Biology subjects

Liu, Y.

Publications and source records attributed to Liu, Y..

At least 1,099 records · Page 61Linked to original sources

bioRxiv2024

Fornix and Uncinate Fasciculus Support Metacognition-Driven Cognitive Offloading

People often use external tools to offload cognitive demands associated with remembering future intentions. While previous research has established a causal role of metacognition in cognitive offloading, the neural mechanisms supporting this metacognitive control process remain unclear. To address this, we conducted a study with 34 participants using diffusion tensor imaging (DTI) to examine how white matter connectivity supports metacognition-driven cognitive offloading. Behaviorally, we replicated prior findings showing that under-confidence in internal memory predicts a bias toward using external reminders. At the neural level, we used diffusion tensor imaging to quantify fractional anisotropy (FA), a measure of microstructural integrity in white matter. We found the microstructural integrity of the superior longitudinal fasciculus (SLF) and cingulum bundle (CB) negatively predicted deviations from the optimal use of reminders. The microstructural integrity of the fornix negatively predicted participants confidence in performing the task when restricted to internal memory. Our findings reveal the microstructural organization of these fronto-temporal-parietal white-matter tracts are related to metacognition driven cognitive offloading. We discuss several aspects of metacognition driven cognitive offloading from a white matter microstructural perspective.

neuroscience↗

bioRxiv2024

Universal features of Alternative splicing in response to diverse environmental stimuli in rice and the vital roles of TFs in AS regulation

BackgroundPre-mRNA alternative splicing (AS) plays essential roles in response to environmental stimuli in plants. However, the universal and specific features of splicing in response to diverse environmental conditions remain not fully understood. Recent studies have shown the co-transcriptional characteristics of splicing, which lead to the reasonable speculation that the elements or factors regulating transcription can also affect splicing. Among of which, the effects of transcription factors on alternative splicing in plants under environmental stimuli are still confusing. A large amount 0f public available RNA sequencing data are valuable resources to be re-analyzed for answering questions beyond the aims of their original studies. ResultsWe explored the universal features of AS using a standard RNA-seq dataset TENOR, which stems from rice samples under controlled diverse conditions to provide comprehensive and comparable AS analysis under various conditions. We found that AS widely occurs in rice under stimuli, with significant tissue specificity, temporal dynamics, commonality among different stresses or treatments as well as significant difference between differential alternative splicing and expressed genes (DASGs and DEGs) in rice under environmental stimuli. The majority of DASGs under various stresses are splicing factors and transcription factors. The correlation analysis shows that the expression level of transcription factors is significantly correlated with the PSI of AS events. The predominant transcription factors correlating with alternative splicing events come from bHLH, bzip and hsfa families. We validated the effects of transcription factors on AS by analyzing RNA-seq data from transcription factor mutants and found substantial differential AS events between mutants and wild type. Furthermore, the significant correlation was discovered between the transcription levels of transcription factors and splicing factors. ConclusionWe found universal features of AS and the predominant AS events of SFs and TFs in plants under diverse environments. We propose that TFs might regulated AS of download genes partly by changing the patterns of their own transcription and splicing to further regulate the transcription of SFs. This work illuminate the studies on the possible mechanisms by which TFs modulate AS in plant, especially under environmental stimuli.

plant biology↗

bioRxiv2024

PI(4)P recruits CIDE proteins to promote the formation of unilocular lipids droplets

Lipid droplets (LDs) are evolutionarily conserved organelles that play important roles in metabolism. Each LD is enclosed by a monolayer of phospholipids, distinct from bilayer membranes. The composition of LD surface phospholipids and their impact on LD growth and function remain to be clearly defined. Phosphoinositides mark cellular organelles and regulate cell signalling and organellar function. Here, we demonstrate that PI(4)P decorates a subset of LDs to recruit and activate the CIDE proteins. Enhanced expression of ORP2 and ORP5, LD-associated lipid transfer proteins that remove PI(4)P from LDs, abolished the localization and function of CIDE proteins. Blocking the synthesis of PI(4)P on LD surface via knocking down PI4K2A also impaired the localization and function of CIDE proteins. In adipocytes, depleting PI(4)P dramatically reduced the size of LDs, as well as adipose tissue mass. In severe steatotic liver, depleting PI(4)P reduced LD accumulation. Our results thus identify a key function of LD surface PI(4)P under physiological conditions and unveil how CIDE proteins are recruited to LDs.

