nutrients for subsequent cash crops like maize (Zea mays L.). The impact of drought on bacterial communities inhabiting these root channels remains largely unknown. Here, we investigated drought-induced shifts in maize rhizosphere bacterial communities and their functional adaptation in cover crop root channels across three soil types in northern Germany (Luvisol, Podzol, and Phaeozem). ResultsUsing a multi-omics approach (16S rRNA gene amplicon sequencing, qPCR, and metaproteomics), we identified significant taxonomic and functional responses to drought. A rise in the abundance of K-strategist bacterial communities indicate a shift towards stress-tolerant populations with drought. Under drought stress, the relative abundances of Acidobacteriota, Actinomycetota, Planctomycetota, and Pseudomonadota increased, while Chloroflexota, Methylomirabilota, Ca. Patescibacteria, and Verrucomicrobiota declined. Functional analyses revealed that drought-stressed aerobic taxa among the Pseudomonadota and Verrucomicrobiota upregulated the glyoxylate cycle, potentially enhancing carbon and energy conservation, and increased antioxidant defences (catalase-glutathione peroxidase and methionine cycle-transsulfuration pathway). These drought-mitigating strategies were especially pronounced in root channels formed by Brassicaceae and Poaceae cover crops in the Luvisol and Podzol soils. ConclusionsThese findings demonstrate the functional plasticity of rhizosphere bacterial communities in reused root channels in response to drought, highlighting the potential to leverage microbiome-mediated resilience for agricultural practices. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=100 SRC="FIGDIR/small/651044v1_ufig1.gif" ALT="Figure 1"> View larger version (33K): org.highwire.dtl.DTLVardef@7c3f69org.highwire.dtl.DTLVardef@127182forg.highwire.dtl.DTLVardef@1a4bb61org.highwire.dtl.DTLVardef@9f7c4_HPS_FORMAT_FIGEXP M_FIG C_FIG

microbiology↗

bioRxiv2025

The China Brain Multi-omics Atlas Project (CBMAP)

The China Brain Multi-omics Atlas Project (CBMAP) aims to generate a comprehensive molecular reference map of over 1,000 human brains (Phase I), spanning a broad age range and multiple regions in China, to address the underrepresentation of East Asian populations in brain research. By integrating genome, epigenome, transcriptome, proteome (including multiple post-translational modifications), and metabolome data, CBMAP is set to provide a rich and invaluable resource for investigating the molecular underpinnings of aging-related brain phenotypes and neuropsychiatric disorders. Leveraging high-throughput omics data and advanced technologies, such as spatial transcriptomics, proteomics, and single-nucleus 3D chromatin structure analysis, this atlas will serve as a crucial resource for the brain science community, illuminating disease mechanisms and enhancing the utility of data from genome-wide association studies (GWAS). CBMAP is also poised to accelerate drug discovery and precision medicine for brain disorders.

neuroscience↗

bioRxiv2025

Key genes and pathways in asparagine metabolism in Alzheimers Disease: a bioinformatics approach

BackgroundAsparagine (Asn) metabolism is essential for maintaining cellular homeostasis and supporting neuronal energy demands. Recent studies have suggested its dysregulation may contribute to Alzheimers disease (AD) pathogenesis; however, the specific genes and regulatory mechanisms involved remain incompletely understood. MethodsFour publicly available microarray datasets (GSE5281, GSE29378, GSE36980, and GSE138260) were utilized to investigate genes with differential expression between control and AD samples. Asparagine metabolism-related genes (AMGs) were retrieved from the GeneCards database, and their intersection with DEGs yielded candidate asparagine metabolism-related differentially expressed genes (AMG-DEGs). Functional enrichment analysis (Gene Set Enrichment Analysis, Gene Ontology and Kyoto Encyclopedia of Genes and Genomes), protein-protein interaction (PPI) network analysis, and centrality scoring identified hub genes. Regulatory mechanisms were investigated through construction of competing endogenous RNA and transcription factor networks. Potential therapeutic compounds were predicted via drug-gene enrichment and evaluated using molecular docking simulations. ResultsThirty-nine AMG-DEGs were identified and found to be enriched in neurodevelopmental, synaptic transmission, and inflammatory signaling pathways. PPI analysis and centrality screening revealed seven hub genes (HPRT1, GAD2, TUBB3, GFAP, CD44, CCL2, and NFKBIA). Regulatory network analysis highlighted specific miRNAs, long non-coding RNAs, and transcription factors involved in their modulation. Drug screening and docking identified Bathocuproine disulfonate, DL-Mevalonic acid, and Phenethyl isothiocyanate as promising compounds with strong binding affinities to hub proteins. ConclusionThis study comprehensively maps the dysregulation of asparagine metabolism in Alzheimers disease and reveals a set of hub genes and regulatory elements potentially involved in disease progression. The predicted therapeutic compounds provide a foundation for further experimental validation and may contribute to the development of novel metabolism-targeted strategies for AD treatment.

