Biology subjects

Ding, Z.

Publications and source records attributed to Ding, Z..

At least 37 records · Page 2Linked to original sources

bioRxiv2026

Arginine synthesis pathway and ASS1 play a critical role in mRNA translation reprogramming and ICI resistance in cutaneous melanoma

Immune checkpoint inhibitors (ICI) have revolutionized cancer treatment, but their efficacy has now reached a plateau. ICIs are the first class of treatment targeting the crosstalk between immune and tumor cells, making it crucial to understand the complex interactions within the tumor microenvironment (TME) to enhance therapeutic responses. The elevated consumption of resources by cancer cells, coupled with limited vascularization, often results in a TME that is deficient in nutrients, leading to competition for resources between cancer and stromal cells. Consequently, targeting tumor metabolism has emerged as a promising strategy to improve the efficacy of ICIs. Through metabolomic analysis, we have identified metabolic alterations in melanoma cells that are resistant to ICIs, specifically an increase in arginine synthesis and upregulation of ASS1, the rate-limiting enzyme in this pathway. By using gain and loss of function models, as well as a pharmacological inhibitor specific for ASS1, we demonstrated that modulations in the expression or activity of ASS1 is associated with translational reprogramming, characterized by an inhibition of the cap-dependent mRNA translation mediated through mTORC1/4EBP1 axis. We also demonstrated that targeting ASS1 in vivo, resensitize tumors initially resistant to ICI. Taken together, our results highlight the interaction between modulations of arginine synthesis pathway, mRNA translation reprogramming, antitumor immunity, and restauration of sensitivity to anti-PD-1. Our work also demonstrates the therapeutic potential of targeting arginine synthesis pathway, and especially ASS1, to offer new treatments to patients suffering from cutaneous melanoma resistant to ICIs.

cancer biology↗

bioRxiv2026

Strong correlation between phantomless and inline phantom-based densitometric calibration of vertebral properties from CT scans of healthy volunteers

Phantom calibration is currently the gold standard for calibrating CT scans and for calculating material properties of dense tissues for computational models. However, in Oncology departments and low-resource settings, it is not routine to include a calibration phantom within the scanning protocol. Therefore, retrospective scan datasets are challenging to calibrate for biomechanical investigations, precluding detailed measurements of material and mechanical properties. In this study, we compared the results from a phantomless calibration technique, where the density within each scan was independently calibrated based on known tissue densities captured within each scan (e.g. air), with those from a traditional inline phantom calibration. To do so we used scans from a cohort of healthy volunteers from the control arm of a clinical trial dataset (ANTELOPE) in which inline calibration phantoms were included. We found that, when selecting air and the aorta as regions for calibration within individual CT scans, a strong individual-specific correlation existed between bone mineral density measured in the phantomless and phantom calibrations. This indicates that the phantomless calibration method can be a useful and reliable tool for quantifying the densitometric material properties of healthy human vertebrae, and provides the opportunity for further analysis of spinal CT scans in either retrospective datasets or in low-resource clinical settings.

bioengineering↗

bioRxiv2025

Chronic stress abnormalize microglial-vascular interaction via AT1R signaling and microglia activation to drive depression-like behaviors

Depression entails a range of pathological processes in the brain, typically characterized by microglia activation, neural dysfunction, and vascular dysregulation. While it is well established that activated microglia inflict damage to neurons through direct and indirect microglia-neuron interactions, their interaction with vasculature and the associated regulation of vascular structure and function in depression remain poorly understood. Here, using a mouse model of depression induced by chronic unpredictable stress (CUS), we find that in stressed mice, activated microglia present reduced motility and decreased contact area with vasculature, which is accompanied by pathological vascular structure and function, marked by reduced vessel density, narrowed vascular diameters, and sluggish blood flow velocity. We observe that vascular structure in the stressed mice is rapidly modified by the vascular-contacted microglia. These vascular-contacted microglia show upregulated angiotensin II type 1 receptor (AT1R) expression, which is not present in the vascular-uncontacted microglia. Furthermore, we demonstrate that AT1R signaling together with microglia activation under chronic stress are critical mediators for the altered microglial-vascular contact situation, vascular dysregulation, as well as the depression-like behaviors. Together, our findings reveal that under CUS, the aberrant microglial-vascular interaction, including the dysregulated microglial vasoregulation arising from AT1R signaling and microglia activation, leads to depression, forging a new link between chronic stress and depression.