cell biology↗

bioRxiv2024

The complete mitochondrial genome of Heikeopsis japonica (Decapoda: Brachyura: Dorippidae): Phylogenetic implications of the family Dorippidae

Characterizing complete mitochondrial genome (mitogenome) supports comprehensive understanding in gene arrangement, molecular evolution and phylogenetic status. Previously, no studies have been conducted on the complete mitogenomes of the Dorippidae family within infraorder Brachyura. Herein, we firstly determined the sequence of Heikeopsis japonica (Decapoda: Brachyura: Dorippidae) mitogenome by high-throughput sequencing. Its mitogenome sequence is 15,980 bp in size, with 13 protein-coding genes, two ribosomal RNA genes, and 22 transfer RNA genes. The genome has a high A + T content of 73.52%, and low G + C content of 26.48%. The AT-skew is negative, -0.0079; and the GC-skew is positive, 0.322. The phylogenetic analysis of H. japonica using 40 Brachyuran mitogenome datasets indicated that Pyrhila pisum of family Leucosiidae had the closet relationship with H. japonica. Further selection pressure analysis of H. japonica suggested the presence of strong positive purification selection in Brachyuran. Meanwhile, a total of 31 residues located in genes atp6, atp8, cox1-3, cob, nad1-5, and nad4L were detected as the positively selected sites. This study reports the first available complete mitogenome of family Dorippidae, and our results could offer a useful phylogenetic implication of Dorippidae in the infraorder Brachyura.

genomics↗

bioRxiv2024

An in vivo screen identifies NAT10 as a master regulator of brain metastasis

Metastasis is the major cause of cancer-related deaths. Emerging evidence has shown that epigenetic regulation plays a fundamental role in cancer metastasis. To better understand the epigenetic regulation of metastasis, we conducted an in vivo shRNA screen for vulnerabilities of brain metastasis and identified N-acetyltransferase 10 (NAT10) as a driver of brain metastasis. Knockdown of NAT10 significantly restrains cancer cell proliferation and migration in vitro, and tumor growth and brain metastasis in vivo. Structure-function analysis of NAT10 showed that its poorly characterized RNA helicase domain is critical for breast cancer cell growth in vitro, while its N-acetyltransferase domain is essential for primary tumor growth and brain metastasis in vivo. Integrative transcriptomic and proteomic analyses revealed key downstream effectors of NAT10, including PHGDH and PSAT1, two catalyzing enzymes for serine biosynthesis implicated in brain metastasis, and HSPA5, known to promote metastasis. We found that distant metastases of breast cancer, especially brain metastases express higher levels of NAT10, PHGDH, PSAT1, and HSPA5. Silencing PHGDH/PSAT1 or HSPA5 in metastatic breast cancer cells inhibits their ability to grow in the serine/glycine-limited condition or migrate, respectively, phenocopying the effects of NAT10 depletion. Moreover, NAT10 promotes the expression of PHGDH, PSAT1, and HSPA5 in its RNA helicase-dependent manner. These findings establish NAT10 as a master regulator of brain metastasis and shed light on the biological functions of its RNA helicase domain, nominating NAT10 as a target for treating metastatic diseases.

cancer biology↗

bioRxiv2024

An Enzyme-Linked Immunosorbent Assay (ELISA)-based Activity Assay for AMP-Activated Protein Kinase (AMPK)

AMP-activated protein kinase (AMPK) is the master regulator of cellular and organismal energy homeostasis, playing an essential role in modulating metabolism as well as other cellular processes. Efforts have been made to discover pharmacological modulators of AMPK activity because of their therapeutic potentials against various diseases. Measuring AMPK activity in vitro is a fundamental step for testing AMPK activators and inhibitors. Here we report an enzyme-linked immunosorbent assay (ELISA)-based AMPK activity assay with simple steps and high sensitivity, which represents an alternative in-house method to the traditional radioactive method as well as other techniques that require special reagents and commercial reagent kits.

biochemistry↗

bioRxiv2024

ER stress-induced TREM2 downregulation exacerbates platelet activation and myocardial infarction in patients with coronary artery disease

