Biology subjects

Ding, S.

Publications and source records attributed to Ding, S..

At least 55 records · Page 3Linked to original sources

bioRxiv2024

Time restricted feeding with or without ketosis influences metabolism-related gene expression in a tissue-specific manner in aged rats

Many of the hallmarks of aging involve alterations in cellular and organismal metabolism. One pathway with the potential to impact several traditional markers of impaired function with aging is the PI3K/AKT metabolic pathway. Regulation of this pathway includes many aspects of cellular function, including protein synthesis, proliferation and survival, as well as many downstream targets, including mTOR and FOXOs. Importantly, this pathway is pivotal to the function of every organ system in the human body. Thus, we investigated the expression of several genes along this pathway in multiple organs, including the brain, liver and skeletal muscle, in aged subjects that had been on different experimental diets to regulate metabolic function since mid-life. Specifically, rats were fed a control ad lib diet (AL), a time restricted feeding diet (cTRF), or a time restricted feeding diet with ketogenic macronutrients (kTRF) for the majority of their adult lives (from 8-25 months). We previously reported that regardless of macronutrient ratio, TRF-fed rats in both macronutrient groups required significantly less training to acquire a biconditional association task than their ad lib fed counterparts. The current experiments expand on this work by quantifying metabolism-related gene expression across tissues and interrogating for potential relationships with cognitive performance. AKT expression was significantly reduced in kTRF fed rats within liver and muscle tissue. However, AKT expression within the perirhinal cortex (PER) was higher in kTRF rats with the best cognitive performance. Within CA3, higher levels of FOXO1 gene expression correlated with poorer cognitive performance in ad libitum fed rats. Together, these data demonstrate diet- and tissue-specific alterations in metabolism-related gene expression and their correlation with cognitive status.

neuroscience↗

bioRxiv2024

Impacts of Structural Properties of Myosin II Filaments on Force Generation

Cells need intracellular forces for their physiological functions, such as migration, cytokinesis, and morphogenesis. The actin cytoskeleton generates a large fraction of the forces via interactions between cytoskeletal components, such as actin filament (F-actin), myosin, and actin cross-linking proteins (ACPs). Myosin II plays the most important role in cellular force generation. Myosin II molecules self-assemble into filaments with different structures depending on myosin II isoforms and other conditions such as pH and ionic concentration. It has remained elusive how force generation in actomyosin structures is affected by the architecture of myosin II filaments. In this study, we employed an agent-based model to investigate the effects of the structural properties of myosin II filaments on force generation in disorganized actomyosin structures. We demonstrated that the magnitude of forces and the efficiency of force generation can vary over a wide range depending on the number and spatial distribution of myosin II filaments. Further, we showed that the number of myosin heads and the length of a bare zone at the center of myosin II filaments without heads highly affect the force generation process in bundles and networks. Our study provides insights into understanding the roles of the structural properties of myosin II filaments in actomyosin contractility.

biophysics↗

bioRxiv2024

Reinforced identity confers cells with cancer hallmarks

Genetic alterations trigger tumorigenesis in a cell type-specific manner, but the biological basis for this, remains unclear. Here we define reinforced original cell identity established by interaction between genetic alterations and original cell type is a pivotal determinant of tumor development. Using AML-M5MLL-AF9 as a model system, we demonstrated that MLL-AF9 enhanced key transcriptional factors (TFs) expression of promonocyte and cooperated with them to amplify their downstream programs for AML hallmarks. Interactions between MLL-AF9 and promonocyte endowed cancer cells with a reinforced promonocyte identity. Reinforced intrinsic cell identity also sustained cancer hallmarks across cancer types. Furthermore, we identified narciclasine, as an effective disruptor of reinforced promonocyte identity, effectively treating AML-M5MLL-AF9. This study not only identified reinforced cell identity as a fundamental tumor driver beyond genetic mutations but also offers a proof-of-concept for reinforced identity- targeted cancer therapy.

