Biology subjects

Deng, H.

Publications and source records attributed to Deng, H..

At least 37 records · Page 2Linked to original sources

bioRxiv2024

Polycomb Repressive Complex 2 promotes atherosclerotic plaque vulnerability

Key findings1. PRC2 regulates EC shear stress responses. 2. PRC2 governs Klf2/4 suppression downstream of Pcdhg. 3. High PRC2 in ASCVD-prone arterial regions suppresses Klf2/4 to promote ASCVD. 4. Athero-protective Klf2/4 induction upon PRC2 inhibition requires Notch signaling. 5. Tazemetostat, an FDA approved PRC2 inhibitor, slows ASCVD progression and improves markers of plaque stability. Atherosclerotic cardiovascular disease (ASCVD), the leading cause of mortality worldwide, is driven by endothelial cell inflammatory activation and counter-balanced by anti-inflammatory transcription factors Klf2 and Klf4 (Klf2/4). Understanding vascular endothelial inflammation to develop effective treatments is thus essential. Here, we identify, Polycomb Repressive Complex (PRC) 2, which blocks gene transcription by trimethylating histone3 Lysine27 in gene promoter/enhancers, as a potent, therapeutically targetable determinant of vascular inflammation and ASCVD progression. Bioinformatics identified PRC2 as a direct suppressor of Klf2/4 transcription. Klf2/4 transcription requires Notch signaling, which reverses PRC2 modification of Klf2/4 promoter/enhancers. PRC2 activity is elevated in human ASCVD endothelium. Treating mice with established ASCVD with tazemetostat, an FDA approved pharmacological inhibitor of PRC2, slowed plaque progression by 50% and drastically improved markers of plaque stability. This study elucidates a fundamental mechanism of vascular inflammation, thus identifying a potential method for treating ASCVD and possibly other vascular inflammatory diseases.

cell biology↗

bioRxiv2024

Combined inhibition of S100A4 and TIGIT suppresses late-stage breast cancer metastasis to the lung by activating T and NK cells

Cancer metastasis is responsible for approximately 90% of cancer-related deaths, but very few treatment options exist currently. While the role of S100A4 in promoting metastasis has been known for decades, this knowledge has not been translated in the clinic. Here, we report that a novel monoclonal antibody against the human S100A4 protein (S1004-11) effectively suppresses breast cancer metastasis in two different mouse models. Importantly, a novel combination of ant-TIGIT and S100A4-11 can suppress lung metastases even in late-stage disease after the lung premetastatic niche (PMN) has already been established similar to a stage when many breast cancer patients are diagnosed. Mechanistically, S1004-11 mAb treatment block the formation of PMN by suppressing neutrophil infiltration and activating natural killer (NK) and T cells in the lung. Single-cell RNA-sequencing and cell:cell communication analyses indicate that TIGIT signaling suppresses NK cells, which is reversed in S100A4-11 treated PMN. In summary, this study provides compelling evidence for a novel mechanism of S100A4 function in PMN formation and the feasibility of using S100A4-11 monoclonal antibody to suppress metastases at different stages of breast cancer progression.

cancer biology↗

bioRxiv2024

Neutrophil extracellular traps promote tumor chemoresistance to anthracyclines

The microenvironment plays an important role in promoting tumor cell chemoresistance, but the mechanisms responsible for this effect are not clear. Here, using models of multiple myeloma (MM) and solid cancers, we demonstrate a novel mechanism mediated by neutrophils, a major cell population in the bone marrow (BM), that protects cancer cells from chemotherapeutics. We show that in response to tumor-derived soluble factors, BM neutrophils release their DNA in the form of neutrophil extracellular traps (NETs). Cell-free DNA derived from NETs is then taken up by tumor cells via endocytosis and localizes to the cytoplasm. We found that both NETs and cell-free DNA taken up by tumor cells can bind anthracyclines, leading to tumor cell resistance to this class of chemotherapeutic agents. Targeting cell-free DNA with Pulmozyme or blocking NET formation with a PAD4 inhibitor abrogates the chemoprotective effect of neutrophils and restores sensitivity of tumor cells to anthracyclines.