Coronary artery disease (CAD) is characterized by the chronic immune-inflammation, excessive endoplasmic reticulum (ER) stress, and platelet hyperactivity; however, whether there is a signaling hub linking these events remains unclear. Here, we identified that triggering receptor expressed on myeloid cells 2 (TREM2), an important pattern recognition receptor of the innate immune system, may serve as one such hub. We found that platelets expressed TREM2 and platelets from CAD patients had decreased TREM2 expression compared to healthy subjects. Decreased TREM2 is associated with platelet hyperactivity in CAD patients. This decrease could be due to excessive ER stress, which downregulated TREM2 through the CHOP-C/EBP axis. Loss of TREM2 not only enhanced platelet activation in response to ADP, collagen, and collagen-related peptide (CRP), but also amplified the platelet inflammatory response. Loss of TREM2 exacerbated mouse mesenteric arterial thrombosis and aggravated experimental myocardial infarction (MI). Moreover, a TREM2-activating antibody inhibited platelet activation, alleviated arterial thrombosis and pulmonary embolism. In addition, TREM2-activating antibody exhibited cardioprotective roles against experimental MI and reduced the inflammatory burden. Mechanistically, TREM2/DAP12/SHIP1 axis negatively regulated platelet activation through reducing PIP3 levels and inhibiting Akt phosphorylation. We also provided evidence supporting sphingosine-1-phospage (S1P) as a physiological agonist of TREM2. In summary, we find that TREM2 connects chronic immune-inflammation, excessive ER stress, and platelet hyperactivity in CAD patients. Downregulating TREM2 by ER stress exacerbates platelet activation and amplifies inflammation response in patients with CAD. TREM2-activating antibodies may have therapeutic potential for CAD patients. Key PointsO_LIPlatelets from CAD patients have decreased TREM2 expression, which is caused by ER stress and associated with platelet hyperactivity. C_LIO_LIS1P-TREM2-SHIP1 pathway inhibits platelet activation, alleviates arterial thrombosis, and exhibits cardioprotective roles against experimental myocardial infarction. C_LI O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=88 SRC="FIGDIR/small/608887v1_ufig1.gif" ALT="Figure 1"> View larger version (26K): org.highwire.dtl.DTLVardef@1e21f2eorg.highwire.dtl.DTLVardef@6d427forg.highwire.dtl.DTLVardef@128af74org.highwire.dtl.DTLVardef@16f48c_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOVisual Abstract.C_FLOATNO Downregulation of platelet TREM2 caused by ER stress in CAD patients leads to platelet hyperactivity and aggravates myocardial ischemia, which is rescued by TREM2-activating antibody. Excessive ER stress in CAD upregulates CHOP, which dimerizes with C/EBP, a transcription factor of TREM2, decreases TREM2 transcription and expression in megakaryocytes and further in platelets. TREM2/DAP12/SHIP1/Akt pathway negatively regulates platelet activation; decreased TREM2 thus aggravates platelet hyperactivity, inflammation, and myocardial infarction, which can be rescued by TREM2 activation including antibody or the small molecule agonist. Physiologically, S1P released from platelet granules is an endogenous agonist of TREM2. C_FIG

pharmacology and toxicology↗

bioRxiv2024

Fc-independent SARS-CoV-2 infection-enhancing antibodies decouple N-terminal and receptor-binding domains by cross-linking neighboring spikes

Antibody dependent enhancement (ADE) is a serious concern in vaccine development. The canonical ADE pathways are dependent on the fragment crystallizable (Fc) region of the antibody. In SARS-CoV-2 several antibodies have been discovered that inflict ADE in vitro. These antibodies target the N-terminal domain (NTD) of the SARS-CoV-2 spike protein. We previously proposed that these NTD-targeting infection-enhancing antibodies (NIEAs) cross-link neighboring spike proteins via their NTDs, and that this results in a decoupling between the NTD and receptor binding domain (RBD), facilitating the "RBD down" to "up" transition. In this study we present a combination of molecular dynamics simulations and cryogenic electron microscopy data that, together, demonstrate that NIEAs are indeed able to cross-link neighboring SARS-CoV-2 spike proteins, and that this cross-linking results in a decoupling of the NTD and RBD domains. These findings provide support for an Fc region independent ADE pathway that is not only relevant for SARS-CoV-2 but also for other viruses of which the spike proteins undergo a conformational change upon host cell entry.

molecular biology↗

bioRxiv2024

Sapphire-Based Optrode for Low Noise Neural Recording and Optogenetic Manipulation