cancer biology↗

bioRxiv2024

Multi-task benchmarking of single-cell multimodal omics integration methods

Single-cell multimodal omics technologies have empowered the profiling of complex biological systems at a resolution and scale that were previously unattainable. These biotechnologies have propelled the fast-paced innovation and development of data integration methods, leading to a critical need for their systematic categorisation, evaluation, and benchmark. Navigating and selecting the most pertinent integration approach poses a significant challenge, contingent upon the tasks relevant to the study goals and the combination of modalities and batches present in the data at hand. Understanding how well each method performs multiple tasks, including dimension reduction, batch correction, cell type classification and clustering, imputation, feature selection, and spatial registration, and at which combinations will help guide this decision. This study develops a much-needed guideline on choosing the most appropriate method for single-cell multimodal omics data analysis through a systematic categorisation and comprehensive benchmarking of current methods. The Stage 1 protocol for this Registered Report was accepted in principle on 30th July 2024. The protocol, as accepted by the journal, can be found at https://springernature.figshare.com/articles/journal_contribution/Multi-task_benchmarking_of_single-cell_multimodal_omics_integration_methods/26789902.

bioinformatics↗

bioRxiv2024

A Self-Assembling Immune-Featured Osteosarcoma Patient/PDX Derived Organoid Model and Biobank for Personalized Immune Therapy

Osteosarcoma (OS) exhibit intra- and inter-heterogeneity, complicating the exploration of effective therapeutic strategies. Traditional in vitro and in vivo models are limited in inheriting biological and genomic heterogeneities of OS patients, even in inheriting the features on tumor microenvironment. The prolonged generation time of current models makes the drug development of OS slow and is not suitable to clinically rapid timing. Here, we introduce methods for generating and biobanking patient/PDX-derived osteosarcoma organoids (OS PD(X)Os) that recapitulate the histological, biological and genomic features of their paired OS patients. OS PD(X)Os can be generated quickly with high reliability in vitro or transplanted to immunodeficient mice. We further demonstrate an immune-featured OS PD(X)O (named iOS) model and its method for testing personalized chemotherapy response, personalized immune therapeutic strategy and target drug development, such as a novel PRMT5MTA inhibitor ARPN2169 on MTAP-deleted OS. Our studies show that iOS models maintain many typical features of OS and could be rapidly employed to investigate patient-specific therapeutic strategies. Additionally, our biobank establishes a rich resource for basic, translational and even clinical OS researches.

cancer biology↗

bioRxiv2024

Freestanding rGO electrodes with tunable porous structures for improved neural recording

Invasive neural electrodes prepared from materials with miniaturized geometrical size could improve the longevity of implants by reducing the chronic inflammatory response. Graphene-based microfibers with tunable porous structures have a large electrochemical surface area (ESA)/geometrical surface area (GSA) ratio that has been reported to possess low impedance and high charge injection capacity (CIC), yet the control of the porous structure remains to be fully investigated. In this study, we introduce wet-spun graphene-based electrodes with pores tuned by sucrose concentrations in the coagulation bath. The electrochemical properties of thermally reduced rGO were optimized by adjusting the ratio of rGO to sucrose, resulting in significantly lower impedance, higher CIC, and higher charge storage capacity (CSC) than platinum microwires. Tensile and insertion tests confirmed that optimized electrodes had sufficient strength to ensure a 100% insertion success rate with low angle shift, thus allowing precise implantation without the need for additional mechanical enhancement. Acute in-vivo recordings from the auditory cortex found low impedance benefits from the recorded amplitude of spikes, leading to an increase in the signal-to-noise ratio (SNR). Ex-vivo recordings from hippocampal brain slices demonstrate that it is possible to record and/or stimulate with graphene-based electrodes with good fidelity compared with conventional electrodes.

neuroscience↗

bioRxiv2024

The neonatal Fc receptor and DPP4 are human astrovirus receptors

Human astroviruses (HAstV) are major global causes of gastroenteritis, but little is known about host factors required for their cellular entry. Here, we utilized complementary CRISPR-Cas9-based knockout and activation screening approaches and identified neonatal Fc receptor (FcRn) and dipeptidyl-peptidase IV (DPP4) as entry factors for HAstV infection of human intestinal epithelial cells. Disruption of FcRn or DPP4 reduced HAstV infection in permissive cells and, reciprocally, overexpression of these factors in non-permissive cells was sufficient to promote infection. We observed direct binding between FcRn and HAstV virions as well as purified spike protein. Finally, inhibitors for DPP4 and FcRn currently in clinical use prevent HAstV infection in cell lines and primary human enteroids. Thus, our results reveal mechanisms of HAstV entry as well as druggable targets. One-Sentence SummaryTargeting FcRn or DPP4 using available therapies effectively prevents human astrovirus infection in human enteroid cultures.