neuroscience↗

bioRxiv2025

White-Matter BOLD Mediates Time-Varying Cortico-Cortical Functional Connectivity

Functional connectivity (FC) measurements in the brain using BOLD fMRI have largely focused on correlations between gray-matter (GM) BOLD signals, ignoring the possible relevance of white-matter (WM) in delineating neural networks. We first employed a tract-informed mediation framework to test whether WM pathways contribute indirect, bundle-specific effects to cortico-cortical coupling. Using resting-state fMRI data from the Human Connectome Project, we quantified pathway-level mediation effects across GM-WM-GM units and found that WM BOLD signals significantly mediated GM-GM associations, with clear tract-dependent heterogeneity. Building upon this, we examined how dynamic features of WM BOLD signals relate to time-varying intra-cortical FC. We found that temporal variability of WM signals, rather than their mean amplitudes, more closely tracked fluctuations in GM-GM dynamic connectivity, with correlations reaching approximately 0.4 across specific tracts. Together, these results indicate that WM BOLD signals are related to how cortical regions interact, underscoring their integral role in large-scale brain network organization.

neuroscience↗

bioRxiv2025

Mechanisms of Ub-independent ODC recognition and translocation by the 26S proteasome revealing proteasome's functional adaptability

While most eukaryotic proteins require ubiquitination for proteasomal degradation, a considerable number of substrates undergo ubiquitin-independent degradation. Ornithine decarboxylase (ODC) is a well-known substrate degraded by the 26S proteasome in a ubiquitin-and cofactor-independent manner. However, the underling mechanism of how ODC is recognized and processed without the ubiquitin tag by the 26S proteasome remain unclear. Here, we present eleven cryo-EM structures of the human 26S proteasome in complex with C-terminal truncated or full-length ODC, capturing the entire degradation process from initial recognition to final unfolding. These structures reveal a dynamic, multivalent recognition process involving sequential engagement with vWA domain of Rpn10, Rpt4/5s coiled-coil, and Rpn2s PC domain, collectively bypassing the need for ubiquitin. Although the folded ODC core is sufficient for initial binding, its flexible C-terminal tail is crucial for allosterically activating the proteasomes AAA+ ATPase motor. Furthermore, we also identify a unique translocation gateway where Rpn11s JAMM motif guides the ODC C-tail into the AAA+ATPase ring, repurposing this deubiquitinase for a novel function. Once activated, the proteasome translocates ODC C-tail and unfolds ODC using its canonical ATP-driven machinery. The continuous structural series from initial substrate recognition through final unfolding elucidates the complete molecular mechanism of ubiquitin-independent ODC degradation.

biophysics↗

bioRxiv2025

Decoding the Valence of Developmental Social Behavior: Dopamine Governs Social Motivation Deficits in Autism

The social motivation theory posits that core social deficits in autism spectrum disorder (ASD) arise from impaired social valence assignment during the social critical period, yet the specific dopaminergic mechanisms governing this process remain unclear. We combined high-resolution behavioral sequencing (Social-seq) with fiber photometry to resolve nucleus accumbens (NAc) dopamine during naturalistic juvenile interactions. Sex-divergent social strategies emerged: males exhibited peer play-dominant interactions with action-contingent dopamine release, while females favored environmental exploration with attenuated social dopamine. Shank3-deficient juveniles exhibited a triad of dopaminergic dysregulation -- blunted signaling during social investigation, pathological inversion during active play, and hyper-responsive to non-social stimuli -- recapitulating ASD-like phenotypes. Closed-loop activation of dopamine during play rescued social deficits, establishing a causal link between phasic dopaminergic signaling and social motivation. These findings identify NAc dopamine as a dynamic encoder of social valence and suggest that temporally precise modulation of dopaminergic circuits may offer therapeutic leverage for ASD-related social impairments.

