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Liang, S.

Publications and source records attributed to Liang, S..

At least 73 records · Page 4Linked to original sources

BTFBS: binding-prediction of bacterial transcription factors and binding sites based on deep learning

BackgroundThe binding of transcription factors (TFs) to TF-binding sites plays a vital role in the process of regulating gene expression and evolution. With the development of machine learning and deep learning, some successes have been achieved in predicting transcription factors and binding sites. Then a natural question arises: for a given transcription factor and a binding site, do they bind? This is the main motivation of this work. ResultsIn this paper, we develop a model BTFBS, which predicts whether the bacterial transcription factors and binding sites combine or not. The model takes both the amino acid sequences of bacterial transcription factors and the nucleotide sequences of binding sites as inputs, and extracts features through convolutional neural network and MultiheadAttention. For the model inputs, we use two negative sample sampling methods: RS and EE. On the test dataset of RS, the accuracy, sensitivity, specificity, F1-score and MCC of BTFBS are 0.91446, 0.89746, 0.93134, 0.91264 and 0.82946, respectively. And on the test dataset of EE, the accuracy, sensitivity, specificity, F1-score and MCC of BTFBS are 0.87868, 0.89354, 0.86394, 0.87996 and 0.75796, respectively. Meanwhile, our findings indicate that the optimal approach for obtaining negative samples in the context of bacterial research is to utilize the whole genome sequences of the corresponding bacteria, as opposed to the shuffling method. ConclusionsThe above results on the test dataset have shown that the proposed BTFBS model has a good performance in predicting the combination of bacterial transcription factors and their binding sites and provides an experimental guide. BTFBS is publicly available at https://github.com/Vceternal/BTFBS.

bioinformatics↗

e3SIM: epidemiological-ecological-evolutionary simulation framework for genomic epidemiology

Infectious disease dynamics are driven by the complex interplay of epidemiological, ecological, and evolutionary processes. Accurately modeling these interactions is crucial for understanding pathogen spread and informing public health strategies. However, existing simulators often fail to capture the dynamic interplay between these processes, resulting in oversimplified models that do not fully reflect real-world complexities in which the pathogens genetic evolution dynamically influences disease transmission. We introduce the epidemiological-ecological-evolutionary simulator (e3SIM), an open-source framework that concurrently models the transmission dynamics and molecular evolution of pathogens within a host population while integrating environmental factors. Using an agent-based, discrete-generation, forward-in-time approach, e3SIM incorporates compartmental models, host-population contact networks, and quantitative-trait models for pathogens. This integration allows for realistic simulations of disease spread and pathogen evolution. Key features include a modular and scalable design, flexibility in modeling various epidemiological and population-genetic complexities, incorporation of time-varying environmental factors, and a user-friendly graphical interface. We demonstrate e3SIMs capabilities through simulations of realistic outbreak scenarios with SARS-CoV-2 and Mycobacterium tuberculosis, illustrating its flexibility for studying the genomic epidemiology of diverse pathogen types.

bioinformatics↗

Tonotopy is not preserved in a descending stage of auditory cortex

Previous studies based on layer specificity suggest that ascending signals from the thalamus to the sensory neocortex preserve spatially organized information, but it remains unknown whether sensory information descending from sensory neocortex to the thalamus also maintains such spatial organization pattern. By focusing on projection specificity, we mapped the tone response properties of two groups of cortical neurons in the primary auditory cortex (A1), based on the relationship between their specific connections to other regions and their function in ascending (thalamocortical recipient, TR neurons) or descending (corticothalamic, CT neurons) auditory information. A clear tonotopic gradient was observed among TR neurons, but not CT neurons. Additionally, CT neurons exhibited markedly higher heterogeneity in their frequency tuning and had broader bandwidth than TR neurons. These results reveal that the information flow descending from A1 to the thalamus via CT neurons is not arrange tonotopically, suggesting that the descending information flow possibly contributes to higher-order feedback processing of diverse auditory inputs.

neuroscience↗

Flight performance, activity and behaviour of breeding pied flycatchers in the wild, revealed with accelerometers and machine learning