cancer biology↗

bioRxiv2024

Co-transcriptional RNA processing boosts zygotic gene activation

Transcription decodes protein-coding genes and interprets regulatory information embedded in the genome by generating RNA. In eukaryotes, gene transcription is coupled with RNA processing via the carboxyl terminal domain (CTD) of RNA polymerase (Pol) II, which enhances messenger RNA (mRNA) production. We propose that co-transcriptional RNA processing is essential for zygotic gene activation (ZGA), transitioning the transcription program from noncoding to protein-coding after fertilization. Truncating the CTD in mouse cells disrupts this coupling, halting global mRNA synthesis and increasing noncoding RNA (ncRNA) levels through enhanced intergenic transcription and RNA stabilization. CTD truncation also triggers epigenetic reprogramming and nuclear reorganization towards totipotency, resembling early cleavage embryos. Mechanistically, the CTD restrains nonproductive polymerase activity in noncoding sequences, while at protein-coding genes requiring RNA processing, it promotes elongation by facilitating polymerase promoter-proximal pausing, transcription directionality, and velocity. Longer CTD lengths enhance gene activity, likely evolving to accommodate the increasing noncoding sequences in mammalian genomes.

developmental biology↗

bioRxiv2024

'Mitotic' kinesin-5 is a dynamic brake for axonal growth

During neuronal development, neurons undergo significant microtubule reorganization to shape axons and dendrites, establishing the framework for efficient wiring of the nervous system. Previous studies from our laboratory demonstrated the key role of kinesin-1 in driving microtubule-microtubule sliding, which provides the mechanical forces necessary for early axon outgrowth and regeneration in Drosophila melanogaster. In this study, we reveal the critical role of kinesin-5, a mitotic motor, in modulating the development of postmitotic neurons. Kinesin-5, a conserved homotetrameric motor, typically functions in mitosis by sliding antiparallel microtubules apart in the spindle. Here, we demonstrate that the Drosophila kinesin-5 homolog, Klp61F, is expressed in larval brain neurons, with high levels in ventral nerve cord (VNC) neurons. Knockdown of Klp61F using a pan-neuronal driver leads to severe locomotion defects and complete lethality in adult flies, mainly due to the absence of kinesin-5 in VNC motor neurons during early larval development. Klp61F depletion results in significant axon growth defects, both in cultured and in vivo neurons. By imaging individual microtubules, we observe a significant increase in microtubule motility, and excessive penetration of microtubules into the axon growth cone in Klp61F-depleted neurons. Adult lethality and axon growth defects are fully rescued by a chimeric human-Drosophila kinesin-5 motor, which accumulates at the axon tips, suggesting a conserved role of kinesin-5 in neuronal development. Altogether, our findings show that at the growth cone, kinesin-5 acts as a brake on kinesin-1-driven microtubule sliding, preventing premature microtubule entry into the growth cone. This regulatory role of kinesin-5 is essential for precise axon pathfinding during nervous system development.

cell biology↗

bioRxiv2024

Cell-type-specific striatal modulation of amygdalar acetylcholine in salience assignment

The salience assignment is pivotal for both natural and artificial intelligence. Pioneering studies established that basal forebrain cholinergic neurons process behaviorally relevant salient information. However, the neural circuit mechanism underlying salience assignment remains poorly understood. Here we show that the acetylcholine (ACh) level in the basolateral amygdala (BLA) dynamically represented behavioral salience. Distinct neuronal subpopulations in the nucleus accumbens (NAc), D1- and D2-expressing medium spiny neurons (MSNs), antagonistically and specifically promote and suppress ACh release in the BLA, but not the cortex and hippocampus. These striatal D1 and D2 MSNs regulate BLA ACh by disinhibiting and inhibiting cholinergic neurons in the basal forebrain subregion substantia innominata (SI), respectively. Optogenetic manipulations of the pathway from striatal D1 and D2 MSNs to the SI opposingly affect associative learning. Our findings uncover an unconventional role of striatal MSNs in salience assignment via regulating the salience-representing amygdalar ACh activity.

