Biology subjects

Zheng, Y.

Publications and source records attributed to Zheng, Y..

At least 199 records · Page 11Linked to original sources

bioRxiv2024

Deciphering RNA regulation with a foundation language model

RNA metabolism is tightly regulated by cis-elements and trans-acting factors. Most information guiding such regulation is encoded in RNA sequences. Considering the similarities in semantic and syntactic features between RNAs and human language, we developed LAMAR, a transformer-based foundation language model for RNA regulation, to decipher general rules underlying RNA processing. The model was pretrained on approximately 15 million sequences from both genome and transcriptome of 225 mammals and 1569 viruses, and further fine-tuned with labeled datasets for various tasks. The resulting fine-tuned models outperformed the state-of-the-art methods in predicting mRNA translation efficiency and mRNA half-life, while achieving comparable accuracy to specifically designed methods in predicting splice sites of pre-mRNAs and internal ribosome entry sites. Our results indicated that a single foundation language model is applicable in the comprehensive analysis of different aspects of RNA regulation, providing new insight into the design and optimization of RNA drugs.

bioinformatics↗

bioRxiv2024

Structure and function of the yeast amino acid-sensing SEAC-EGOC supercomplex

The Seh1-associated complex (SEAC) transduces amino acid signals to the Target of Rapamycin Complex 1 (TORC1), a master regulator of cell growth located on the vacuole membrane. The SEAC acts as a GTPase activating protein (GAP) for Gtr1, a small GTPase that forms a heterodimer with Gtr2, and as part of the EGO complex (EGOC), relays nutrient signals to TORC1. The SEAC is composed of two subcomplexes, SEACIT, an inhibitor of TORC1 that contains the GAP activity, and SEACAT, that has been proposed to regulate the activity of SEACIT. However, molecular details of its regulation are unclear. Here, we determined the cryo-electron microscopy structure of the SEAC-EGOC supercomplex and studied its function in TORC1 amino acid signalling. A single SEAC can interact with two EGOC molecules via SEACIT, binding exclusively to the "active" version of the EGOC as their interaction depends on Gtr1 being loaded with GTP. SEACAT does not modulate nor interact with the EGOC. The GAP activity of the SEAC is essential for the regulation of TORC1 by amino acids, and its loss phenocopies the lack of Gtr1-Gtr2, establishing the SEAC-EGOC complex as an amino acid-sensing hub. Despite being located far from the active site, deletion of Sea2, or its N-terminal {beta}-propeller domain, also results in defects in amino acid signalling to TORC1. We propose that the SEAC-EGOC supercomplex integrates coatomer-like mechanisms of regulation via bidirectional feedback between GAP-GTPase (SEACIT-EGOC) and coat (SEACAT) modules that explain the functional interaction between Sea2 and the GAP activity. Given the conservation between the SEAC and its mammalian ortholog GATOR, we envision that this mechanism is similar in different organisms.

biochemistry↗

bioRxiv2024

Dissociable after-effects of prosocial acts: Effort is costly for others but valued for self

Engaging in prosocial behavior requires effort, yet people are often averse to exerting effort for others benefit. However, it remains unclear how effort exertion affects subsequent reward evaluation during prosocial acts. Here, we combined high-temporal-resolution electroencephalography with a paradigm that independently manipulated effort and reward for self and others to elucidate the neural mechanisms underlying the reward after-effect of prosocial effort expenditure. We found dissociable reward after-effects for self-benefiting and other-benefiting effort. For self-benefiting rewards, the reward positivity (RewP) increased with effort demand, suggesting an effort-enhancement effect. In contrast, for other-benefiting rewards, the RewP decreased as effort increased, demonstrating an effort-discounting effect. Critically, this dissociation was contingent upon high reward magnitude and modulated by individual differences in effort discounting, yet remained distinct from performance evaluation. Our findings reveal distinct neural computations for self- and other-benefiting efforts, offering new insights into how prior effort expenditure shapes reward evaluation during prosocial behavior.

neuroscience↗

bioRxiv2024

Single-cell proteomics of pre-implantation mouse embryos uncovers distinct asymmetry of certain proteins among early blastomeres

