Biology subjects

Song, Y.

Publications and source records attributed to Song, Y..

At least 217 records · Page 12Linked to original sources

bioRxiv2023

Quantitative Learning of Cellular Features From Single-cell Transcriptomics Data Facilitates Effective Drug Repurposing

In this study, we have devised a computational framework SuperFeat that allows for the training of a machine learning model and evaluate the canonical cellular states/features in pathological tissues that underlie the progression of disease. This framework also enables the identification of potential drugs that target the presumed detrimental cellular features. This framework was constructed on the basis of an artificial neural network with the gene expression profiles serving as input nodes. The training data comprised single-cell RNA-seq datasets that encompassed the specific cell lineage during the developmental progression of cell features. A few models of the canonical cancer-involved cellular states/features were tested by such framework. Finally, we have illustrated the drug repurposing pipeline, utilizing the training parameters derived from the adverse cellular states/features, which has yielded successful validation results both in vitro and in vivo. SuperFeat is accessible at https://github.com/weilin-genomics/rSuperFeat.

cell biology↗

bioRxiv2023

Stratification of enterochromaffin cells by single-cell expression analysis

Dynamic interactions between gut mucosal cells and the external environment are essential to maintain gut homeostasis. Enterochromaffin (EC) cells transduce both chemical and mechanical signals and produce 5-hydroxytryptamine (5-HT) to mediate disparate physiological responses. However, the molecular and cellular basis for functional diversity of ECs remains to be adequately defined. Here, we integrated single-cell transcriptomics with spatial image analysis to identify fourteen EC clusters that are topographically organized along the gut. Subtypes predicted to be sensitive to the chemical environment and mechanical forces were identified that express distinct transcription factors and hormones. A Piezo2+ population in the distal colon was endowed with a distinctive neuronal signature. Using a combination of genetic, chemogenetic and pharmacological approaches, we demonstrated Piezo2+ ECs are required for normal colon motility. Our study constructs a molecular map for ECs and offers a framework for deconvoluting EC cells with pleiotropic functions.

cell biology↗

bioRxiv2023

Mining alternative splicing patterns in scRNA-seq data using scASfind

Single-cell RNA-seq is widely used for transcriptome profiling, but most analyses have focused on gene-level events, with much less attention devoted to alternative splicing. Here, we present scASfind, a novel computational method to allow for quantitative analysis of cell type-specific splicing events. scASfind utilizes an efficient data structure to store the percent spliced-in value for each splicing event. This makes it possible to exhaustively search for patterns among all differential splicing events, allowing us to identify marker events, mutually exclusive events, and large blocks of exons that are specific to one or more cell types. These methods allow researchers to compare cells based on isoforms rather than genes, thereby enabling more nuanced characterization of cell types and states. We demonstrate the advantages of scASfind on two mouse and one human datasets, identifying differences across the several key genes that cannot be detected using gene expression alone.

bioinformatics↗

bioRxiv2023

Russula (Basidiomycota, Russulales, Russulaceae) subsect. Roseinae down under.

The present contribution presents species of Russula subsect. Roseinae Sarnari from the southern hemisphere. Russula incrustata Buyck, sp. nov. and R. koniamboensis Buyck, sp. nov. are described from New Caledonia, R. purpureotincta R. F. R. McNabb from New Zealand is redescribed in detail and two secotioid species, R. albobrunnea T. Lebel from Australia and R. kermesina (R. F. R. McNabb) T. Lebel from New Zealand are shown to be the first known secotioid taxa in Roseinae. The systematic placement and importance of these southern taxa is discussed.

molecular biology↗

bioRxiv2023

Comparative single-nucleus RNA-seq analysis captures shared and distinct responses to beneficial and pathogenic microbes in roots

Distinguishing and differentially responding to beneficial and pathogenic microbes are fundamental for plants to maintain microbiome homeostasis and promoting plant fitness. Using a recently developed protoplast-free single-nucleus RNA-seq approach, we generated single-cellular atlas of root responses to beneficial and pathogenic microbes. Notably, we identified triterpene biosynthesis as a novel cell type specific response to root pathogens and genetically confirmed the role of triterpene biosynthesis in regulating beneficial/pathogenic microbe ratios in a two-strain mixed community. Our results provide novel insights and vital resources for further elucidating novel regulators of beneficial and pathogenic microbe colonization and microbiome homeostasis.