microbiology↗

bioRxiv2024

Aging limits stemness and tumorigenesis in the lung by reprogramming iron homeostasis

Aging is associated with a decline in the number and fitness of adult stem cells1-4. Aging-associated loss of stemness is posited to suppress tumorigenesis5,6, but this hypothesis has not been tested in vivo. Here, using physiologically aged autochthonous genetically engineered mouse models and primary cells7,8, we demonstrate aging suppresses lung cancer initiation and progression by degrading stemness of the alveolar cell of origin. This phenotype is underpinned by aging-associated induction of the transcription factor NUPR1 and its downstream target lipocalin-2 in the cell of origin in mice and humans, leading to a functional iron insufficiency in the aged cells. Genetic inactivation of the NUPR1--lipocalin-2 axis or iron supplementation rescue stemness and promote tumorigenic potential of aged alveolar cells. Conversely, targeting the NUPR1-- lipocalin-2 axis is detrimental to young alveolar cells via induction of ferroptosis. We find that aging-associated DNA hypomethylation at specific enhancer sites associates with elevated NUPR1 expression, which is recapitulated in young alveolar cells by inhibition of DNA methylation. We uncover that aging drives a functional iron insufficiency, which leads to loss of stemness and tumorigenesis, but promotes resistance to ferroptosis. These findings have significant implications for the therapeutic modulation of cellular iron homeostasis in regenerative medicine and in cancer prevention. Furthermore, our findings are consistent with a model whereby most human cancers initiate in young individuals, revealing a critical window for such cancer prevention efforts.

cancer biology↗

bioRxiv2024

Effect of Circadian Rhythm Modulated Blood Flow on Nanoparticle based Targeted Drug Delivery in Virtual In Vivo Arterial Geometries

Delivery of drug using nanocarriers tethered with vasculature-targeting epitopes aims to maximize the therapeutic efficacy of the drug while minimizing the drug side effects. Circadian rhythm which is governed by the central nervous system has implications for targeted drug delivery due to sleep-wake cycle changes in blood flow dynamics. This paper presents an advanced fluid dynamics modeling method that is based on viscous incompressible shear-rate fluid (blood) coupled with an advection-diffusion equation to simulate the formation of drug concentration gradients in the blood stream and buildup of concentration at the targeted site. The method is equipped with an experimentally calibrated nanoparticle-endothelial cell adhesion model that employs Robin boundary conditions to describe nanoparticle retention based on probability of adhesion, a friction model accounting for surface roughness of endothelial cell layer, and a dispersion model based on Taylor-Aris expression for effective diffusion in the boundary layer. The computational model is first experimentally validated and then tested on engineered bifurcating arterial systems where impedance boundary conditions are applied at the outflow to account for the downstream resistance at each outlet. It is then applied to a virtual geometric model of an in vivo arterial tree developed through MRI-based image processing techniques. These simulations highlight the potential of the computational model for drug transport, adhesion, and retention at multiple sites in virtual in vivo models. The model provides a virtual platform for exploring circadian rhythm modulated blood flow for targeted drug delivery while minimizing the in vivo experimentation. Statement of SignificanceA novel integration of nanoparticle-based drug delivery framework with shear-rate dependent blood flow model is presented. The framework is comprised of a unique combination of mechanics-based dispersion model, an asperity model for endothelium surface roughness, and a stochastic nanoparticle-endothelial cell adhesion model. Simulations of MRI based in vivo carotid artery system showcase the effects of vessel geometry on nanoparticle adhesion and retention at the targeted site. Vessel geometry and target site location impact nanoparticle adhesion; curved and bifurcating regions favor local accumulation of drug. It is also shown that aligning drug administration with circadian rhythm and sleep cycle can enhance the efficacy of drug delivery processes. These simulations highlight the potential of the computational modeling for exploring circadian rhythm modulated blood flow for targeted drug delivery while minimizing the in vivo experimentation.