During pre-implantation mouse embryonic development, blastomeres undergo division and differentiation, reaching a distinctive level of heterogeneity, hence the completion of the first cell fate determination. However, when the initial asymmetry emerges and how this heterogeneity amplifies, particularly at the protein level, remain elusive. Here, by mass spectrometry-based single-blastomere proteomics, we identified proteins exhibiting significant heterogeneity in abundance among mouse blastomeres as early as the 2-cell stage. Differential gene expression among blastomeres, as indicated by intra-embryo variation in RNA abundance detected through single-cell RNA sequencing, was insufficient to fully explain the corresponding disparities in protein abundance. Instead, the asymmetric distribution of protein molecules during cell division was observed, serving as another mechanism contributing to protein heterogeneity, independent of RNA expression.

developmental biology↗

bioRxiv2024

Tumor-induced endothelial RhoA activation mediates tumor cell transendothelial migration and metastasis

Abstract/SummaryThe endothelial barrier plays an active role in transendothelial tumor cell migration during metastasis, however, the endothelial regulatory elements of this step remain obscure. Here we show that endothelial RhoA activation is a determining factor during this process. Breast tumor cell-induced endothelial RhoA activation is the combined outcome of paracrine IL-8-dependent and cell-to-cell contact {beta}1 integrin-mediated mechanisms, with elements of this pathway correlating with clinical data. Endothelial-specific RhoA blockade or in vivo deficiency inhibited the transendothelial migration and metastatic potential of human breast tumor and three murine syngeneic tumor cell lines, similar to the pharmacological blockade of the downstream RhoA pathway. These findings highlight endothelial RhoA as a potent, universal target in the tumor microenvironment for anti-metastatic treatment of solid tumors.

physiology↗

bioRxiv2024

The exit of naïve pluripotency contains a lipid metabolism-induced checkpoint for genome integrity.

Pluripotent progenitors undergo dramatic cellular and biochemical transformations during peri-implantation development. These large-scale reprogramming events are fundamental for subsequent differentiation, but how they are integrated and co-ordinated with the preservation of genome integrity remain unknown. Here, we uncover a metabolism-induced telomere checkpoint that takes place in pluripotent progenitors as they form rosette-like epithelial structures. We show that the glycolytic switch at the exit of naive pluripotency is preceded by an acceleration of mitochondrial respiration and de novo lipogenesis, fuelling the accumulation of lipid droplets required for morphogenesis. We find that downstream of these CIDEA-promoted metabolic events is the induction of ZSCAN4, a key pluripotency-associated regulator of telomere stability. Surprisingly, the build-up of lipid droplets corresponds to a transient shortening of telomeres, which triggers the activation of an elongation mechanism via ZSCAN4. Thus, telomere homeostasis can be safeguarded as essential lipid metabolic reprogramming unfolds to drive developmental progression.

developmental biology↗

bioRxiv2024

AusAMF: database of arbuscular mycorrhizal fungal communities in Australia

MotivationArbuscular mycorrhizal (AM) fungi are integral to plant nutrient acquisition, carbon cycling, and ecosystem resilience, yet our knowledge of their biogeography is severely limited, especially in the Southern Hemisphere. Australia, despite its landmass and unique geoecological characteristics, has been vastly undersampled, leaving a significant gap in our understanding of AM fungal diversity and distribution. The AusAMF database was created to address this deficiency, the first release comprises AM fungal community data from 610 sampling locations across mainland Australia and Tasmania, collected between 2011 and 2023. Using standardised sampling, DNA extraction, sequencing methods and platforms, this database provides a robust resource for exploring spatial patterns in AM fungal diversity, community composition, and the ecological drivers shaping AM fungal biogeography. The AusAMF database will continue to be updated and maintain standardised approaches to facilitate future research into plant-mycorrhizal interactions, nutrient cycling, and to understand the broader role of AM fungi in ecosystem processes. The data here will provide the foundation for more informed management and conservation efforts in Australia while providing valuable data for global-scale analyses. Main types of variables containedGeoreferenced occurrence and abundance of high-throughput amplicon sequences of arbuscular mycorrhizal (AM) fungi. Spatial location and grainAustralia. Decimal degrees between 0.000001 - 0.1 resolution. Time period and grain2011-2023. Month and year of sampling. Major taxa and level of measurementArbuscular mycorrhizal fungi identified to family, genus, and virtual taxon (VT). Geographic occurrence and amplicon sequence abundance. Software formatInteract with data via online application. Dataset available as .csv files and raw sequencing data as .fastq files.