Flight behaviours have been extensively studied from different angles such as their kinematics, aerodynamics and more general their migration pattern. Nevertheless, much is still unknown about the daily flight activity of birds, in terms of their performance, behaviour and the potential differences between males and females. The recent development of miniaturized accelerometers allows us a glimpse into the daily life of a songbird. Here, we tagged 26 pied flycatchers (Ficedula hypoleuca) with accelerometers and analysed using machine learning approaches their flight performance, activity and behaviour during their chick rearing period. We found that during two hours of foraging chick-rearing pied flycatchers were flying 13.7% of the time. Almost all flights (>99%) were short flights lasting less than 10s. Flight activity changed throughout the day and was highest in the morning and lowest in the early afternoon. Male pied flycatcher had lower wing loading than females, and peak flight accelerations were inversely correlated with wing loading. Despite this, we found no significant differences in flight activity and performance between sexes. This suggests that males possess a higher potential flight performance, which they not fully utilized during foraging flights. Our results thus suggest that male and female pied flycatcher invest equally in parental care, but that this comes at a reduced cost by the male, due to their higher flight performance potential.

animal behavior and cognition↗

Mar1, an HMG-box protein, regulates n-alkane adsorption and cell morphology of the dimorphic yeast Yarrowia lipolytica

The dimorphic yeast Yarrowia lipolytica possesses an excellent ability to utilize n-alkane as a sole carbon and energy source. Although there are detailed studies on the enzymes that catalyze the reactions in the metabolic processes of n-alkane in Y. lipolytica, the molecular mechanism underlying the incorporation of n-alkane into the cells remains to be elucidated. Because Y. lipolytica adsorbs n-alkane, we postulated that Y. lipolytica incorporates n-alkane through direct interaction with it. We isolated and characterized mutants defective in adsorption to n-hexadecane. One of the mutants harbored a nonsense mutation in MAR1 (Morphology and n-alkane Adsorption Regulator) encoding a protein containing a high mobility group box. The deletion mutant of MAR1 exhibited defects in adsorption to n-hexadecane and filamentous growth on solid media, whereas the strain that overexpressed MAR1 exhibited hyperfilamentous growth. Fluorescence microscopic observations suggested that Mar1 localizes in the nucleus. RNA-seq analysis revealed the alteration of the transcript levels of several genes, including those encoding transcription factors and cell surface proteins, by the deletion of MAR1. These findings suggest that MAR1 is involved in the transcriptional regulation of the genes required for n-alkane adsorption and cell morphology transition. IMPORTANCEY. lipolytica, a dimorphic yeast capable of assimilating n-alkane as a carbon and energy source, has been extensively studied as a promising host for bioconversion of n-alkane into useful chemicals and bioremediation of soil and water contaminated by petroleum. While the metabolic pathway of n-alkane in this yeast and the enzymes involved in this pathway have been well-characterized, the molecular mechanism to incorporate n-alkane into the cells is yet to be fully understood. Due to the ability of Y. lipolytica to adsorbs to n-alkane, it has been hypothesized that Y. lipolytica incorporates n-alkane through direct interaction with it. In this study, we identified a gene, MAR1, which plays a crucial role in the transcriptional regulation of the genes necessary for the adsorption to n-alkane and the transition of the cell morphology in Y. lipolytica. Our findings provide valuable insights that could lead to advanced applications of Y. lipolytica in n-alkane bioconversion and bioremediation.

microbiology↗

Quorum Sensing Positively Regulates CPS-dependent Autographiviridae Phages Infection in Vibrio alginolyticus