plant biology↗

bioRxiv2023

Seed tuber imprinting shapes the next-generation potato microbiome

Potato seed tubers are colonized and inhabited by soil-borne microbes, some of which can positively or negatively impact the performance of the emerging daughter plant in the next season. In this study, we investigated the intergenerational inheritance of microbiota from seed tubers to next-season daughter plants by amplicon sequencing of bacterial and fungal microbiota associated with tubers and roots of two seed potato genotypes produced in six different fields. We observed that field of production and potato genotype significantly affected the seed tuber microbiome composition and that these differences persisted during winter storage of the seed tubers. When seed tubers from different production fields were planted in a single trial field, the microbiomes of daughter tubers and roots of the emerging plants could still be distinguished according to the field of origin of the seed tuber. Remarkably, we found little evidence of direct vertical inheritance of field-unique microbes from the seed tuber to the daughter tubers or roots. Hence, we hypothesize that this intergenerational "memory" is imprinted in the seed tuber, resulting in differential microbiome assembly strategies depending on the field of production of the seed tuber.

microbiology↗

bioRxiv2023

miRNA-encoded regulatory peptides modulate cadmium tolerance and accumulation in rice

MicroRNAs (miRNAs) are small non-coding RNAs that play a vital role in plant responses to abiotic and biotic stress. Recently, it has been discovered that some primary miRNAs (pri-miRNAs) encode regulatory short peptides called miPEPs. However, the presence of miPEPs in rice, and their functions in response to abiotic stress, particularly stress induced by heavy metals, remain poorly understood. Here, we identified a functional small peptide (miPEP156e) encoded by pri-miR156e that regulates the expression of miR156 and its target SPL genes, thereby affecting miR156-mediated cadmium (Cd) tolerance in rice. Overexpression of miPEP156e led to a reduction in the accumulation of reactive oxygen species (ROS) and Cd in plants under Cd stress, resulting in improved rice Cd tolerance, as observed in miR156-overexpressing lines and seedlings treated with exogenous miPEP156e. In contrast, miPEP156e mutants displayed sensitivity to Cd stress due to the elevated accumulation of ROS and Cd. Transcriptome analysis further revealed that miPEP156e improved rice Cd tolerance by modulating Cd transporter and ROS scavenging genes. Moreover, we identified five novel miPEPs involved in regulating Cd resistance through exogenous treatment of seedlings with synthetic corresponding miPEPs. Our study provides insights into the regulatory mechanism of miPEP156e in rice response to Cd stress and demonstrates the potential of miPEPs as an effective tool for improving crop abiotic stress tolerance.

plant biology↗

bioRxiv2023

CircRNAs and their regulatory networks associated with the antioxidant enzymes and immune responses of Asian honey bee larvae to fungal infection

Non-coding RNA (ncRNA) plays an important role in the regulation of immune responses, growth, and development in plants and animals. Here, the identification, characteristic investigation, and molecular verification of circRNAs in Apis cerana cerana larval guts were conducted, and the expression pattern of larval circRNAs during Ascosphaera apis infection was analyzed. This was followed by exploration of the potential regulatory part of differentially expressed circRNAs (DEcircRNAs) in host immune responses. A total of 3178 circRNAs in the larval guts of A. c. cerana were identified, with a length distribution ranging from 15 nt to 96007 nt. Additionally, 45, 33, and 48 up-regulated circRNAs, as well as 110, 62, and 38 down-regulated circRNAs were identified in the A.-apis-inoculated 4-, 5-, and 6-day-old larval guts in comparison with the corresponding uninoculated larval guts. These DEcircRNAs were predicted to target 29, 25, and 18 parental genes, which were relative to 12, 20, and 17 GO terms as well as 144, 114, and 61 KEGG pathways, including five cellular and four humoral immune pathways containing melanization, phagosomes, lysosomes, endocytosis, apoptosis, MAPK, Ras, and Jak-STAT signaling pathways. Furthermore, complex competing endogenous RNA (ceRNA) regulatory networks were detected as being formed among DEcircRNAs, DEmiRNAs, and DEmRNAs. The target DEmRNAs were engaged in 36, 47, and 47 GO terms as well as 331, 332, and 331 pathways, including six cellular and six humoral immune-related pathways. In total, nineteen DEcircRNAs, five DEmiRNAs, and three mRNAs were included in the sub-networks relative to three antioxidant enzymes, including superoxide dismutase (SOD), catalase (CAT), and glutathione S-transferase (GST). Finally, back-splicing sites within 15 circRNAs and the difference in the 15 DEcircRNAs expression between uninoculated and A.-apis-inoculated larval guts were confirmed utilizing molecular methods. These findings not only enrich our understanding of bee host-fungal pathogen interactions, but also lay a foundation for illuminating the mechanism underlying the DEcircRNA-mediated immune defense of A. c. cerana larvae against A. apis invasion.