ecology↗

bioRxiv2024

Molecular recording of cellular protein kinase activity with chemical labeling

Protein kinases control most cellular processes and aberrant kinase activity is involved in numerous diseases. To investigate the link between specific kinase activities and cellular phenotypes in heterogeneous cell populations and in vivo, we introduce molecular recorders of kinase activities for later analysis. Based on split-HaloTag and a phosphorylation-dependent molecular switch, our recorders become rapidly labeled in the presence of a specific kinase activity and a fluorescent HaloTag substrate. The kinase activity in a given cell controls the degree of fluorescent labeling whereas the recording window is set by the presence of the fluorescent substrate. We have designed specific recorders for four protein kinases, including protein kinase A. We apply our protein kinase A recorder for the sorting of heterogeneous cell populations and subsequent transcriptome analysis, in genome-wide CRISPR screens to discover regulators of PKA activity and for the tracking of neuromodulation in freely moving mice.

biochemistry↗

bioRxiv2024

Astrocyte-derived MFG-E8 facilitates microglial synapse elimination in Alzheimer's disease mouse models

Region-specific synapse loss is an early pathological hallmark in Alzheimers disease (AD). Emerging data in mice and humans highlight microglia, the brain-resident macrophages, as cellular mediators of synapse loss; however, the upstream modulators of microglia-synapse engulfment remain elusive. Here, we report a distinct subset of astrocytes, which are glial cells essential for maintaining synapse homeostasis, appearing in a region-specific manner with age and amyloidosis at onset of synapse loss. These astrocytes are distinguished by their peri-synaptic processes which are bulbous in morphology, contain accumulated p62-immunoreactive bodies, and have reduced territorial domains, resulting in a decrease of astrocyte-synapse coverage. Using integrated in vitro and in vivo approaches, we show that astrocytes upregulate and secrete phagocytic modulator, milk fat globule-EGF factor 8 (MFG-E8), which is sufficient and necessary for promoting microglia-synapse engulfment in their local milieu. Finally, we show that knocking down Mfge8 specifically from astrocytes using a viral CRISPR-saCas9 system prevents microglia-synapse engulfment and ameliorates synapse loss in two independent amyloidosis mouse models of AD. Altogether, our findings highlight astrocyte-microglia crosstalk in determining synapse fate in amyloid models and nominate astrocytic MFGE8 as a potential target to ameliorate synapse loss during the earliest stages of AD.

neuroscience↗

bioRxiv2024

Fornix and Uncinate Fasciculus Support Metacognition-Driven Cognitive Offloading

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

neuroscience↗

bioRxiv2024

Orally surface engineered probiotic system for ulcerative colitis therapy via modulating gut microbiota and immune homeostasis

Oral probiotics have emerged as a promising therapeutical strategy for effectively managing ulcerative colitis (UC) in the world. The existing researches successfully preserve probiotic viability in the upper gastrointestinal tract, but they fall short in achieving precise release profile and effective colonization of probiotics at the site of colitis in colon as well as the understanding of therapeutic mechanism with suboptimal efficacy. This constraint poses a significant barrier to rational design and effective development of oral probiotic system. Here, we fabricate an orally layered-by-layered probiotic (Escherichia coli Nissle 1917, EcN) system (so-called CML@EcN) based on carboxymethyl modified lignin (CML) which can significantly protect EcN in gastric and small intestinal microenvironment and efficiently control release EcN in colon. Interestingly, the release and proliferation process of EcN in the colon are detected and can be modeled as a plug-flow mode. We derive a mathematical expression that highly matches the experimental results, providing a theoretical basis for quantitatively calculation of the release process. Furthermore, CML@EcN significantly alleviates symptoms in dextran sulfate sodium (DSS)-induced UC mice by modulating the multiple organ immune disorder and gut microbiota (GM)/metabolites profile as well as reconstructing the colon barrier. Importantly, we explore the mechanism of immune homeostasis regulation via metabolism from GM. Moreover, the CML armour is excreted and would not influence the process. This work not only reports a novel oral therapeutic for UC treatment with high efficacy as well as the exploration of mechanism between GM and immune homeostasis, but also provides a general approach to engineer probiotics for oral administration.

microbiology↗

bioRxiv2024

A Hippocampal-parietal Network for Reference Frame Coordination

Navigating space and forming memories based on spatial experience are crucial for survival, including storing memories in an allocentric (map-like) framework and conversion into body-centered action. The hippocampus and parietal cortex (PC) comprise a network for coordinating these reference frames, though the mechanism remains unclear. We used a task requiring remembering previous spatial locations to make correct future action and observed that hippocampus can encode the allocentric place, while PC encodes upcoming actions and relays this to hippocampus. Transformation from location to action unfolds gradually, with Came From signals diminishing and future action representations strengthening. PC sometimes encodes previous spatial locations in a route-based reference frame and conveys this to hippocampus. The signal for the future location appears first in PC, and then in hippocampus, in the form of an egocentric direction of future goal locations, suggesting egocentric encoding recently observed in hippocampus may originate in PC (or another "upstream" structure). Bidirectional signaling suggests a coordinated mechanism for integrating map-like, route-centered, and person-centered spatial reference frames at the network level during navigation.