neuroscience↗

bioRxiv2025

A role of villin-dependent F-actin organization in peroxisome motility in Arabidopsis cells

Actin microfilaments (F-actin) serve as the track for directional movement of organelles in plants. To understand how the F-actin network is employed for the movement of peroxisomes, essential organelles in plant metabolism, we analyzed mutants of three villin (VLN) genes, which encode the primary actin-bundling factor and are most actively expressed in vegetative tissues in Arabidopsis thaliana. We found that the vln4 mutation greatly exacerbated the growth and subcellular defects in vln2 vln3. Compared to the wild-type cells, the double and triple vln mutants exhibit progressive reduction of stable F-actin bundles and rapid remodeling of the fine filaments. The defective F-actin network did not prevent peroxisomes from taking on both rapid and slow movements along the tracks but caused significantly reduced speed of movement and displacement distance of peroxisomes. Using a correlation analysis method, we classified the complex heterogeneous peroxisome movement patterns into clusters reflecting distinct movement directionalities. The vln triple mutant had significantly reduced number of peroxisomes with long-range and linear movement. Our results provide insights into how VLN-dependent F-actin organization is coupled with the complex pattern of peroxisome movement.

plant biology↗

bioRxiv2025

It matters who you are: Biography modulates the neural dynamics of facial identity representation

Recognizing the face of a person is an essential capacity to our social life. However, to interact properly with others we also need to know to which person a face belongs. Here we tested how person knowledge modulates face processing. Participants were familiarized with highly variable faces, associated with artificial biographies. Crucially, participants were allocated randomly into two groups, trained on the identical faces of the same persons, but with reversed person knowledge associated with the faces. Multivariate pattern analyses were used to examine the time course of identity representations in the EEG data. We estimated cross-participant, leave-one-participant-out pairwise identity classifications within the same face-person association groups and compared them to the those performed across association groups. We observed that face-person knowledge associations led to a robust familiarity signal from 300 ms and to a rapidly emerging identity representation, starting from 80 ms. Importantly, the shared associations within participant groups led to a longer-lasting and stronger face identity representation over the right posterior electrode cluster when compared to cross-group comparisons with reversed associations. The direct comparison of within and cross-group classifications showed that an early stage of identity representation, between 250 and 370 ms, is significantly modulated by face-biography associations. Our findings suggest that top-down, person recognition memory related information modulates visual face identity representation already at an early processing stage. Our study provides new insights into the spatiotemporal dynamics of how person-related conceptual, biographical knowledge modulates familiar identity representation.

neuroscience↗

bioRxiv2025

Modular Engineering of Escherichia coli for Enhanced Nickel Uptake, Survival, Biomineralization, and Hydrogen-Supported Bioremediation

Nickel contamination poses increasing environmental and industrial challenges, demanding effective and sustainable remediation strategies. Here, we present a modular synthetic biology approach to engineer Escherichia coli for efficient nickel enrichment, resilience in toxic environments, intracellular biomineralization, and hydrogen-based co-culture stability. Our system comprises four functional modules: (1) a nickel enrichment module, in which the fusion protein NixA-F1v outperformed existing uptake systems, and a mutant repressor RcnRC35L enhanced retention by suppressing nickel efflux; (2) a survival module where heterologous expression of Helicobacter pylori Hpn conferred tolerance to high nickel concentrations, and YejM increased phage resistance; (3) a nickel microparticle module enabling intracellular bioconversion of nickel into detectable microparticles even without engineered uptake proteins; and (4) a hydrogen supply module supporting co-culture stability through E. coli-cyanobacteria adhesion for sustained hydrogen production. These modules were experimentally validated through comparative uptake assays, survival profiling, and microscopy-based particle detection. Our findings demonstrate a customizable and integrative microbial platform for metal bioremediation and biosensing, with potential applications in environmental engineering and industrial waste treatment.

synthetic biology↗

bioRxiv2025

Chemically Synthesized Ultra-long DNA as Building Blocks to Accelerate Complex Gene Construction in Synthetic Biology