neuroscience↗

bioRxiv2024

Interplay of Anchor and Latch Residues at Enzyme Active Site in Preserving Induced Fit Configurations for Efficient Catalysis: A Case Study of CARNMT1 for Histidine Methylation

Determining the origin of high catalytic efficiency of enzymes has been a central goal in biochemical research. But our understanding of the mechanisms by which enzymes achieve enormous rate enhancements is still incomplete. One of wildly accepted strategies to achieve rate enhancements by enzymes is to position catalytic residues precisely in enzyme-substrate complexes and form reactive conformations for catalysis. Such catalytic strategy through positioning may also serve as the basis for transition state stabilization. Although considerable efforts have been made to determine relationships between enzyme activities and the formation of reactive conformations of enzyme-substrate complexes, there is considerable uncertainty concerning the ability of enzymes to preserve reactive conformations during enzyme-catalyzed reactions. The failure of properly maintaining reactive conformations during reactions may prevent residues from exerting catalytic effects and lead to significant reductions of activities. Here QM/MM MD and free energy simulations are performed for CARNMT1 to determine the importance and requirements for preservation of catalytic competent reactive conformations during enzyme-catalyzed reactions. For CARNMT1, the existence of wild-type reactive conformation is directly related to the conformation of His347. Therefore, the conformation of His347 can be used to monitor preservation or collapse of the reactive conformation during catalysis. It is found that for wild-type the reactive conformation can not only be formed in the enzyme-substrate complex but also be preserved well after the reaction passes TS. For the Tyr386Ala, Tyr396Asp and Tyr398Ala mutants, the wild-type like reactive conformations can be formed in the mutant-substrate complexes but collapse in the early stage of reaction. Such pre-mature collapse of the reactive conformation in the mutants prevents the residues to fully exert catalytic effects and leads to a significant reduction of catalytic efficiency. The results suggest that the ability of enzymes to preserve reactive conformations with well-positioned catalytic residues during enzyme-catalyzed reactions can be an important factor for efficient catalysis, and this property of enzymes deserves attention.

biochemistry↗

bioRxiv2024

CRMP/UNC-33 maintains neuronal microtubule arrays by promoting individual microtubule rescue

Microtubules (MTs) are intrinsically dynamic polymers. In neurons, staggered individual microtubules form stable, polarized acentrosomal MT arrays spanning the axon and dendrite to support long-distance intracellular transport. How the stability and polarity of these arrays are maintained when individual MTs remain highly dynamic is still an open question. Here we visualize MT arrays in vivo in C. elegans neurons with single microtubule resolution. We find that the CRMP family homolog, UNC-33, is essential for the stability and polarity of MT arrays in neurites. In unc-33 mutants, MTs exhibit dramatically reduced rescue after catastrophe, develop gaps in coverage, and lose their polarity, leading to trafficking defects. UNC-33 is stably anchored on the cortical cytoskeleton and forms patch-like structures along the dendritic shaft. These discrete and stable UNC-33 patches concentrate free tubulins and correlate with MT rescue sites. In vitro, purified UNC-33 preferentially associates with MT tips and increases MT rescue frequency. Together, we propose that UNC-33 functions as a microtubule-associated protein (MAP) to promote individual MT rescue locally. Through this activity, UNC-33 prevents the loss of individual MTs, thereby maintaining the coverage and polarity of MT arrays throughout the lifetime of neurons.

cell biology↗

bioRxiv2024

Biodegradation Potential of Neptunomonas naphthovoran - NAG-2N-126 for Crude Oil Pollution Mitigation: Experimental and Modelling Insights