neuroscience↗

bioRxiv2025

High-throughput plasma proteomic platforms: Insights from a multi-ethnic Asian cohort

We compared three leading affinity-based and mass-spectrometry-based proteomic platforms (SomaScan11K, Olink Explore HT, Orbitrap Astral with Seer Proteograph [MS-Seer]) in a multi-ethnic Asian cohort, to inform biomarker discovery and functional genomic studies of global populations. We found limited overlap (1,740 proteins) across the three platforms, with modest correlations (0.34-0.10). SomaScan had lower missingness (<1%) and CV (<10%), compared to Olink (51%, 23%) and MS-Seer (12%, 19%). The new assays in Olink Explore HT (absent in Explore3072) primarily drove its higher missingness and CV. The number of phenotypic associations varied by trait, while the number of genetic associations (cis-pQTLs at P<5e-08) were similar for Olink and SomaScan. Protein levels differed between ethnicities, with SomaScan identifying more ethnicity-differentiated proteins than Olink (FDR<0.05). Finally, SomaScan ANML normalization attenuated biologically relevant associations in our study. These findings underscore the importance of platform evaluation and data normalization strategies for application in large-scale, diverse population cohorts.

bioinformatics↗

bioRxiv2025

Degeneration and Impaired Resilience of Skull Bone and Hematopoietic Bone Marrow

Bone marrow health is central to transplantations, blood formation, and cancer progression. However, the bone marrow niche deteriorates with age, impairing haematopoietic stem cell function. Contrary to a recent report1 suggesting skull marrow resists ageing, our multi-laboratory investigation reveals the opposite: the skull marrow is among the vulnerable sites of age-related decline. Ageing skull niches consistently show loss of mesenchymal and osteoprogenitors, suppression of angiogenic and lymphatic programs, adipocyte accumulation, vascular senescence, DNA replication stress, mitochondrial dysfunction, cellular senescence, and heightened inflammation. Proteomic profiling further highlights this vulnerability, demonstrating that vertebral niches--unlike the skull--are relatively spared from these ageing hallmarks. Together, these convergent datasets overturn the notion of skull-specific resilience and instead establish the skull marrow as a fragile, degenerating environment. These findings redefine marrow ageing and highlight the skull as a critical, clinically relevant target for sustaining blood and immune health and reducing vulnerability to haematological disease.

cell biology↗

bioRxiv2025

Epigenetic Programming of Estrogen Receptor in Adipose Tissue by High Fat Diet Regulates Obesity-Induced Inflammation

Adipose inflammation plays a key role in obesity-induced metabolic abnormalities. Epigenetic regulation, including DNA methylation, is a molecular link between environmental factors and complex diseases. Here we found that high fat diet (HFD) feeding induced a dynamic change of DNA methylome in mouse white adipose tissue (WAT) analyzed by reduced representative bisulfite sequencing. Interestingly, DNA methylation at the promoter of estrogen receptor (Esr1) was significantly increased by HFD, concomitant with a down-regulation of Esr1 expression. HFD feeding in mice increased the expression of DNA methyltransferase 1 (Dnmt1) and Dnmt3a, and binding of DNMT1 and DNMT3a to Esr1 promoter in WAT. Mice with adipocyte-specific Dnmt1 deficiency displayed increased Esr1 expression, decreased adipose inflammation and improved insulin sensitivity upon HFD challenge; while mice with adipocyte-specific Dnmt3a deficiency showed a mild metabolic phenotype. Using a modified CRISPR/RNA-guided system to specifically target DNA methylation at the Esr1 promoter in WAT, we found that reducing DNA methylation at Esr1 promoter increased Esr1 expression, decreased adipose inflammation and improved insulin sensitivity in HFD-challenged mice. Our study demonstrates that DNA methylation at Esr1 promoter plays an important role in regulating adipose inflammation, which may contribute to obesity-induced insulin resistance.