molecular biology↗

bioRxiv2023

Complex epistatic interactions between ELF3, PRR9, and PRR7 regulates the circadian clock and plant physiology

Circadian clocks are endogenous timekeeping mechanisms that coordinate internal physiological responses with the external environment. EARLY FLOWERING3 (ELF3), PSEUDO RESPONSE REGULATOR (PRR9), and PRR7 are essential components of the plant circadian clock and facilitate entrainment of the clock to internal and external stimuli. Previous studies have highlighted a critical role for ELF3 in repressing the expression of PRR9 and PRR7. However, the functional significance of activity in regulating circadian clock dynamics and plant development is unknown. To explore this regulatory dynamic further, we firstly employed mathematical modelling to simulate the effect of the prr9/prr7 mutation on the elf3 circadian phenotype. These simulations suggested that simultaneous mutations in prr9/prr7 could rescue the elf3 circadian arrythmia. Following these simulations, we generated all Arabidopsis elf3/prr9/prr7 mutant combinations and investigated their circadian and developmental phenotypes. Although these assays could not replicate the results from the mathematical modelling, our results have revealed a complex epistatic relationship between ELF3 and PRR9/7 in regulating different aspects of plant development. ELF3 was essential for hypocotyl development under ambient and warm temperatures, while PRR9 was critical for root thermomorphogenesis. Finally, mutations in prr9 and prr7 rescued the photoperiod insensitive flowering phenotype of the elf3 mutant. Together, our results highlight the importance of investigating the genetic relationship amongst plant circadian genes.

plant biology↗

bioRxiv2023

Accurately identifying nucleic-acid-binding sites through geometric graph learning on language model predicted structures

The interactions between nucleic acids and proteins are important in diverse biological processes. The high-quality prediction of nucleic-acid-binding sites continues to pose a significant challenge. Presently, the predictive efficacy of sequence-based methods is constrained by their exclusive consideration of sequence context information, whereas structure-based methods are unsuitable for proteins lacKing Known tertiary structures. Though protein structures predicted by AlphaFold2 could be used, the extensive computing requirement of AlphaFold2 hinders its use for genome-wide applications. Based on the recent breaKthrough of ESMFold for fast prediction of protein structures, we have developed GLMSite, which accurately identifies DNA and RNA-binding sites using geometric graph learning on ESMFold predicted structures. Here, the predicted protein structures are employed to construct protein structural graph with residues as nodes and spatially neighboring residue pairs for edges. The node representations are further enhanced through the pre-trained language model ProtTrans. The networK was trained using a geometric vector perceptron, and the geometric embeddings were subsequently fed into a common networK to acquire common binding characteristics. Then two fully connected layers were employed to learn specific binding patterns for DNA and RNA, respectively. Through comprehensive tests on DNA/RNA benchmarK datasets, GLMSite was shown to surpass the latest sequence-based methods and be comparable with structure-based methods. Moreover, the prediction was shown useful for the inference of nucleic-acid-binding proteins, demonstrating its potential for protein function discovery. The datasets, codes, together with trained models are available at https://github.com/biomed-AI/nucleic-acid-binding.

bioinformatics↗

bioRxiv2023

BOston Neonatal Brain Injury Dataset for HypoxicIschemic Encephalopathy (BONBID-HIE): Part I. MRI and Manual Lesion Annotation

Hypoxic ischemic encephalopathy (HIE) is a brain injury that occurs in 1 [~]5/1000 term neonates. Accurate identification and segmentation of HIE-related lesions in neonatal brain magnetic resonance images (MRIs) is the first step toward predicting prognosis, identifying high-risk patients, and evaluating treatment effects. It will lead to a more accurate estimation of prognosis, a better understanding of neurological symptoms, and a timely prediction of response to therapy. We release the first public dataset containing neonatal brain diffusion MRI and expert annotation of lesions from 133 patients diagnosed with HIE. HIE-related lesions in brain MRI are often diffuse (i.e., multi-focal), and small (over half the patients in our data having lesions occupying <1% of brain volume). Segmentation for HIE MRI data is remarkably different from, and arguably more challenging than, other segmentation tasks such as brain tumors with focal and relatively large lesions. We hope that this dataset can help fuel the development of MRI lesion segmentation methods for HIE and small diffuse lesions in general.

neuroscience↗

bioRxiv2023

Pancreatic Tumor-Derived Extracellular Vesicles Stimulate Schwann Cell Phenotype Indicative of Perineural Invasion via IL-8 Signaling