Certain applications of synthetic biology rely on the construction of large and complex DNA sequences. Current DNA synthesis technologies are limited in their capacity to generate ultra-long oligonucleotide for complex gene construction with extensive repetitive motifs and uneven base distribution efficiently. Here, we report a novel platform named UCOS (short for Ultralong Complex Oligonucleotides Synthesis) that enables the efficient synthesis of long, complex, and challenging DNA fragments. This platform employs nonporous silica microspheres as the solid support instead of traditional CPG (Controlled Pore Glass) solid support, full-length enrichment based on 5 flank sequence hybridization and an error-removing enzyme for correct sequence selection, substantially enhancing the fidelity of intricate, ultralong oligonucleotides. Using this approach, we successfully synthesized challenging sequences up to 600nt in length, encompassing tandem repeats and uneven base distributions. Overall, this novel platform demonstrates exceptional efficiency and reliability in handling ultralong DNA fragments with highly repetitive and complex features. It provides a strong foundation for advancing synthetic biology and shows great potential as a powerful tool for constructing challenging genes and enabling the customized synthesis of functional genetic elements.

synthetic biology↗

bioRxiv2025

Wnt/Beta-Catenin Signaling Is Active in Neuroendocrine Prostate Cancer

Wnt/beta-Catenin signaling plays a critical role in prostate cancer (PCa) progression, yet its precise contributions in neuroendocrine prostate cancer (NEPCa) remain incompletely understood. In this study, we utilized TRAMP/Wnt-reporter mice to monitor Wnt/beta-Catenin activity and investigated transcriptional alterations associated with NEPCa development. RNA sequencing and pathway enrichment analyses identified neuroactive ligand-receptor interaction, MAPK, calcium, and cAMP signaling as key pathways enriched in NEPCa. Although Wnt signaling was not among the top-enriched pathways, elevated Axin2 expression and increased Wnt-reporter activity suggest its involvement in NEPCa progression. We observed upregulated expression of Wnt3, Wnt6, Dvl2, Dvl3, and Lef1 in NEPCa, coupled with reduced expression of Yap1 and Frat1, which are involved in beta-Catenin degradation. Pharmacological inhibition of Wnt/beta-Catenin signaling using FC101 significantly suppressed PCa growth, underscoring its potential as a therapeutic target. These findings reveal that Wnt/beta-Catenin signaling is active in NEPCa through multiple mechanisms and highlight the need for further investigation into the regulatory interplay between Wnt and YAP1 in prostate cancer.

cancer biology↗

bioRxiv2025

METTL1/WDR4-mediated m7G Hypermethylation of SCLT1 mRNA Promotes Gefitinib Resistance in Non-small Cell Lung Cancer

Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) have produced durable complete responses, but the eventual development of acquired resistance presents a huge challenge in the treatment of non-small cell lung cancer (NSCLC). N7-methylguanosine (m7G), a prevalent post-transcriptional modification within RNA, play regulatory roles in RNA stability, expression dynamics, and functional diversity. Despite these insights, the contribution of m7G methylation to EGFR-TKIs resistance remains poorly characterized. Here, we identified substantial upregulation of mRNA internal m7G modifications and their associated methyltransferase complex composed of methyltransferase-like 1 (METTL1) /WD repeat domain 4 (WDR4) were significantly elevated in NSCLC specimens, correlating with therapeutic resistance. Functional assays confirmed that METTL1/WDR4 enhances gefitinib resistance in both cellular and animal models via the internal RNA m7G methyltransferase activity in NSCLC. Mechanistically, m7G MeRIP-seq coupled with RNA-seq identified sodium channel and clathrin linker 1 (SCLT1) as the m7G target of METTL1/WDR4. METTL1/WDR4 knockdown may result in a decrease in both the demethylation level and mRNA stability of the SCLT1 transcript, while overexpression of wild-type METTL1, but not its catalytically inactive mutant, rescues mRNA stability. METTL1/WDR4-mediated m7G modification of SCLT1 regulates gefitinib resistance by activating the NF-{kappa}B signaling. These results establish aberrant mRNA internal m7G modification as a novel resistance mechanism and propose therapeutic targeting of the METTL1/WDR4-SCLT1-NF-{kappa}B axis cascade to overcome EGFR-TKIs resistance.

molecular biology↗

bioRxiv2025

Interaction with tumor cell spheroids induces suppression in primary human cytotoxic T cells