Quorum sensing (QS) orchestrates many bacterial behaviors, such as virulence and biofilm formation, across bacterial populations. Nevertheless, the underlying mechanism of QS regulating CPS-dependent phage-bacterium interactions remains unclear. In the present study, we report that QS upregulated the expression of CPS-dependent phage receptors, thus increasing phage adsorption and infection rates in V. alginolyticus. We found that QS upregulated the expression of the ugd gene, leading to increased synthesis of Autographiviridae phage receptor capsular polysaccharide (CPS) synthesis in V. alginolyticus. The signal molecule autoinducer-2 (AI-2) released by V. alginolyticus from different sources can potentially enhance CPS-dependent phage infection. Therefore, our data suggest that inhibiting quorum sensing may reduce rather than improve the therapeutic efficacy of CPS-specific phages. IMPORTANCEPhage resistance is a direct threat to phage therapy, and understanding phage-host interactions, especially bacteria block phage infection, is essential for developing successful phage therapy. In the present study, we demonstrate for the first time that V. alginolyticus uses QS to promote CPS-specific phage infection by upregulating the expression of ugd, which is necessary for the synthesis of Autographiviridae phage receptor capsular polysaccharide (CPS). Although increased CPS-specific phage susceptibility is a novel trade-off mediated by QS, it results in the upregulation of virulence factors, promoting biofilm development and enhanced capsular polysaccharide production in V. alginolyticus. This suggests that inhibiting QS may improve the effectiveness of antibiotic treatment, but it may also reduce the efficacy of phage therapy.

microbiology↗

Scm6A: A fast and low-cost method for quantifying m6A modifications at the single-cell level

It is widely accepted that m6A exhibits significant intercellular specificity, which poses challenges for its detection using existing m6A quantitative methods. In this study, we introduce Scm6A, a machine learning-based approach for single-cell m6A quantification. Scm6A leverages input features derived from the expression levels of m6A trans regulators and cis sequence features, and found that Scm6A offers remarkable prediction efficiency and reliability. To further validate the robustness and precision of Scm6A, we applied a winscore-based m6A calculation method to conduct m6A-seq analysis on CD4+ and CD8+ T-cells isolated through magnetic-activated cell sorting (MACS). Subsequently, we employed Scm6A for analysis on the same samples. Notably, the m6A levels calculated by Scm6A exhibited a significant positive correlation with m6A quantified through m6A-seq in different cells isolated by MACS, providing compelling evidence for Scm6As reliability. We also used the scm6A-seq method to validate the reliability of our approach. Additionally, we performed single-cell level m6A analysis on lung cancer tissues as well as blood samples from COVID-19 patients, and demonstrated the landscape and regulatory mechanisms of m6A in different T-cell subtypes from these diseases. In summary, our work has yielded a novel, dependable, and accurate method for single-cell m6A detection. We are confident that Scm6A will have broad applications in the realm of m6A-related research.

bioinformatics↗

Pan-cancer Analysis Reveals m6A Variation and Cell-specific Regulatory Network in Different Cancer Types

As the most abundant mRNA modification in mRNA, N6-methyladenosine (m6A) plays a crucial role in RNA fate, impacting cellular and physiological processes in various tumor types. However, our understanding of the function and role of the m6A methylome in tumor heterogeneity remains limited. Herein, we collected and analyzed m6A methylomes across nine human tissues from 97 m6A-seq and RNA-seq samples. Our findings demonstrate that m6A exhibits different heterogeneity in most tumor tissues compared to normal tissues, which contributes to the diverse clinical outcomes in different cancer types. We also found that the cancer type-specific m6A level regulated the expression of different cancer-related genes in distinct cancer types. Utilizing a novel and reliable method called "m6A-express", we predicted m6A- regulated genes and revealed that cancer type-specific m6A-regulated genes contributed to the prognosis, tumor origin and infiltration level of immune cells in diverse patient populations. Furthermore, we identified cell-specific m6A regulators that regulate cancer-specific m6A and constructed a regulatory network. Experimental validation was performed, confirming that the cell-specific m6A regulator CAPRIN1 controls the m6A level of TP53. Overall, our work reveals the clinical relevance of m6A in various tumor tissues and explains how such heterogeneity is established. These results further suggest the potential of m6A for cancer precision medicine for patients with different cancer types.

bioinformatics↗

Decision Characteristics Underlying Non-Suicidal Self-Injury in Patients with Major Depressive Disorder