Crude oil contamination poses a significant threat to the environment, demanding effective bioremediation strategies. While microbial biodegradation holds promise, there is a notable absence of exploration, particularly regarding the biodegradation potential of Neptunomonas naphthovoran strain NAG-2N-126. This study addresses this gap by investigating the bioremediation potential of NAG-2N-126 through experimental analyses and mathematical modelling. Our findings reveal the strains rapid growth on crude oil, with the microbial biomass predicted to undergo a 3.5-fold increase over the experimental period. Additionally, the strain exhibited high efficiency in degrading aromatic compounds, achieving an impressive 41% degradation rate within the initial 20-day period. Oxygen availability emerged as a critical factor influencing microbial growth and biodegradation processes, with simulations indicating a 20% decrease in degradation rates under oxygen-deprived conditions. Mathematical modelling provided insights into the complex dynamics involved, contributing to the understanding of microbial hydrocarbon degradation. However, further research is warranted to optimize growth conditions and scale up findings for practical applications in environmental cleanup efforts. By delving into this underexplored area, this study highlights the importance of NAG-2N-126 in crude oil bioremediation and underscores the need for further research to optimize its application in environmental cleanup efforts. IMPORTANCEThis study presents novel insights into microbial biodegradation of crude oil, addressing a critical environmental challenge. With an estimated 24 billion BOE potentially remaining in the North Sea reservoir and over 2,000 oil spills reported since 2011, including 215 in marine protection areas, the urgency of developing effective bioremediation strategies is paramount. By investigating the growth kinetics and biodegradation efficiency of the bacterial strain N. naphthovoran NAG-2N-126 under controlled laboratory conditions, we elucidate its potential for crude oil remediation. Our findings highlight the strains remarkable ability to degrade aromatic hydrocarbons, offering promise for sustainable bioremediation strategies. Furthermore, through the development of mathematical models, we provide valuable insights into microbial population dynamics and substrate utilization rates during crude oil degradation. This research contributes to advancing our understanding of bioremediation processes and offers practical implications for mitigating environmental pollution and promoting ecosystem health.

microbiology↗

bioRxiv2024

Peripheral B Lymphocyte Serves as A Reservoir for The Persistently Covert Infection of Mandarinfish Siniperca chuatsi Ranavirus

Genus Ranavirus in family Iridoviridae is composed of large members with various genomic sizes and viral gene contents, infecting a variety of ectothermic vertebrates including reptile, amphibians and bony fish worldwide. Mandarinfish ranavirus (MRV) is a very distinctive member among genus Ranavirus. Persistently convert infection of MRV were previously observed in natural outbreak of MRV, but the underlying mechanism remains unclear. We here evidenced that mandarinfish peripheral B lymphocytes are implemented as viral reservoirs to maintain persistent and covert infection. When mandarinfish were infected with sublethal dosage of MRV under nonpermissive temperature (19 {o}C) and permissive temperature (26 {o}C), respectively, all fish in 19 {o}C group survived and entered persistent phase of infection characterized with very low viral load in white blood cell, whereas partial fish died of MRV infection in 26 {o}C group, and the survivals then initiated persistent status. Gradually raising temperature, vaccination and dexamethasone treatment can reactivate the quiescent MRV to replicate and result in partial mortality. The viral reservoir investigates showed that IgM+-labelled B lymphocytes but not CD3{Delta}+-labelled T lymphocytes and MRC-1+-labelled macrophages are target cells for the persistent infection of MRV. Moreover, the quiescent MRV could not be reactivated by heat-killed Escherichia coli, indicating a very different reactivation mechanism from that of other known rannaviral member. Collectively, we are the first to confirm the presence of B cell-dependent persistent and covert infection of ranavirus, and provide a new clue for better understanding the complex infection mechanism of vertebrate iridovirus, especially regarding ranavirus. IMPORTANCEViruses known as HIV, HBV and EBV etc. evade host immune clearance by establishing long-term even lifelong persistent or latent infection. In vertebrate iridovirus, FV3, the type species of genus Ranavirus was evidenced to establish persistent infection by using Xenopus peritoneal macrophages as reservoirs. MRV is a very distinctive ranavirus from FV3 with very different genomic content and host species. We here uncovered MRV establishes persistent and covert infection by using peripheral B lymphocytes as virus reservoirs. During persistent infection, very low copies of quiescent MRV were harbored in peripheral B lymphocytes. Water temperature stress, vaccination stimulation, and dexamethasone treatment can reactivate quiescent MRV to replicate in abundance via a non-TLR5-mediated manner, and results in recurrence of MRV disease. Our finding suggests the diversity and complexity of the pathogenic mechanisms among ranaviruses, and also has important scientific significance for in-depth understanding of the infection and immunity interaction of vertebrate iridoviruses.