Cytotoxic T lymphocytes (CTL) are key effectors in the anti-tumor immune response. However, their function is commonly suppressed in tumors in the form of exhausted CTL. Understanding molecular mechanisms of suppression and of therapeutics to overcome them is of substantial basic and translational importance yet hindered by limited access to large numbers of exhausted CTL in vitro. Here we use three-dimensional tissue culture to generate primary human CTL with suppressed function. Using a 21-antibody flow cytometry panel and determination of calcium signaling and cell couple maintenance, we show that these cells closely resemble exhausted CTL from tumors. For better understanding of in vitro human primary CTL as key tools in therapeutic development, before and after induction of suppression, we have determined the dependence of CTL function on technicalities of in vitro CTL generation, antigen dose and affinity across two T cell receptors and multiple tumor cell lines. We have investigated morphology and subcellular F-actin distributions of CTL as a key regulators of effector function. Primary human CTL formed cell couples with tumor target cells even in the absence of antigen. Yet, gradual stabilization of such cell couples was associated with increasing CTL effector function. Induction of suppression substantially destabilized CTL tumor cell couples. This comprehensive characterization of the phenotype of in vitro primary human CTL, including a suppressed state, should facilitate their wider use in basic and translational research.

immunology↗

bioRxiv2025

Methylome and transcriptome analysis reveals the impact of psychological stress on the skin

Psychological stress has been shown to impact skin and DNA methylome, but the mechanisms are poorly understood. Here, we collected multi-omics data from 60 stressed and 60 relaxed individuals to test the hypothesis that psychological stress may impact skin via epigenetic modification and downstream altered gene expression. Each volunteer completed a series of questionnaires and assessments to measure their psychological stress levels and skin condition. Suction blister samples were collected for analyze skin cytokines, DNA methylome, and transcriptome. The dataset generated allowed for the identification of 289 differentially methylated probes(DMPs) and 10 differentially expressed genes (DEGs). Integration of methylation and expression data revealed seven functional epigenetic modules(P<0.05), which were involved in the glutamatergic synapse. In line with previous studies on the prefrontal cortex/hippocampus, we found that psychological stress also affects the glutamatergic synapse in the skin. There was no significant group difference in cytokines, while the stressed group had more severe skin darkening (P=7.36x10-6). This study provides important insight into the impact of psychological stress on the skin and contributes a comprehensive multi-omics dataset resource for the healthy epidermis.

genetics↗

bioRxiv2025

MCMC-CE: A Novel and Efficient Algorithm for Estimating Small Right-Tail Probabilities of Quadratic Forms with Applications in Genomics

Quadratic forms of multivariate normal variables play a critical role in statistical applications, particularly in genomics and bioinformatics. However, accurately computing small right-tail probabilities (p-values) for large-scale quadratic forms is computationally challenging due to the intractability of their probability distributions, as well as significant numerical constraints and computational burdens. To address these problems, we propose MCMC-CE, an innovative algorithm that integrates Markov Chain Monte Carlo (MCMC) sampling with the cross-entropy (CE) method, coupled with leading-eigenvalue extraction and Satterthwaite-type approximation techniques. Our approach efficiently estimates small p-values for quadratic forms with their ranks exceeding 10,000. Through extensive simulation studies and real-world applications in genomics, including genome-wide association studies and pathway enrichment analyses, our method demonstrates advantageous numerical accuracy and computational reliability compared to existing approaches such as Davies, Imhofs, Farebrothers, Liu-Tang-Zhangs and saddlepoint approximation methods. MCMC-CE provides a robust and scalable solution for accurately computing small p-values for quadratic forms, facilitating more precise statistical inference in large-scale genomic studies.

bioinformatics↗

bioRxiv2025

A protective bispecific antibody targets both Nipah virus surface glycoproteins and limits viral escape

Nipah virus (NiV) and Hendra virus (HeV) are highly pathogenic henipaviruses without approved human vaccines or therapies. Here, we report on a highly potent bispecific therapeutic that combines an anti-fusion (F) nanobody with an anti-receptor binding protein (RBP) antibody to deliver a dual-targeting biologic that is resistant to viral escape. We show that the nanobody, DS90, engages a unique, conserved site within prefusion F of NiV and HeV, and provides neutralization and complete protection from NiV disease. Bispecific engineering of DS90 with the anti-RBP mAb m102.4 results in neutralization, elimination of viral escape and superior protection from NiV disease compared to leading monovalent approaches. These findings carry implications for the development of cross-neutralizing immunotherapies that limit the emergence of henipaviral escape mutants.

microbiology↗

bioRxiv2025

Inhibiting B-cell-mediated Immunosuppression to Enhance the Immunotherapy Efficacy in Hepatocellular Carcinoma