BackgroundNon-suicidal self-injury (NSSI) behavior is significantly prevalent in both adolescents and psychiatric populations, particularly in individuals with major depressive disorder (MDD). NSSI can be considered a result of risky decision-making in response to negative emotions, where individuals choose self-harm over other less harmful alternatives, suggesting a potential decision-making deficit in those engaging in NSSI. This study delves into the complex relationship between NSSI and depression severity in decision-making and its cognitive underpinnings. MethodsWe assessed decision behaviors in 57 MDD patients with NSSI, 42 MDD patients without NSSI and 142 healthy controls using the Balloon Analogue Risk Task, which involves risk-taking, learning, and exploration in uncertain scenarios. Using computational modeling, we dissected the nuanced cognitive dimensions influencing decision behaviors. A novel statistical method was developed to elucidate the interaction effects between NSSI and depression severity. ResultsContrary to common perceptions, we found that individuals with NSSI behaviors were typically more risk-averse. Meanwhile, there was a complex interaction between NSSI and depression severity in shaping risk-taking behaviors. As depressive symptoms intensified, these individuals with NSSI began to perceive less risk and behave more randomly. ConclusionsThis research provides new insights into the cognitive aspects of NSSI and depression, highlighting the importance of considering the influence of comorbid mental disorders when investigating the cognitive underpinnings of such behaviors, especially in the context of prevalent cross-diagnostic phenomena like NSSI behaviors.

neuroscience↗

Linking root-associated fungal and bacterial functions to root economics

Tree roots form symbioses with soil microbes to acquire nutrients, but the relationships between root nutrient acquisition strategies and microbial community composition remain poorly understood. Here, we measured root traits and root-associated fungal and bacterial guilds in 336 trees of 52 species from a subtropical forest. We found a fungal gradient from ectomycorrhizal to saprotrophic dominance, which corresponded with a shift from organic to mineral nutrient economics. This fungal gradient was aligned with the increase of root nitrogen concentration, suggesting a linkage from simple root trait to fungal-mediated carbon-nutrient cycling. We also found that the functional composition of fungal and bacterial communities was closely correlated with host root-zone pH, which often varied among coexisting trees. Root-zone pH was independent of the common root traits, underpinning a potential new gradient in the root trait space. Our findings integrate microbial functions into the root economics framework, thereby advancing the understanding of diversity of nutrient acquisition strategies across forest trees.

ecology↗

metaExpertPro: a computational workflow for metaproteomics spectral library construction and data-independent acquisition mass spectrometry data analysis

BackgroundAnalysis of mass spectrometry-based metaproteomic data, in particular large-scale data-independent acquisition MS (DIA-MS) data, remains a computational challenge. Here, we aim to develop a software tool for efficiently constructing spectral libraries and analyzing extensive datasets of DIA-based metaproteomics. ResultsWe present a computational pipeline called metaExpertPro for metaproteomics data analysis. This pipeline encompasses spectral library generation using data-dependent acquisition MS (DDA-MS), protein identification and quantification using DIA-MS, functional and taxonomic annotation, as well as quantitative matrix generation for both microbiota and hosts. To enhance accessibility and ease of use, all modules and dependencies are encapsulated within a Docker container. By integrating FragPipe and DIA-NN, metaExpertPro offers compatibility with both Orbitrap-based and PASEF-based DDA and DIA data. To evaluate the depth and accuracy of identification and quantification, we conducted extensive assessments using human fecal samples and benchmark tests. Performance tests conducted on human fecal samples demonstrated that metaExpertPro quantified an average of 45,000 peptides in a 60-minute diaPASEF injection. Notably, metaExpertPro outperformed three existing software tools by characterizing a higher number of peptides and proteins. Importantly, metaExpertPro maintained a low factual False Discovery Rate (FDR) of less than 5% for protein groups across four benchmark tests. Applying a filter of five peptides per genus, metaExpertPro achieved relatively high accuracy (F-score = 0.67-0.90) in genus diversity and demonstrated a high correlation (rSpearman = 0.73-0.82) between the measured and true genus relative abundance in benchmark tests. Additionally, the quantitative results at the protein, taxonomy, and function levels exhibited high reproducibility and consistency across the commonly adopted public human gut microbial protein databases IGC and UHGP. In a metaproteomic analysis of dyslipidemia patients, metaExpertPro revealed characteristic alterations in microbial functions and potential interactions between the microbiota and the host. ConclusionsmetaExpertPro presents a robust one-stop computational solution for constructing metaproteomics spectral libraries, analyzing DIA-MS data, and annotating taxonomic as well as functional data.