physiology↗

bioRxiv2025

Applying Self-Supervised Tissue Patch Encoders to Enable Cellular Graph Encoding

Recent advances in computation pathology have seen the development of various forms of foundational models that have enabled high-quality, generalpurpose feature extraction from tissue patches. However, most of these models are somewhat limited in their ability to capture cell-to-cell spatial relationships essential for understanding tissue microenvironments. To address this issue, self-supervised learning (SSL) applied to cellular graph models is a promising avenue of investigation as this would afford one the ability to capture cell-level interpretability of the tissue microenvironment and learn relationships from the cellular topology. Compared to SSL on tissue patches, developing cellular graph models requires considerable computation and algorithmic effort, starting with accurate cell detection/segmentation from tissue and then subsequently requiring adequate cell-level feature extraction. In this study, we demonstrate that a pretrained tissue patch encoder, originally trained in the context of the token used in conventional vision transformer frameworks can also serve effectively as a cellular graph encoder for cellbased patches. We report three key findings: 1) the pretrained tissue patch encoder acts as a powerful graph-level feature extractor for cellular graphs in tissue patches; 2) it also can function as a celllevel feature extractor, allowing each cell to be contextualized within its local tissue microenvironment environment; 3) the cell patch size and positional embeddings are critical factors for high-quality cellular graph feature extraction. To validate and support these insights, we evaluate our approach on various tissue region classification tasks from three different types of cancers. Experimental results demonstrate that our method achieves performance comparable to the current state-of-the-art foundation models in computational pathology. These results highlight the potential of pretrained tissue patch encoders in cellular graph modeling, which can enable insights into how the cellular features and topology are related to various biological processes and phenomena.

bioinformatics↗

bioRxiv2025

Application and Characterization of the Multiple Instance Learning Framework in Flow Cytometry

For decades, flow cytometry has allowed for single-cell profiling based on selected biomarkers and is widely used in both clinical and research settings. One major limitation of most conventional flow cytometry analyses is the dependency on a mostly manual gating process. This generally involves sequentially selecting biomarkers to isolate phenotype-associated cell populations, an approach that is both labor-intensive and prone to bias. To address this challenge, we introduce the application of a series of multi-instance learning frameworks for automated flow cytometry data analysis. Our models demonstrate strong performance across diverse biomedical applications, including cancer subtyping based on tumor-infiltrating immune cells, HIV survival stratification, AML minimal residual disease prediction, and COVID-19 severity assessment. We further examine how network architecture affects predictive performance and the detection of rare but clinically significant cell populations. Notably, our models utilize attention mechanisms to directly identify phenotype-associated cell subsets, serving as an interpretable, data-driven alternative to fully manual gating. These findings underscore the potential of multi-instance learning as a scalable and interpretable framework for flow cytometry, with broad applications in precision medicine and translational immunology.

bioinformatics↗

bioRxiv2025

BrainVAE: Exploring the role of white matter BOLD in preclinical Alzheimer disease classification

INTRODUCTIONLike gray matter (GM), white matter (WM) BOLD functional signals change in preclinical AD. However, the potential of WM BOLD for identifying preclinical AD remains underexplored. METHODSWe developed BrainVAE, a transformer-based variational autoencoder with interpretability, to classify preclinical AD and normal controls using resting-state fMRI data. We benchmarked BrainVAE against nine alternative models under three input configurations: WM-only, GM-only, and combined WM+GM. Interpretability analysis was also performed to investigate each brain regions contribution to the classification task. RESULTSBrainVAE outperformed other models and performed well (accuracy = 83.42%, F1-score = 91.62%, AUC = 64.50%) using the combined input compared to WM-only and GM-only. Specific WM bundles--including corpus callosum, fornix, and corticospinal tract--were among the most influential features contributing to the classification. DISCUSSIONIncorporating WM BOLD signals improves the distinction of preclinical AD from controls, underscoring the potential role of WM BOLD features for detecting early-stage AD. HighlightsO_LIBrainVAE integrates white and gray matter BOLD signals for classification of pre-AD and controls. C_LIO_LIBrainVAE achieves high accuracy (83.42%) and F1-score (91.62%) in identifying pre-AD. C_LIO_LIModels using combined WM+GM inputs outperform those using WM-only or GM-only inputs. C_LIO_LIWM regions, such as corpus callosum and fornix, contribute significantly to model predictions. C_LIO_LIResults suggest WM BOLD signals are informative markers for early AD detection. C_LI

neuroscience↗

bioRxiv2025

Effect of Transcranial Light Stimulation on the Neurovascular Unit in the Human Brain