BackgroundImmunotherapy is efficacious in hepatocellular carcinoma (HCC), but the benefits are limited to a minority of patients. Most HCC patients show resistance to immune checkpoint blockade (ICB). Agonists of the stimulator of interferon genes (STING), potent immune stimulators, showed limited effectiveness. Using preclinical models, we studied the mechanisms of resistance to ICB and STING agonism. MethodsMurine HCA-1 and RIL-175 HCCs were orthotopically grown in mice with underlying liver fibrosis, to mimic the presentation of human HCC. Established tumors were treated with a STING agonist (BMS-986301) or anti-PD1 ICB, and mice were followed to evaluate safety and efficacy, as well as the mechanisms of treatment resistance by RNA sequencing, flow cytometry, and immunofluorescence, B-cell depletion and T-cell immunoglobulin and mucin domain 1 (TIM-1) ICB. ResultsUnbiased analyses of transcriptomic data from murine HCC tissues from ICB-treated mice showed an increased abundance of intratumoral CD8+ T cells and B cells. STING agonism alone showed efficacy in the ICB-responsive RIL-175 HCC model but more limited efficacy in the ICB-resistant HCA-1 model. STING agonism increased circulating IL-10 and intratumoral infiltration by B-cells, including TIM-1+ B cells, and promoted the formation of tertiary lymphoid structure (TLS)-like structures, especially in the peritumoral areas. Strikingly, adding B cell depletion to ICB or STING agonism treatment significantly increased survival. Interestingly, unlike ICB, STING agonism also had a pronounced anti-metastatic activity. In addition, the combination of STING agonism and TIM-1 blockade augmented B cell differentiation and antigen presentation in vitro and improved the anti-tumor effects in murine HCC in vivo. This approach decreased the number of TIM-1+ B cells in the tumor and shifted B cells to higher expression of CD86 and MHC class II, enhancing the antigen presentation capability and further boosting the antitumor efficacy of CD8+ cytotoxic T cells. ConclusionOur findings demonstrate that B cells are associated with ICB- and STING-mediated therapy resistance, and that depleting B-cells or targeting TIM-1 enhances both innate and acquired therapeutic efficacy in HCC.

cancer biology↗

bioRxiv2025

Understanding monocyte-driven neuroinflammation in Alzheimers disease using human brain organoid microphysiological systems

Increasing evidence suggests that Alzheimers disease (AD) pathogenesis strongly correlates with neuroinflammation. Peripheral monocytes are crucial components of the human immune system that may play a role in neuroinflammation, but their contribution to AD pathogenesis is largely understudied partially due to the lack of appropriate human models. Here, we present human cortical organoid microphysiological systems (hCO-MPSs) for modeling dynamic AD neuroinflammation mediated by monocytes. By incorporating 3D printed devices into an existing cortical organoid protocol, 96 hCO-MPSs can be established with significantly reduced necrosis and hypoxia as well as enhanced viability within a commonly used 96 well plate, and each hCO-MPS consists of a doughnut-shaped hCO and a 3D printed device per well. Using this approach, monocytes from AD patients exhibit higher infiltration, decreased amyloid-beta (A{beta}) clearance, and stronger inflammatory responses compared to monocytes from age-matched control donors. Moreover, pro-inflammatory effects such as elevated astrocyte activation and neuronal apoptosis were observed to be induced by AD monocytes. Furthermore, the significant increase in the expression of IL1B and CCL3, both at the transcriptional and protein levels, indicated the pivotal role of these cytokine and chemokine in monocyte-mediated AD neuroinflammation. Our findings provide insight for understanding monocytes role in AD pathogenesis, and the user-friendly MPS models we present are compatible with existing laboratory settings, highlighting their potential for modeling neuroinflammation and developing new therapeutics for various neuroinflammatory diseases.

bioengineering↗

bioRxiv2025

Chemical inhibition of a bacterial immune system

The rise of antibiotic resistance motivates a revived interest in phage therapy. However, bacteria possess dozens of anti-bacteriophage immune systems that confer resistance to therapeutic phages. Chemical inhibitors of these anti-phage immune systems could be employed as adjuvants to overcome resistance in phage-based therapies. Here, we report that anti-phage systems can be selectively inhibited by small molecules, thereby sensitizing phage-resistant bacteria to phages. We discovered a class of chemical inhibitors that inhibit the type II Thoeris anti-phage immune system. These inhibitors block the biosynthesis of a histidine-ADPR intracellular alarm signal by ThsB and prevent ThsA from arresting phage replication. These inhibitors promiscuously inhibit type II Thoeris systems from diverse bacteria--including antibiotic-resistant pathogens. Chemical inhibition of the Thoeris defense improved the efficacy of a model phage therapy against a phage-resistant strain of P. aeruginosa in a mouse infection, suggesting a therapeutic potential. Furthermore, these inhibitors may be employed as chemical tools to dissect the importance of the Thoeris system for phage defense in natural microbial communities.

biochemistry↗