microbiology↗

Engraftment and injury repair in regionally conditioned rat lung in vivo by lung progenitors derived from human pluripotent stem cells.

Although lung disease is a major cause of mortality, the mechanisms involved in human lung regeneration are unclear because of the lack of experimental models. Here we report a novel model where human pluripotent stem cell-derived expandable cell lines sharing features of airway secretory and basal cells engraft in the distal rat lung after conditioning by locoregional de-epithelialization followed by irradiation and immunosuppression. The engrafting cells, which we named distal lung epithelial progenitors (DLEPs), contributed to alveolar epithelial cells and generated KRT5-pods, structures involved in distal lung repair after severe injury, but only rarely to distal airways. Most strikingly, however, injury induced by the conditioning regimen was largely prevented by the engrafting DLEPs. The approach described here provides a model to study mechanisms involved in human lung regeneration, and potentially lays the foundation for the preclinical development of cell therapy to treat lung injury and disease.

cell biology↗

Multi-modal microvascular cerebral blood flow velocity mapping with 14T single-vessel MRI and optical microscopy in the mouse brain

In this study, we imaged the same penetrating cortical vessels in a mouse using ultrahigh field single-vessel MRI at 14 T and high-resolution optical microscopy imaging. The optical imaging was performed through a chronic sealed cranial window, while the single-vessel MRI was facilitated by a custom-designed, chronically implanted radiofrequency coil surrounding the window. The MRI and optical imaging were performed sequentially focused on the same penetrating cortical arterioles and surfacing venules within the whisker barrel cortex. With MRI, we obtained high-resolution multi-gradient echo (MGE) images and single-vessel phase contrast (PC) velocity maps. With optical imaging, we acquired microvascular angiograms using 2-Photon Microscopy (2PM) and Optical Coherence Tomography (OCT) and measured the blood flow velocity using Dynamic Light Scattering OCT (DLS-OCT). The MGE images, PC-based MRI velocity maps, OCT angiograms, and DLS-OCT velocity maps were coregistered with the 2PM microvascular angiograms. Using these tools, we cross-validated blood flow velocity in the penetrating cortical arterioles and surfacing venules measured by single-vessel MRI and OCT at rest. Our novel method demonstrates the possibility of combining ultrahigh field single-vessel MRI and high-resolution optical methods (e.g., 2PM and OCT) for studying brain structure and function with single microvessel precision.

bioengineering↗

Systematic elucidation of independently modulated genes in Lactobacillus plantarum reveals a trade-off between secondary and primary metabolism

Lactobacillus plantarum is a probiotic bacteria widely used in food and health industries, but its gene regulatory information is limited in existing databases, which impedes the research of its physiology and its applications. To obtain a better understanding of the transcriptional regulatory network of L. plantarum, independent component analysis (ICA) of its transcriptomes was used to derive 45 sets of independently modulated genes (iModulons). Those iModulons were annotated for associated transcription factors (TFs) and functional pathways, and active iModulons in response to different growth conditions were identified and characterized in detail. Eventually, the analysis of iModulon activities reveals a trade-off between regulatory activities of secondary and primary metabolism in L. plantarum.

systems biology↗

Integrative Transcriptomic Analysis of Anterior and Posterior IOP-Controlling Tissues in Glaucoma Reveals Enrichment of MHC-II Pathway and T-Cell Infiltration Signatures