Electrophysiological recordings of neurons in deep brain regions using optogenetic stimulation are essential to understanding and regulating the role of complex neural activity in biological behavior and cognitive function. Optogenetic techniques have significantly advanced neuroscience research by enabling the optical manipulation of neural activities. Because of the significance of the technique, constant advancements in implantable optrodes that integrate optical stimulation with low-noise, large-scale electrophysiological recording are in demand to improve the spatiotemporal resolution for various experimental designs and future clinical applications. However, robust and easy-to-use neural optrodes that integrate neural recording arrays with high-intensity light emitting diodes (LEDs) are still lacking. Here, we propose a neural optrode based on Gallium Nitride (GaN) on sapphire technology, which integrates a high-intensity blue LED with a 5x2 recording array monolithically for simultaneous neural recording and optogenetic manipulation. To reduce the noise interference between the recording electrodes and the LED, which is in close physical proximity, three metal grounding interlayers were incorporated within the optrode, and their ability to reduce LED-induced artifacts during neural recording was confirmed through both electromagnetic simulations and experimental demonstrations. The capability of the sapphire optrode to record action potentials has been demonstrated by recording the firing of mitral/tuft cells in the olfactory bulbs of mice in vivo. Additionally, the elevation of action potential firing due to optogenetic stimulation observed using the sapphire probe in medial superior olive (MSO) neurons of the gerbil auditory brainstem confirms the capability of this sapphire optrode to precisely access neural activities in deep brain regions under complex experimental designs.

neuroscience↗

bioRxiv2024

Insomnia score: predictive ability of insomnia, high-diagnostic and prognostic value for cancer.

ObjectiveThis study utilized bioinformatics methods to investigate the association between insomnia and cancer. MethodsWe identified key insomnia-related genes and constructed an insomnia score (riskScore = {sum} Expressiongene * Coefficient) based on an insomnia dataset using differential analysis, Weighted Gene Co-expression Network Analysis (WGCNA), and Least Absolute Shrinkage and Selection Operator (LASSO) regression. The predictive ability of the insomnia score was validated in the insomnia dataset using Receiver Operating Characteristic (ROC) analysis. Finally, the diagnostic and prognostic value of the insomnia score was assessed in a pan-cancer cohort. ResultsDifferential analysis, WGCNA, and LASSO screening of the insomnia dataset yielded three key insomnia-related genes (PTMA, NLRP8, and CCBE1). An insomnia score was then constructed using the formula: riskScore = -0.8039667 * ExpressionPTMA + - 3.1975230 * ExpressionNLRP8 + -0.4957560 * ExpressionCCBE1. The ROC analysis demonstrated that the insomnia score has excellent predictive ability for insomnia. Furthermore, pan-cancer analysis illustrated the diagnostic and prognostic value of the insomnia score across various cancers. ConclusionWe successfully constructed an insomnia score and demonstrated its diagnostic and prognostic value in multiple cancers.

bioinformatics↗

bioRxiv2024

Genetic differentiation and adaptive evolution of buff-tailed bumblebees in Asia

Bumblebees are ecologically and economically important pollinating insects, so their declines resulting from environmental changes have received intensive attention. Understanding how environmental factors shape the genetic differentiation of natural populations and identifying the genetic basis of local adaptation will provide insights into how species may cope with environmental changes. The buff-tailed bumblebee (Bombus terrestris) has a wide natural distribution range and has been successfully domesticated to produce commercial colonies for greenhouse pollination. Previous population genetics studies on B. terrestris have mainly focused on populations in Europe; however, populations in Asia, representing the eastern side of its natural distribution, have been less thoroughly sampled. To fill this gap, we collected wild B. terrestris samples from Asia, as well as wild B. terrestris from Europe and samples from domesticated colonies. We conducted whole-genome resequencing for 77 collected B. terrestris workers and performed population genomics analysis. Our results revealed significant genetic differentiation (FST= 0.076) between buff-tailed bumblebees in Europe and Asia, along with notable morphological and physiological differences. Consequently, B. terrestris in Asia represents a distinct new genetic resource. Demographic analysis suggested that the population size of buff-tailed bumblebees had increased during historic cold periods, confirming their cold-adapted characteristics. Selective sweep analysis identified 331 genes under selection in the genomes of Asian B. terrestris, likely involved in their adaptation to high ultraviolet radiation, low temperature, and low precipitation in their habitats. Our research provides insights into the population genetic structure and genetic basis of local adaptation in the buff-tailed bumblebee, which will be useful for its conservation and management.

bioinformatics↗

bioRxiv2024

Behavior- and circuit-specific cortico-striatal decoupling during the early development of Parkinson's disease-like syndrome