biophysics↗

bioRxiv2024

AptaGPT: Advancing aptamer design with a generative pre-trained language model

Aptamers, synthetic oligonucleotide ligands, have shown significant promise for therapeutic and diagnostic applications owing to their high specificity and affinity for target molecules. However, the conventional Systematic Evolution of Ligands by Exponential Enrichment (SELEX) for aptamer selection is time-consuming and often yields limited candidates. To address these limitations, we introduce AptaGPT, a novel computational strategy that leverages a Generative Pre-trained Transformer (GPT) model to design and optimize aptamers. By training on SELEX data from early rounds, AptaGPT generated a diverse array of aptamer sequences, which were then computationally screened for binding using molecular docking. The results of this study demonstrated that AptaGPT is an effective tool for generating potential high-affinity aptamer sequences, significantly accelerating the discovery process and expanding the potential for aptamer research. This study showcases the application of generative language models in bioengineering and provides a new avenue for rapid aptamer development.

bioinformatics↗

bioRxiv2024

Recruitment of CTCF to the SIRT1 promoter after Oxidative Stress mediates Cardioprotective Transcription

Because most DNA-binding transcription factors (dbTFs), including the architectural regulator CTCF, bind RNA and exhibit di-/multimerization, a central conundrum is whether these distinct properties are regulated post-transcriptionally to modulate transcriptional programs. Here, investigating stress-dependent activation of SIRT1, encoding an evolutionarily-conserved protein deacetylase, we show that induced phosphorylation of CTCF acts as a rheostat to permit CTCF occupancy of low-affinity promoter DNA sites to precisely the levels necessary. This CTCF recruitment to the SIRT1 promoter is eliciting a cardioprotective cardiomyocyte transcriptional activation program and provides resilience against the stress of the beating heart in vivo. Mice harboring a mutation in the conserved low-affinity CTCF promoter binding site exhibit an altered, cardiomyocyte-specific transcriptional program and a systolic heart failure phenotype. This transcriptional role for CTCF reveals that a covalent dbTF modification regulating signal-dependent transcription serves as a previously unsuspected component of the oxidative stress response.

cell biology↗

bioRxiv2024

African Swine Fever Virus Protein B263R Inhibits Autophagy by Promoting Proteasomal Degradation of Beclin1

African swine fever (ASF) is a highly contagious viral disease that affects both domestic and wild pigs, leading to substantial economic losses in the swine industry. However,the precise role of ASFV-encoded viral protein in viral replication and disease has remained elusive. In our study, we elucidated that B263R inhibited autophagy by interacting with Beclin1. Mechanistically, the binding of B263R to Beclin1 promotes its degradation through the mediation of K48-linked ubiquitination at site K31. Notably, the knockdown of Beclin1 mitigated the effect of B263R on reducing the levels of LC3-II, thus further affirming the pivotal role of Beclin1 in B263R-mediated autophagy inhibition. The proliferation of recombinant adenovirus inherently expressing B263R significantly decreased, underscoring the inherent role of B263R-mediated autophagy in virus replication. These findings shed light on the molecular mechanisms employed by ASFV to evade host cell autophagic defenses and offered potential targets for therapeutic interventions against ASFV infection. IMPORTANCEUnderstanding the mechanisms underlying the evasion of host cellular defenses by the African swine fever virus (ASFV) is of pivotal significance owing to its profound impact on the global swine industry. The precise functional roles of ASFV proteins in virus replication and disease remain incompletely characterized. In this study, it is demonstrated that a specific ASFV protein, B263R, acts to inhibit autophagy by interacting with Beclin1, thereby facilitating its degradation. The elucidation of this molecular pathway not only advances our comprehension of ASFV pathogenesis but also furnishes potential targets for therapeutic interventions against ASFV infection. By unraveling the intricate interplay between ASFV and host cell autophagy, this scholarly endeavor contributes invaluable insights to the development of strategies aimed at mitigating the spread of ASFV and minimizing its adverse repercussions on the swine industry.