BackgroundGlaucoma is a multifactorial neurodegenerative disease indicating by abnormalities in the whole eye, apart from optic neuropathy, and is often associated with abnormal intraocular pressure (IOP). However, the underlying pathological mechanisms of glaucoma and the management of IOP remain largely unaddressed. Emerging evidence suggests the involvement of immune changes in glaucoma. Therefore, characterizations of immune alternations by molecular profiling of IOP-controlling tissues from both anterior and posterior eye segments including trabecular meshwork (TM) and choroid may provide insights to the disease mechanism. MethodsBulk TM microarray data (GSE138125 and GSE27276) from primary open-angle glaucoma (POAG) and choroid single-cell transcriptome data (GSE203499) from glaucoma were downloaded from Gene Expression Omnibus (GEO) database. The two qualified TM datasets were integrated. Analyses of differential expression genes (DEGs), functional and pathway annotations, immune infiltration, and disease-related modules were performed using the POAG bulk data. Similarly, DEGs and pathway annotations, single-cell trajectory and switch gene analysis, and cell-cell communications were conducted using the choroid single-cell RNA-sequencing data. Finally, integrated analyses from the two studies were conducted to determine the glaucomatous changes between anterior and posterior IOP-controlling eye tissues. ResultsA total of 102 DEGs between POAG and healthy tissues were identified from the TM data. Gene set enrichment analysis revealed five glaucoma-enriched pathways: ATP generation and metabolism, cornification and keratinization, metabolism of reactive oxygen species (ROS), humoral immune response, and platelet aggregation. Significant immune infiltrations were observed in POAG tissue, including total T cells (excluding CD8+ T cells), NK cells, monocytic lineage, endothelial cells, and fibroblasts. Furthermore, the POAG enriched pathways are primarily from T-cell infiltrations. On the other hand, fourteen distinct cell clusters were identified from the choroid single-cell data. The most evident findings were fibrosis, represented by extracellular matrix (ECM), the actin-binding pathways enrichment in pericyte-fibroblast transition, reduction in light sensitivity of melanocytes, and complex immune changes among all cell types in the pathological conditions compared to control. Taken together, an integrated analyses between the TM microarray and choroid single-cell data result in 111 significantly dysregulated genes in the disease state. These key genes participated in immune and inflammatory reactions (DUSP1, ADM, CD74, CEBPD, HLA-DPA1, ZNF331), served as potential biomarkers for neurodegenerative and autoimmune diseases (such as NR4A2), or regulated membrane integrity, vasculature calcification, ECM interactions, and cell morphology (PTP4A1, MGP, and RASD1). Overall, our integrated data analyses might provide insight to the understanding of the disease mechanism. ConclusionBy integrating bulk microarray data from TM and single-cell transcriptome data from the choroid, we systematically evaluated the glaucomatous transcriptomic changes between the anterior and posterior IOP-controlling tissue from ocular. Results indicated there was a significantly enrichment of genes belonging to the MHC-II pathway and T-cell infiltration in the disease state, opening new avenues for biomarkers discovery and therapeutic interventions to glaucoma.

bioinformatics↗

Structural basis for EROS binding to human phagocyte NADPH oxidase NOX2

EROS (essential for reactive oxygen species) is a recently identified molecular chaperone of NOX2 (gp91phox), the catalytic subunit of phagocyte NADPH oxidase. Deficiency in NOX2 expression or function due to genetic mutations leads to chronic granulomatous disease (CGD) with recurrent bacterial and fungal infections. To delineate how EROS interacts with NOX2, we solved the cryo-EM structure of the EROS-NOX2-p22phox heterotrimeric complex. EROS binds to NOX2 in plasma membrane through its anti-parallel -helices H1 and H2, and in cytoplasm through multiple {beta}-strands that form hydrogen bonds with the C terminal fragment of NOX2. EROS binding alters the conformation of the TM2 and TM6 transmembrane helices, increases the distance between the two hemes, and causes dislocation of the binding site for flavin adenine dinucleotide (FAD). EROS colocalizes with NOX2 on cell surface of neutrophil-like HL-60 cells and forms a heterotrimer with mature NOX2-p22phox in transfected cells. Phorbol myristate acetate, an activator of NOX2, induces dissociation of EROS from NOX2 in a NanoLuc complementation assay with concurrent production of superoxide in reconstituted cells. Taken together, these findings provide a structural basis for EROS-NOX2 interaction and suggest a previously unidentified function of EROS in regulating NOX2 activation.