neuroscience↗

bioRxiv2024

Achieve Handle Level Random Access in Encrypted DNA Archival Storage System via Frequency Dictionary Mapping Coding

DNA as a storage medium has the characteristics of high storage density and durability, but the existing DNA storage system has a high latency, and lacks the consideration of data security. In order to improve the availability of DNA storage, this paper proposes that Frequency Dictionary Mapping Coding (FDMC) implements handle-level random access in DNA Archival storage, and a hybrid e-molecular encryption strategy and multi-level error correction algorithm are provided to ensure data security and integrity. The results of the simulation and wet experiments demonstrate that FDMC can achieve handle-level random access in lossless encrypted DNA storage systems, which balances security and convenience. In terms of read and write consistency, FDMC has significant advantages in storage density and robustness of data recovery. Even in the extreme case of DNA sequence loss of 10%, it can still recover 91.74% of the original data while ensuring storage density above 1.80 bits/nt. In summary, FDMC improves the application range of DNA as a storage medium and bridges the gap between DNA storage and traditional storage modes in the storage and reading of large-scale archives.

bioengineering↗

bioRxiv2024

Exploiting functional regions in the viral RNA genome as druggable entities

RNA-targeting compounds or small interfering RNAs (siRNAs) offer a potent means for controlling viral infections. An essential prerequisite to their design depends on identifying conserved and functional viral RNA structures in cells. Techniques that probe RNA structures in situ have been developed recently including SHAPE-MaP, which has been helpful in analyzing the secondary structures of RNA. In this study, we report on the application of SHAPE-MaP to the Porcine Epidemic Diarrhoea Virus (PEDV) RNA genome to categorize different functional regions including potential quadruplex forming sequence and target sites of siRNA. Our results show that these structures can be exploited to inhibit viral proliferation and that SHAPE-MaP is an effective method to the identification of secondary structures in RNA genomes.

genomics↗

bioRxiv2024

A transgene-free, human peri-gastrulation embryo model with trilaminar embryonic disc-, amnion- and yolk sac-like structures

The ultimate outcome of the gastrulation in mammalian development is a recognizable trilaminar disc structure containing organized cell lineages with spatially defined identities in an emerging coordinate system1-4. Despite its importance in human development, gastrulation remains difficult to study. Stem cell-based embryo models, including those that recapitulate different aspects of pre- and peri-gastrulation human development5-15, are emerging as promising tools for studying human embryogenesis16-18. However, it remains unclear whether existing human embryo models are capable of modeling the development of the trilaminar embryonic disc structure, a hallmark of human gastrulation. Here we report a transgene-free human embryo model derived solely from primed human pluripotent stem cells (hPSCs), which recapitulates various aspects of peri-gastrulation human development, including formation of trilaminar embryonic layers situated between dorsal amnion and ventral definitive yolk sac and primary hematopoiesis. We term this model the peri-gastrulation trilaminar embryonic disc (PTED) embryoid. The development of PTED embryoid does not follow natural developmental sequences of cell lineage diversification or spatial organization. Instead, it exploits both extrinsic control of tissue boundaries and intrinsic self-organizing properties and embryonic plasticity of the diverse peri-gastrulation-stage cell lineages, leading to the emergence of in vivo-like tissue organization and function at a global scale. Our lineage tracing study reveals that in PTED embryoids, embryonic and extraembryonic mesoderm cells, as well as embryonic and extraembryonic endoderm cells, share common progenitors emerging during peri-gastrulation development. Active hematopoiesis and blood cell generation are evident in the yolk sac-like structure of PTED embryoids. Together, PTED embryoids provide a promising and ethically less challenging model for studying self-organizing properties of peri-gastrulation human development.

developmental biology↗

bioRxiv2024

FourierMIL: Fourier filtering-based multiple instance learning for whole slide image analysis