microbiology↗

bioRxiv2024

Coupled metalipidomics-metagenomics reveal structurally diverse sphingolipids produced by a wide variety of marine bacteria

Microbial lipids, used as taxonomic markers and physiological indicators, have mainly been studied through cultivation. However, this approach is limited due to the scarcity of cultures of environmental microbes, thereby restricting insights into the diversity of lipids and their ecological roles. Addressing this limitation, here we apply for the first time metalipidomics combined with metagenomics in the Black Sea, classifying and tentatively identifying 1,623 lipid-like species across 18 lipid classes. We discovered over 200 novel, abundant, and structurally diverse sphingolipids in euxinic waters, including unique 1-deoxysphingolipids with long-chain fatty acids and sulfur-containing groups. Genomic analysis revealed that members of 38 bacterial phyla in the Black Sea can synthesize sphingolipids, representing a fourfold increase from previously known capabilities and accounting for up to 25% of the microbial community. These sphingolipids appear to be involved in oxidative stress response and cell wall remodeling. Our findings underscore the effectiveness of multi-omics approaches in exploring microbial chemical ecology.

microbiology↗

bioRxiv2024

Temperature-dependent Spike-ACE2 interaction of Omicron subvariants is associated with viral transmission

The continued evolution of SARS-CoV-2 requires persistent monitoring of its subvariants. Omicron subvariants are responsible for the vast majority of SARS-CoV-2 infections worldwide, with XBB and BA.2.86 sublineages representing more than 90% of circulating strains as of January 2024. In this study, we characterized the functional properties of Spike glycoproteins from BA.2.75, CH.1.1, DV.7.1, BA.4/5, BQ.1.1, XBB, XBB.1, XBB.1.16, XBB.1.5, FD.1.1, EG.5.1, HK.3 BA.2.86 and JN.1. We tested their capacity to evade plasma-mediated recognition and neutralization, ACE2 binding, their susceptibility to cold inactivation, Spike processing, as well as the impact of temperature on Spike-ACE2 interaction. We found that compared to the early wild-type (D614G) strain, most Omicron subvariants Spike glycoproteins evolved to escape recognition and neutralization by plasma from individuals who received a fifth dose of bivalent (BA.1 or BA.4/5) mRNA vaccine and improve ACE2 binding, particularly at low temperatures. Moreover, BA.2.86 had the best affinity for ACE2 at all temperatures tested. We found that Omicron subvariants Spike processing is associated with their susceptibility to cold inactivation. Intriguingly, we found that Spike-ACE2 binding at low temperature was significantly associated with growth rates of Omicron subvariants in humans. Overall, we report that Spikes from newly emerged Omicron subvariants are relatively more stable and resistant to plasma-mediated neutralization, present improved affinity for ACE2 which is associated, particularly at low temperatures, with their growth rates.

microbiology↗

bioRxiv2024

Differential tissue deformability underlies shape divergence of the embryonic brain and spinal cord under fluid pressure

An expanded brain enables the complex behaviours of vertebrates that promote their adaptation in diverse ecological niches1-3. Initial morphological differences between the brain and spinal cord emerge as the antero-posteriorly patterned neural plate folds to form the neural tube4-7 during embryonic development. Following neural tube closure, a dramatic expansion of the brain diverges its shape from the spinal cord8, setting their distinct morphologies for further development9,10. How the brain and the spinal cord expand differentially remains unclear. Here, using the chicken embryo as a model, we show that the hindbrain expands through dorsal tissue thinning under a positive hydrostatic pressure from the neural tube lumen11,12 while the dorsal spinal cord shape resists the same pressure. Using magnetic droplets and atomic force microscopy, we reveal that the dorsal tissue in the hindbrain is more fluid than in the spinal cord. The dorsal hindbrain harbours more migratory neural crest cells13 and exhibits reduced apical actin and a disorganised laminin matrix compared to the dorsal spinal cord. Blocking the activity of neural crest-associated matrix metalloproteinases inhibited dorsal tissue thinning, leading to abnormal brain morphology. Transplanting early dorsal hindbrain cells to the spinal cord was sufficient to create a region with expanded brain-like morphology including a thinned-out roof. Our findings open new questions in vertebrate head evolution and neural tube defects, and suggest a general role of mechanical pre-pattern in creating shape differences in epithelial tubes.