microbiology↗

bioRxiv2024

Tunable Universal OR-gated CAR T cells for AML

Abstract/SummaryAcute myeloid leukemia (AML) is a hematopoietic malignancy characterized by antigen heterogeneity and poor prognosis. A potential therapeutic approach to address this heterogeneity is targeting multiple surface antigens to prevent antigen escape and relapse. Chimeric antigen receptor (CAR) T cells are an adoptive cell therapy that have demonstrated remarkable clinical success in the treatment of B cell malignancies, and many efforts are underway to adapt them to myeloid malignancies. To tackle the heterogeneity of AML, logically targeting multiple antigens through an "A OR B" gated CAR circuit would be desirable. Here we combined FLT3 antigen targeting with the well characterized CD33 myeloid marker as a combinatorial OR gate approach using our split, universal, programmable (SUPRA) CAR platform. The split platform affords tunability over activation levels and multiplexed targeting that cannot be achieved through a tandem bispecific approach. We systematically characterized the specificity and sensitivity of different SUPRA CAR adapters against each target individually and in combination against a panel of target cell lines. Our results demonstrate that this CAR system can effectively target two antigens with equivalent efficacy to conventional CARs while reducing the engineering burden associated with designing CAR T cells against multiple antigens. Furthermore, we can characterize an effective dose range where off-target cytotoxicity against hematopoietic stem and progenitor cells is minimized. With the recent clinical advances in universal CAR designs, our SUPRA OR gate has the potential to provide an effective and safer solution to treating AML.

synthetic biology↗

bioRxiv2024

Rbbp8nl contributes to resistance to anticancer immunotherapy by creating a non-inflamed tumor microenvironment and attenuating CD8+ T cell infiltration

Immune checkpoint blockade (ICB) monotherapy has limited efficacy, and it is crucial to explore predictive markers for the efficacy of immunotherapy and its use as new therapeutic targets or sensitization targets in combination with immunotherapy. Pan-cancer research using RNA sequencing data from The Cancer Genome Atlas (TCGA) revealed that RBBP8NL is particularly overexpressed in the tumor microenvironment (TME) of different malignancies. Additionally, there is a negative correlation between RBBP8NL and immune modulators, T cell inflammatory scores, immunological checkpoints, cancer immune cycle, and tumor-infiltrating immune cells (TIICs), so it can be inferred that RBBP8NL shapes the non-inflammatory TME in BLCA. BLCA patients with high RBBP8NL expression have a low response rate to immunotherapy, and they are more likely to experience hyperprogression of the illness. Interestingly, anti-RBBP8NL with immunotherapy could work better together than they do separately. According to the results of the multi-omics analysis, RBBP8NL inhibits the recruitment of cytotoxic lymphocytes. Furthermore, RBBP8NLs predictive significance for immunotherapy success has been confirmed across several immunotherapy cohorts. In summary, RBBP8NL is a crucial component of the TME and a developing target for binding to ICB as well as a biomarker to direct precision medicine.

cancer biology↗

bioRxiv2024

Characterization of Cancer Stem Cells in Laryngeal Squamous Cell Carcinoma by Single-Cell RNA Sequencing

Cancer stem cells (CSCs) constitute a pivotal element within the tumor microenvironment (TME), driving the initiation and progression of cancer. However, the identification of CSCs and their underlying molecular mechanisms in laryngeal squamous cell carcinoma (LSCC) remains a formidable challenge. We employed single-cell RNA sequencing of matched primary tumor tissues, paracancerous tissues, and local lymph nodes from three LSCC patients. Two distinct clusters of stem cells originating from epithelial populations were delineated and verified as CSCs and normal stem cells (NSCs) respectively. CSCs were abundant in the paracancerous tissues compared to the tumor tissues. CSCs showed high expression of stem cell marker genes such as PROM1, ALDH1A1, and SOX4, and increased activity of tumor-related hypoxia, Wnt/{beta}-catenin, and notch signaling pathways. We then explored the intricate crosstalk between CSCs and the TME cells and identified targets within the TME that related with CSCs. We also find eight marker genes of CSCs that correlated significantly with the prognosis of LSCC patients. Furthermore, bioinformatics analyses showed that drugs such as erlotinib, OSI-027, and ibrutinib selectively targeted the CSC-specifically expressed genes. In conclusion, our results represent the first comprehensive characterization of CSCs properties in LSCC at the single-cell level.