Recent advancements in computer vision, driven by convolutional neural network, multilayer perceptron and transformer architectures, have significantly improved the analysis on natural images. Despite their potential, the application of these architectures in digital pathology, specifically for analyzing gigapixel-resolution whole-slide images (WSIs), remains challenging due to the extensive and variable sizes of these images. Here we present a multiple instance learning framework that leverages the discrete Fourier transform and learns from WSIs. Dubbed as FourierMIL, our framework is designed to capture both global and local dependencies within WSIs. To validate the efficacy of our model, we conducted extensive experiments on a prevalent computational pathology challenge: tumor classification. Our results demonstrate that FourierMIL outperforms existing state-of-the-art methods, marking a significant advancement in the field of digital pathology and highlighting the potential of attention-free architectures in managing the complexities related to WSI analysis. The code will be released for public access upon the manuscripts acceptance.

bioinformatics↗

bioRxiv2024

The Identification Markers of activated myofibroblast subsets in the Human Lung Fibrosis Ecosystem via integrated omics Analysis

BackgroundThe aberrant remodeling of the extracellular matrix (ECM) is closely associated with lung fibrosis. However, the mechanisms underlying ECM remodeling in pulmonary fibrosis (PF) remain unclear. The advent of single-cell RNA sequencing (scRNA-seq) has provided valuable insights into the diverse phenotypic and functional characteristics of human PF. Nevertheless, the dynamic of ECM remodeling in terms of ECM synthesizing and the potential activating markers of myofibroblasts in the human PF microenvironment still needs to be investigated. MethodsWe performed integrative scRNA-seq analyses on high-fidelity PF data from a public platform by filtering out the low-quality counts and doublets using two doublet prediction methods. Next, we investigated the dynamic of the ECM signature in diverse cells in PF and screened the potential markers of myofibroblasts via fitting a successful polynomial regression model. Finally, the markers of activated myofibroblasts were identified using bulk RNA-seq of pulmonary tissue. ResultsFirst, we depicted the pathogenic landscape and demonstrated the heterogeneity of ECM in PF by integratively analyzing single-cell RNA-seq data, and we hypothesized that myofibroblasts played a significant role in ECM formation. Second, our results successfully displayed the biological dynamic changes of ECM and investigated the 73 positive correlated genes of myofibroblasts in PF via a polynomial regression model. Then, the bulk RNA-seq results further identified eight new activating markers of myofibroblasts, such as MFAP2, MXRA5, and LRRC17 via transcriptomic signature, correlation and ROC scores. Finally, the results of cell-cell interaction indicated that myeloid cells may be involved in regulating ECM remodeling through proliferation mediated by myofibroblasts that secrete POSTN, suggesting that ECM remodeling in PF is a complex and multi-participated process. ConclusionsIn summary, we provided insights into the contributions of ECM in human PF by integrative analysis and highlighted potential clinical utilities of myofibroblast subsets as therapeutic targets.

bioinformatics↗

bioRxiv2024

Genomic and single-cell characterization of patient-derived tumor organoid models of head and neck squamous cell carcinoma

Head and Neck Squamous Cell Carcinoma (HNSCC) remains a significant health burden due to tumor heterogeneity and treatment resistance, emphasizing the need for improved biological understanding and tailored therapies. This study enrolled 31 HNSCC patients for the establishment of patient-derived tumor organoids (PDOs), which faithfully maintained genomic features and histopathological traits of primary tumors. Long-term culture preserved key characteristics, affirming PDOs as robust representative models. PDOs demonstrated predictive capability for cisplatin treatment responses, correlating ex vivo drug sensitivity with patient outcomes. Bulk and single-cell RNA sequencing unveiled molecular subtypes and intratumor heterogeneity (ITH) in PDOs, paralleling patient tumors. Notably, a hybrid epithelial-mesenchymal transition (hEMT)-like ITH program is associated with cisplatin resistance and poor patient survival. Functional analyses identified amphiregulin (AREG) as a potential regulator of the hybrid epithelial/mesenchymal state. Moreover, AREG contributes to cisplatin resistance via EGFR pathway activation, corroborated by clinical samples. In summary, HNSCC PDOs serve as reliable and versatile models, offer predictive insights into ITH programs and treatment responses, and uncover potential therapeutic targets for personalized medicine. One Sentence SummaryThis study establishes patient-derived tumor organoids (PDOs) from 31 Head and Neck Squamous Cell Carcinoma (HNSCC) patients, faithfully recapitulating characteristics of primary tumors and accurately predicting clinical responses to cisplatin treatment. We reveal intertumoral heterogeneity within PDOs and a hybrid epithelial-mesenchymal transition (hEMT) program conferring cisplatin resistance, highlighting amphiregulin (AREG) as a regulator of cellular plasticity and potential therapeutic target for HNSCC treatment.

cancer biology↗