developmental biology↗

bioRxiv2023

Selective lipid recruitment by an archaeal DPANN symbiont from its host

The symbiont Ca. Nanohaloarchaeum antarcticus is obligately dependent on its host Halorubrum lacusprofundi for lipids and other metabolites due to its lack of certain biosynthetic genes. However, it remains unclear which specific lipids or metabolites are acquired from its host, and how the host responds to infection. Here, we explored the lipidome dynamics of the Ca. Nha. antarcticus - Hrr. lacusprofundi symbiotic relationship during co-cultivation. By using a comprehensive untargeted lipidomic methodology, our study reveals that Ca. Nha. antarcticus selectively recruits 110 lipid species from its host, i.e. nearly two-thirds of the total number of host lipids. Lipid profiles of co-cultures displayed shifts in abundances of bacterioruberins and menaquinones and changes in degree of bilayer-forming glycerolipid unsaturation. This likely results in increased membrane fluidity and improved resistance to membrane disruptions, consistent with compensation for higher metabolic load and mechanical stress on host membranes when in contact with Ca. Nha. antarcticus cells. Notably, our findings differ from previous observations of other DPANN symbiont-host systems, where no differences in lipidome composition were reported. Altogether, our work emphasizes the strength of employing untargeted lipidomics approaches to provide details into the dynamics underlying a DPANN symbiont-host system.

microbiology↗

bioRxiv2023

Pharmacologically inducing regenerative cardiac cells by small molecule drugs

Adult mammals, unlike some lower organisms, lack the ability to regenerate damaged hearts through cardiomyocytes (CMs) dedifferentiation into cells with regenerative capacity. Developing conditions to induce such naturally unavailable cells with potential to proliferate and differentiate into CMs, i.e., regenerative cardiac cells (RCCs), in mammals will provide new insights and tools for heart regeneration research. In this study, we demonstrate that a two-compound combination, CHIR99021 and A-485 (2C), effectively induces RCCs from human embryonic stem cell (hESC)-derived TNNT2+ CMs in vitro, as evidenced by lineage tracing experiments. Functional analysis shows that these RCCs express a broad spectrum of cardiogenesis genes and have the potential to differentiate into functional CMs, endothelial cells (ECs), and smooth muscle cells (SMCs). Importantly, similar results were observed in neonatal rat CMs both in vitro and in vivo. Remarkably, administering 2C in adult mouse hearts significantly enhances survival and improves heart function post-myocardial infarction. Mechanistically, CHIR99021 is crucial for the transcriptional and epigenetic activation of genes essential for RCC development, while A-485 primarily suppresses H3K27Ac and particularly H3K9Ac in CMs. Their synergistic effect enhances these modifications on RCC genes, facilitating the transition from CMs to RCCs. Therefore, our findings demonstrate the feasibility and reveal the mechanisms of pharmacological induction of RCCs from endogenous CMs, which could offer a promising regenerative strategy to repair injured hearts.

cell biology↗

bioRxiv2023

Cryptosporidium infection of human small intestinal epithelial cells induces type III interferon and impairs infectivity of Rotavirus.

Cryptosporidiosis is a major cause of severe diarrheal disease in infants from resource poor settings. The majority of infections are caused by the human-specific pathogen C. hominis and absence of in vitro growth platforms has limited our understanding of host-pathogen interactions and development of effective treatments. To address this problem, we developed a stem cell-derived culture system for C. hominis using human enterocytes differentiated under air-liquid interface (ALI) conditions. Human ALI cultures supported robust growth and complete development of C. hominis in vitro including all life cycle stages. C. hominis infection induced a strong interferon response from enterocytes, likely driven by an endogenous dsRNA virus in the parasite. Prior infection with Cryptosporidium induced type III IFN secretion and consequently blunted infection with Rotavirus, including live attenuated vaccine strains. The development of hALI provides a platform for further studies on human-specific pathogens, including clinically important coinfections that may alter vaccine efficacy.

microbiology↗