bioinformatics↗

bioRxiv2024

Gamma protocadherins in vascular endothelial cells inhibit Klf2/4 to promote atherosclerosis

Atherosclerotic cardiovascular disease (ASCVD) is the leading cause of mortality worldwide1. Laminar shear stress (LSS) from blood flow in straight regions of arteries protects against ASCVD by upregulating the Klf2/4 anti-inflammatory program in endothelial cells (ECs)2-8. Conversely, disturbed shear stress (DSS) at curves or branches predisposes these regions to plaque formation9,10. We previously reported a whole genome CRISPR knockout screen11 that identified novel inducers of Klf2/4. Here we report suppressors of Klf2/4 and characterize one candidate, protocadherin gamma A9 (Pcdhga9), a member of the clustered protocadherin gene family12. Pcdhg deletion increases Klf2/4 levels in vitro and in vivo and suppresses inflammatory activation of ECs. Pcdhg suppresses Klf2/4 by inhibiting the Notch pathway via physical interaction of cleaved Notch1 intracellular domain (NICD Val1744) with nuclear Pcdhg C-terminal constant domain (CCD). Pcdhg inhibition by EC knockout (KO) or blocking antibody protects from atherosclerosis. Pcdhg is elevated in the arteries of human atherosclerosis. This study identifies a novel fundamental mechanism of EC resilience and therapeutic target for treating inflammatory vascular disease.

cell biology↗

bioRxiv2023

Development of attenuated coxsackievirus B3 vectored intranasal pre-emptive pan-coronavirus vaccine

SARS-CoV-2 has the ability to evade immunity, resulting in breakthrough infections even after vaccination. Similarly, zoonotic coronaviruses pose a risk of spillover to humans. There is an urgent need to develop a pre-emptive pan-coronavirus vaccine that can induce systemic and mucosal immunity. Here, we employed a combination of immune-informatics approaches to identify shared immunodominant linear B- and T-cell epitopes from SARS-CoV-2 variants of concern (VOCs) and variants of interest (VOIs), as well as zoonotic coronaviruses. Epitope-guided vaccine were designed and the attenuated coxsackievirus B3 vectored intranasal vaccines rCVB3-EPI and rCVB3-RBD-trimer were constructed. The immunogenicity of these candidate vaccines was evaluated using Balb/c mice. The results demonstrated effective immune responses, including the production of SARS-CoV-2-specific IgG and sIgA antibodies, as well as T cell-mediated responses. However, further verification is required to assess cross-reactivity with various variants. Our intranasal pre-emptive pan-coronavirus vaccine design framework offers an appealing candidate for future vaccine development.

microbiology↗

bioRxiv2023

Paternal genomic resources from the YanHuang cohort suggested a Weakly-Differentiated Multi-source Admixture model for the formation of Hans founding ancestral lineages