Transcranial light stimulation (tLS) is emerging as a non-invasive approach for enhancing brain function and treating neurological disorders; however, its impact on the human neurovascular unit (NVU) remains poorly understood. Herein, we combined photon transport modeling with multimodal neuroimaging to reveal how light influences vascular and neuronal responses in the human brain. Simulations of photon propagation through transcranial tissue captured key scattering and attenuation patterns, guiding the localization of light effects in vivo. Using simultaneous functional magnetic resonance imaging and arterial spin labeling, we showed that tLS significantly increased blood oxygenation level-dependent signals and cerebral blood flow in the light-affected regions. These hemodynamic changes co-occurred with a reduction in cortical excitability, as revealed by electroencephalographic source reconstruction and transcranial magnetic stimulation-evoked potentials. To probe the underlying mechanism, we incorporated inhibitory neural inputs into the computational NVU model. The model predicted that tLS enhances inhibitory neuronal activity and nitric oxide release, driving vasodilation and elevating metabolic support. These findings revealed that transcranial photons can differentially modulate neuronal and vascular components of the NVU--suppressing excitability while promoting perfusion--thereby suggesting a novel therapeutic avenue for targeting neurovascular dynamics in cognitive and clinical applications.

neuroscience↗

bioRxiv2025

RIP2 inhibits DOCK8-mediated platelet dense granule release and alleviates experimental myocardial infarction

ObjectiveReceptor-interacting protein 2 (RIP2) is an essential mediator of inflammation and innate immunity downstream of pattern recognition receptors (PRRs). Platelets express RIP2, while its role in platelet activation, thrombosis, and myocardial infarction (MI) is unknown. Approach and ResultsHere we show that RIP2 deficiency enhances platelet dense granule secretion in response to GPIb and GPVI activation; platelet aggregation in whole blood and adhesion under arterial shear are also increased. Consistently, RIP2 inhibitor WEHI-345 potentiates human platelet dense granule secretion and inhibits RIP2 phosphorylation induced by thrombin and collagen. These phenotypes are translated into shorter bleeding time, accelerated FeCl3-induced arterial thrombosis. Importantly, platelets from patients with coronary artery disease and mice with atherosclerosis express lower RIP2, and RIP2 deficiency deteriorates MI and cardiac function in a mouse ischemia/reperfusion model. Mechanistically, we found that platelets express dedicator of cytogenesis protein 8 (DOCK8), which is sequestered by phosphorylated RIP2 (p-RIP2), causing inhibition of Cdc42 activation and subsequent dense granule release. ConclusionsIn conclusion, RIP2 inhibits platelet activation, thrombosis, and ameliorates MI. Our results also suggest that a novel PRR-independent pathway, p-RIP2-DOCK8-Cdc42, negatively regulates platelet activation downstream of GPIb and GPVI. Platelet RIP2 pathway may be promising for therapeutic intervention of atherothrombotic diseases from early atherosclerosis stage to arterial thrombosis and MI. HighlightsO_LIRIP2 inhibits platelet dense granule release NOD2-independenly via pRIP2-DOCK8-Cdc42. C_LIO_LIThe negative regulation of RIP2 on platelet activation is translated into enhanced thrombosis, exacerbated myocardial infarction (MI). C_LIO_LIRIP2 pathway booster may be an approach for therapeutic intervention of atherothrombotic diseases. C_LI

molecular biology↗

bioRxiv2025

ARIH1 deficiency impairs spatial learning and memory via GIRK2 upregulation in hippocampal CaMKII-expressing neurons in mice