Inter-brain region activity coupling is essential for enabling coordinated neural communication, facilitating complex brain processes including motor behaviors. In Parkinsons Disease (PD) patients, cortico-striatal decoupling is widely reported while its onset and cellular mechanism remain largely unclear. Using dual-site fiber photometry and Cre transgenic mouse lines, we examined activity coordination between M1 cortex and dorsal striatum (cortico-striatal coupling) with cell-type resolution. This method identifies motor behavior-specific coupling patterns with different contribution from striatal D1R- and D2R-expressing medium spiny neurons (MSNs). In an -synuclein preformed fibrils (PFF) induced PD-like mouse model, cortico-striatal coupling associated with digging behavior is selectively disrupted as early as two months post-induction, whose progressive deterioration correlates with later-onset behavioral deficits. Optogenetic disruption of cortico-striatal coupling is sufficient to induce digging deficits in wild-type mice. Furthermore, such decoupling is mainly mediated by impaired D1R MSNs, which can be rescued by D1 receptor activation or L-DOPA. These findings demonstrate that early-onset, behavior- and cell type-specific cortico-striatal decoupling emerges early during the development of PD-like symptoms.

neuroscience↗

bioRxiv2024

S-RNase Evolution in Self-Incompatibility: Phylogenomic Insights into Synteny with S-Like Genes

S-RNases are essential in the gametophytic self-incompatibility (GSI) system of many flowering plants, where they act as stylar-S determinants. Despite their significance, the syntenic genomic origin and evolutionary trajectory of S-RNase genes in eudicots have remained largely unclear. Here, we performed large-scale phylogenetic and microsynteny network analyses of RNase T2 genes across 130 angiosperm genomes, encompassing 35 orders and 56 families. Based on the connections observed in the synteny network, particularly the persisting synteny block in none-SI Cucurbitaceae species, we infer that well-characterized S-RNase genes (Class III-A RNase genes) were duplicated and evolved from Class I S-like RNase genes, possibly as a result of the gamma triplication event shared by core eudicots. Additionally, we identified frequent lineage-specific gene transpositions of S-RNase genes across diverse angiosperm lineages, including Rosaceae, Solanaceae, and Rutaceae families, accompanied by a significant increase in transposable element (TE) activity near these genes. Our findings delineate the precise genomic origin and evolutionary path of eudicot S-RNase genes, enhancing our understanding of the evolution of the S-RNase-based GSI system.

evolutionary biology↗

bioRxiv2024

Translation efficiency covariation across cell types is a conserved organizing principle of mammalian transcriptomes

Characterizing shared patterns of RNA expression between genes across conditions has led to the discovery of regulatory networks and novel biological functions. However, it is unclear if such coordination extends to translation. Here, we uniformly analyzed 3,819 ribosome profiling datasets from 117 human and 94 mouse tissues and cell lines. We introduce the concept of translation efficiency covariation (TEC), identifying coordinated translation patterns across cell types. We nominate candidate mechanisms driving shared patterns of translation regulation. TEC is conserved across human and mouse cells and uncovers gene functions that are not evident from RNA or protein co-expression. Moreover, our observations indicate that proteins that physically interact are highly enriched for positive covariation at both translational and transcriptional levels. Our findings establish TEC as a conserved organizing principle of mammalian transcriptomes.

bioinformatics↗

bioRxiv2024

Predicting the translation efficiency of messenger RNA in mammalian cells

The degree to which translational control is specified by mRNA sequence is poorly understood in mammalian cells. Here, we constructed and leveraged a compendium of 3,819 ribosomal profiling datasets, distilling them into a transcriptome-wide atlas of translation efficiency (TE) measurements encompassing >140 human and mouse cell types. We subsequently developed RiboNN, a multitask deep convolutional neural network, and classic machine learning models to predict TEs in hundreds of cell types from sequence-encoded mRNA features, achieving state-of-the-art performance (r=0.79 in human and r=0.78 in mouse for mean TE across cell types). While the majority of earlier models solely considered 5' UTR sequence1, RiboNN integrates contributions from the full-length mRNA sequence, learning that the 5' UTR, CDS, and 3' UTR respectively possess [~]67%, 31%, and 2% per-nucleotide information density in the specification of mammalian TEs. Interpretation of RiboNN revealed that the spatial positioning of low-level di- and tri-nucleotide features (i.e., including codons) largely explain model performance, capturing mechanistic principles such as how ribosomal processivity and tRNA abundance control translational output. RiboNN is predictive of the translational behavior of base-modified therapeutic RNA, and can explain evolutionary selection pressures in human 5' UTRs. Finally, it detects a common language governing mRNA regulatory control and highlights the interconnectedness of mRNA translation, stability, and localization in mammalian organisms.