The large-scale human genome revolution and rapidly advanced statistical innovation have updated our understanding of the fine-scale and complex genetic structure, the entire landscape of genetic diversity and the evolutionary trajectories of spatiotemporally different ancients and ethnolinguistically diverse modern populations. Recent ancient DNA research provided a detailed and complex admixture picture of ancient Europeans but limited insights into East Asians as the few available genomes. Y-chromosome variations in the male-specific regions, served as molecular archaeological tool, have unique evolutionary features that can be utilized to reconstruct the origin and subsequent interaction of ancient East Asian paternal lineages. We launched the YanHuang cohort using our designed highest-resolution capture sequencing panel to explore the detailed evolutionary trajectory of the Han Chinese, one of the largest ethnic groups in the world. We reported one of the largest uniparental genomic resources and observed multiple founding paternal lineages dominant in ancient western Eurasian, Siberian and East Asian participating in the formation of the gene pool of the Han Chinese. We identified fine-scale paternal genetic structure correlated with different patterns of ancient population interaction and geographical mountain barriers (Qinling-Huaihe line and Nanling Mountains), suggesting isolation-enhanced and admixture-introduced genetic differentiation enhanced the complexity of the Han Chinese genomic diversity. We observed a strong direct correlation between the frequency of multiple founding lineages of the Han Chinese and the proportion of subsistence-related ancestry sources related to western pastoralists, Holocene Mongolian Plateau people and ancient East Asians, reflecting the ancient migration events contributed to our identified patterns of Chinese paternal genomic diversity. We finally provided one novel and the most plausible admixture-by-admixture model, the Weakly-Differentiated Multi-Source Admixture model, as the major genetic mechanism to illuminate our observed pattern of complex interactions of multiple ancestral sources and landscape of the Han Chinese paternal genetic diversity. Generally, we presented one large-scale uniparental genomic resource from the YanHuang cohort, portrayed one novel admixture formation model and presented the entire genomic landscape with multiple ancestral sources related to ancient herders, hunter-gatherers and farmers who participated in the ancestral formation of the Han Chinese.

evolutionary biology↗

bioRxiv2023

cSTAR analysis identifies endothelial cell cycle as a key regulator of flow-dependent artery remodeling

Fluid shear stress (FSS) from blood flow is sensed by vascular endothelial cells (ECs) to determine vessel stability, remodeling and susceptibility to atherosclerosis and other inflammatory diseases but the regulatory networks that govern these behaviors are only partially understood. We used cSTAR, a powerful new computational method, to define EC transcriptomic states under low shear stress (LSS) that triggers vessel inward remodeling, physiological shear stress (PSS) that stabilizes vessels, high shear stress (HSS) that triggers outward remodeling, and oscillatory shear stress (OSS) that confers disease susceptibility, all in comparison to cells under static conditions (STAT). We combined these results with the LINCS database where EC transcriptomic responses to drug treatments to define a preliminary regulatory network in which the cyclin-dependent kinases CDK1/2 play a central role in promoting vessel stability. Experimental analysis showed that PSS induced a strong late G1 cell cycle arrest in which CDK2 was activated. EC deletion of CDK2 in mice resulted in inward artery remodeling and both pulmonary and systemic hypertension. These results validate use of cSTAR to determine EC state and in vivo vessel behavior, reveal unexpected features of EC phenotype under different FSS conditions, and identify CDK2 as a key element within the EC regulatory network that governs artery remodeling.

cell biology↗

bioRxiv2023

omicsMIC: a Comprehensive Benchmarking Platform for Robust Comparison of Imputation Methods in Mass Spectrometry-based Omics Data

Mass spectrometry is a powerful and widely used tool for generating proteomics, lipidomics, and metabolomics profiles, which is pivotal for elucidating biological processes and identifying biomarkers. However, missing values in spectrometry-based omics data may pose a critical challenge for the comprehensive identification of biomarkers and elucidation of the biological processes underlying human complex disorders. To alleviate this issue, various imputation methods for mass spectrometry-based omics data have been developed. However, a comprehensive and systematic comparison of these imputation methods is still lacking, and researchers are frequently confronted with a multitude of options without a clear rationale for method selection. To address this pressing need, we developed omicsMIC (mass spectrometrybased omics with Missing values Imputation methods Comparison platform), an interactive platform that provides researchers with a versatile framework to simulate and evaluate the performance of 28 diverse imputation methods. omicsMIC offers a nuanced perspective, acknowledging the inherent heterogeneity in biological data and the unique attributes of each dataset. Our platform empowers researchers to make data-driven decisions in imputation method selection based on real-time visualizations of the outcomes associated with different imputation strategies. The comprehensive benchmarking and versatility of omicsMIC make it a valuable tool for the scientific community engaged in mass spectrometry-based omics research. OmicsMIC is freely available at https://github.com/WQLin8/omicsMIC.

bioinformatics↗