Alterations of Ariadne RBR E3 Ubiquitin Protein Ligase 1 (ARIH1), a human homologue of Drosophila Ari, have been associated with a number of human diseases. Given the importance of ubiquitin-proteasome system in learning and memory, whether ARIH1 involves in the process has not been explored. Here we report that ARIH1-deficent mice exhibited a defect in learning and memory evidenced in Morris water maze and in novel object recognition tests without changes in basal motor activity, anxiety, and depressive behaviors. We found that ARIH1 deficiency resulted in an upregulation of G protein-gated inwardly rectifying potassium channel 2 (GIRK2) in dorsal hippocampus that was attributed to the impaired ubiquitination and degradation. Locally injection of ARIH1-expressing lentivirus to restore the ARIH1 expression of dorsal hippocampus in ARIH1+/- mice restored the impaired learning and memory. Moreover, selective knockdown ARIH1 in dorsal hippocampal calcium-calmodulin-dependent protein kinase II (CaMKII)-expressing neurons, but not for parvalbumin+ (PV) or somatostatin+ (SST) neurons, in naive mice was sufficient to mimic the damage in learning and memory of ARIH1+/- mice. Lastly, we demonstrated that systemically or locally inhibition of GIRK activity was able to improve ARIH1 deficiency-induced decline of learning and memory in ARIH1+/- mice. The present study discovered the clear role of ARIH1 in mediating learning and memory, defect of ARIH1 resulted in upregulation of GIRK2 in hippocampal CaMKII-expressing neurons via modulating the ubiquitination and degradation GIRK2.

neuroscience↗

bioRxiv2024

Multi-View Integrative Approach For Imputing Short-Chain Fatty Acids and Identifying Key factors predicting Blood SCFA

Short-chain fatty acids (SCFAs) are the main metabolites produced by bacterial fermentation of dietary fiber within gastrointestinal tract. SCFAs produced by gut microbiotas (GMs) are absorbed by host, reach bloodstream, and are distributed to different organs, thus influencing host physiology. However, due to the limited budget or the poor sensitivity of instruments, most studies on GMs have incomplete blood SCFA data, limiting our understanding of the metabolic processes within the host. To address this gap, we developed an innovative multi-task multi-view integrative approach (M2AE, Multi-task Multi-View Attentive Encoders), to impute blood SCFA levels using gut metagenomic sequencing (MGS) data, while taking into account the intricate interplay among the gut microbiome, dietary features, and host characteristics, as well as the nuanced nature of SCFA dynamics within the body. Here, each view represents a distinct type of data input (i.e., gut microbiome compositions, dietary features, or host characteristics). Our method jointly explores both view-specific representations and cross-view correlations for effective predictions of SCFAs. We applied M2AE to two in-house datasets, which both include MGS and blood SCFAs profiles, host characteristics, and dietary features from 964 subjects and 171 subjects, respectively. Results from both of two datasets demonstrated that M2AE outperforms traditional regression-based and neural-network based approaches in imputing blood SCFAs. Furthermore, a series of gut bacterial species (e.g., Bacteroides thetaiotaomicron and Clostridium asparagiforme), host characteristics (e.g., race, gender), as well as dietary features (e.g., intake of fruits, pickles) were shown to contribute greatly to imputation of blood SCFAs. These findings demonstrated that GMs, dietary features and host characteristics might contribute to the complex biological processes involved in blood SCFA productions. These might pave the way for a deeper and more nuanced comprehension of how these factors impact human health.

bioinformatics↗

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

Defining the cardiac fibroblast secretome in the healthy and infarcted mouse heart

Cardiac fibroblasts (CF) are key players after myocardial infarction (MI), but their signaling is only incompletely understood. Here we report a first secretome atlas of CF in control (cCF) and post-MI hearts (miCF), combining a rapid cell isolation technique with SILAC and click chemistry. In CF, numerous paracrine factors involved in immune homeostasis were identified. Comparing secretome, transcriptome (SLAMseq), and cellular proteome disclosed protein turnover. In miCF at day 5 post-MI, significantly upregulated proteins included SLIT2, FN1, and CRLF1 in mouse and human samples. Comparing the miCF secretome at day 3 and 5 post-MI showed the dynamic nature of protein secretion. Specific in-vivo labeling of miCF proteins via biotin ligase TurboID using the POSTN promotor mirrored the in-vitro data. In summary, we have identified numerous paracrine factors specifically secreted from CF in mice and humans. This secretome atlas may lead to new biomarkers and/or therapeutic targets for the activated CF.

physiology↗