immunology↗

α-catenin mechanosensitivity as a route to cytokinesis failure through sequestration of LZTS2

Epithelial cells can become polyploid upon tissue injury, but mechanosensitive cues that trigger this state are poorly understood. Using -catenin (-cat) knock-out Madin Darby Canine Kidney (MDCK) cells reconstituted with wild-type and mutant forms of -cat as a model system, we find that an established -cat actin-binding domain unfolding mutant designed to reduce force-sensitive binding to F-actin (-cat-H0-FABD+) can promote cytokinesis failure, particularly along epithelial wound-fronts. Enhanced -cat coupling to cortical actin is neither sufficient nor mitotic cell-autonomous for cytokinesis failure, but critically requires the mechanosensitive Middle-domain (M1-M2-M3) and neighboring cells. Disease relevant -cat M-domain missense mutations known to cause a form of retinal pattern dystrophy (-cat E307K or L436P) are associated with elevated binucleation rates via cytokinesis failure. Similar binucleation rates are seen in cells expressing an -cat salt-bridge destabilizing mutant (R551A) designed to promote M2-M3 domain unfurling at lower force thresholds. Since binucleation is strongly enhanced by removal of the M1 as opposed to M2-M3 domains, cytokinetic fidelity is most sensitive to -cat M2-M3 domain opening. To identify -cat conformation-dependent proximity partners that contribute to cytokinesis, we used a biotin-ligase approach to distinguished proximity partners that show enhanced recruitment upon -cat M-domain unfurling (R551A). We identified Leucine Zipper Tumor Suppressor 2 (LZTS2), an abscission factor previously implicated in cytokinesis. We confirm that LZTS2 enriches at the midbody, but discover it also localizes to tight and tricellular junctions. LZTS2 knock-down promotes binucleation in both MDCK and Retinal Pigmented Epithelial (RPE) cells. -cat mutants with persistent M2-M3 domain opening showed elevated junctional enrichment of LZTS2 from the cytosol compared -cat wild-type cells. These data implicate LZTS2 as a mechanosensitive effector of -cat that is critical for cytokinetic fidelity. This model rationalizes how persistent mechano-activation of -cat may drive tension-induced polyploidization of epithelia post-injury and suggests an underlying mechanism for how pathogenic -cat mutations drive macular dystrophy.

cell biology↗

The multi-Siglec inhibitor AL009 reprograms suppressive macrophages and activates innate and adaptive tumor immunity

Sialic acid-binding immunoglobulin-type lectins (Siglecs) are cell surface receptors that regulate innate and adaptive immunity, with inhibitory Siglecs promoting immune tolerance. In the tumor microenvironment, overexpression of sialic acid glycans exploits inhibitory Siglec signaling, leading to a cancer-permissive phenotype. AL009 is an engineered Siglec-9-Fc fusion molecule that functions as a sialic acid trap and reprograms suppressive macrophages to activate an anti-tumor immune response. AL009 treatment of human myeloid-derived suppressor cells, an in vitro model of tumor-associated macrophages, resulted in an increase in proinflammatory cytokines and chemokines, changes in cell surface markers, and potent relief of T cell inhibition in a co-culture assay. In syngeneic mouse (Mus musculus) tumor models, AL009 engineered with a mouse Fc (AL009m) reduced tumor growth as a monotherapy and in combination with the checkpoint inhibitor anti-PD-L1. In addition, AL009m synergized with the tumor-targeting therapy anti-TRP1 to reduce lung nodules in the B16-F10 intravenous model. Pharmacodynamic marker analysis in syngeneic and humanized mouse tumor models supported an AL009 mechanism of action based on reprogramming tumor-associated macrophages and enhanced T cell activation. Future clinical studies are warranted to further elucidate the safety and efficacy of AL009.

cancer biology↗