bioinformatics↗

bioRxiv2024

Local photo-crosslinking of native tissue matrix regulates cell function

Within most tissues, the extracellular microenvironment provides mechanical cues that guide cell fate and function. Changes in the extracellular matrix such as aberrant deposition, densification and increased crosslinking are hallmarks of late-stage fibrotic diseases that often lead to organ dysfunction. Biomaterials have been widely used to mimic the mechanical properties of the fibrotic matrix and study cell function. However, the initiation of fibrosis has largely been overlooked, due to the challenges in recapitulating early fibrotic lesions within the native extracellular microenvironment. Using visible light mediated photochemistry, we induced local crosslinking and stiffening of extracellular matrix proteins within ex vivo murine and human tissue. In ex vivo lung tissue of epithelial cell lineage-traced mice, local matrix crosslinking mimicked early fibrotic lesions that increased alveolar epithelial cell spreading, differentiation and extracellular matrix remodeling. However, inhibition of cytoskeletal tension or integrin engagement reduced epithelial cell spreading and differentiation, resulting in alveolar epithelial cell dedifferentiation and reduced extracellular matrix deposition. Our findings emphasize the role of local extracellular matrix crosslinking and remodeling in early-stage tissue fibrosis and have implications for ex vivo disease modeling and applications to other tissues.

bioengineering↗

bioRxiv2024

Timing anti-PD-L1 checkpoint blockade immunotherapy to enhance tumor irradiation

BackgroundThe ability of radiotherapy (RT) to drive anti-tumor immunity is limited by adaptive resistance. While RT induces inflammation and recruits activated tumor-infiltrating lymphocytes (TILs) including cytotoxic T lymphocytes (CTLs), the resulting radiation- and IFN{gamma}-dependent PD-L1 expression restores an immunosuppressed tumor microenvironment. Unleashing an effective anti-tumor response may require precise sequencing of RT and checkpoint blockade immunotherapy (CBI) to block PD-L1 signaling before it can mediate its suppressive effects. MethodsFlank tumors formed in BALB/c mice with syngeneic CT26 colon or 4T1 mammary carcinoma cells were treated with otherwise ineffective doses of ionizing radiation (10 Gy) followed by CBI (0.2 mg anti-PD-L1, i.v.) after 0, 1, 3, 5 or 7 days, comparing tumor response. Anti-PD-L1 delivery was measured by fluorescence, TILs by flow cytometry and immunofluorescence, PD-L1 expression by immunohistochemistry, and tumor size by calipers. Results In both CT26 and 4T1 tumors, 10 Gy alone resulted in a transient growth delay associated with infiltrating CTLs peaking at 3 days and PD-L1 at 5 days. CTLs returned toward baseline by 7 days, consistent with adaptive resistance. Anti-PD-L1 failed to potentiate radiation except when injected 5 days after 10 Gy, which prevented CTL depletion and led to tumor elimination. Potentially contributing to compound effects, anti-PD-L1 penetrated tumors and bound PD-L1 more efficiently after irradiation. ConclusionsOptimal timing to exploit radiation-induced permeability to enhance CBI delivery and interrupt adaptive resistance by blocking PD-L1 as it peaks may offer a general strategy to enhance external beam radiotherapy by protecting activated TILs and potentiating anti-tumor immune response.

cancer biology↗

bioRxiv2024

Dual-Targeted Microbubbles Promote Apoptosis of M1 Macrophages by Inhibiting Telomerase Activity for Atherosclerosis Therapy

It is known that M1 macrophages are the dominant phenotype in progressive atherosclerosis (AS). Studies have shown that telomerase in macrophages can be activated during the atherosclerosis formation, but how to regulate the telomerase activity of M1 macrophages is the focus of treatment of AS. Herein, we report a dual-targeted microbubbles delivery system encapsulating the telomerase inhibitor BIBR1532 (Ab-MMB1532), designed for precise targeted therapy of AS. The Ab-MMB1532 exhibits excellent biocompatibility and remarkable targeting capability towards M1 macrophages with its targeting advantage notably accentuated under high shear forces. Furthermore, it significantly downregulates telomerase activity. Metabolomics analysis indicates that the decrease in telomerase activity upregulates the expression of aspartic acid, a key protein in the Caspase pathway of apotosis. In vivo, Ab-MMB1532 efficiently targeted and accumulated within AS lesions, leading to significantly delay of the AS progression by inhibiting telomerase activity and promoting apoptosis of M1 macrophages after 4-week treatment. In summary, Ab-MMB1532 provides a new approach for potentially safer and more effective treatment of AS in the future.

bioengineering↗