Pancreatic cancer remains a pre-eminent cause of cancer-related deaths with late-stage diagnoses leading to an 11% five-year survival rate. Moreover, perineural invasion (PNI), in which cancer cells migrate into adjacent nerves, occurs in an overwhelming majority of patients, further enhancing tumor metastasis. PNI has only recently been recognized as a key contributor to cancer progression; thus, there are insufficient treatment options for the disease. Attention has been focused on glial Schwann cells (SC) for their mediation of pancreatic PNI. Under stress, SCs dedifferentiate from their mature state to facilitate the repair of peripheral nerves; however, this signaling can also re-direct cancer cells to accelerate PNI. Limited research has explored the mechanism that causes this shift in SC phenotype in cancer. Tumor-derived extracellular vesicles (TEV) have been implicated in other avenues of cancer development, such as pre-metastatic niche formation in secondary locations, yet how TEVs contribute to PNI has not been fully explored. In this study, we highlight TEVs as initiators of SC activation into a PNI-associated phenotype. Proteomic and pathway assessments of TEVs revealed an elevation in interleukin-8 (IL-8) signaling and nuclear factor kappa B (NF{kappa}B) over healthy cell-derived EVs. TEV-treated SCs exhibited higher levels of activation markers, which were successfully neutralized with IL-8 inhibition. Additionally, TEVs increased NF{kappa}B subunit p65 nuclear translocation, which may lead to increased secretion of cytokines and proteases indicative of SC activation and PNI. These findings present a novel mechanism that may be targeted for the treatment of pancreatic cancer PNI. Statement of SignificanceIdentifying pancreatic tumor extracellular vesicles as key players in Schwann cell activation and perineural invasion by way of IL-8 will educate for more specialized and effective targets for an under-valued disease.

cancer biology↗

bioRxiv2023

Hypothalamic neuronal activation in primates drives naturalistic goal-directed eating behavior

Eating addiction is the primary cause of modern obesity. Although the causal role of the lateral hypothalamic area (LHA) for eating is demonstrated in rodents, there is no evidence in primates regarding naturalistic eating behaviors. We investigated the role of LHA GABAergic (LHAGABA) neurons in eating by chemogenetics in three macaques. LHAGABA neuron activation significantly increased naturalistic goal-directed behaviors and food motivation, which was specific for palatable food. PET and MRS validated the chemogenetic activation. Rs-fMRI result revealed that functional connectivity (FC) between the LHA and frontal areas was increased, while the FC between the frontal cortices was decreased after the LHAGABA neuron activation. Thus, our study elucidates the role of LHAGABA neurons in eating and obesity therapeutics for primates and humans.

neuroscience↗

bioRxiv2023

HUWE1 Amplifies Ubiquitin Modifications to Broadly Stimulate Clearance of Proteins and Aggregates

Selective breakdown of proteins and aggregates is crucial for maintaining normal cellular activities and is involved in the pathogenesis of diverse diseases. How the cell recognizes and tags these targets in different structural states for degradation by the proteasome and autophagy pathways has not been well understood. Here, we discovered that a HECT-family ubiquitin ligase HUWE1 is broadly required for the efficient degradation of soluble factors and for the clearance of protein aggregates/condensates. Underlying this capacity of HUWE1 is a novel Ubiquitin-Directed ubiquitin Ligase (UDL) activity which recognizes both soluble substrates and aggregates that carry a high density of ubiquitin chains and rapidly expand the ubiquitin modifications on these targets. Ubiquitin signal amplification by HUWE1 recruits the ubiquitin-dependent segregase p97/VCP to process these targets for subsequent degradation or clearance. HUWE1 controls the cytotoxicity of protein aggregates, mediates Targeted Protein Degradation and regulates cell-cycle transitions with its UDL activity.

molecular biology↗

bioRxiv2023

Beclin1-Deficient Adipocytes Promote Tumor Progression by YAP/TAZ-dependent Adipocyte Transformation

Adipocytes are crucial components of the tumor microenvironment (TME) that play a prominent role in supporting tumor growth. However, the characteristics of cancer-associated adipocytes (CAAs) that contribute to the pro-tumorigenic niche remain to be fully established. Here, we used adipocyte-specific Beclin1 KO (BaKO) mice to investigate the role of maladaptive adipocytes in promoting tumor progression. BECN1-deficient adipocytes exhibited downregulation of adipogenic markers and activation of YAP/TAZ signaling, similar to the traits observed in CAAs. Thus, we generated adipocyte-specific Becn1/Yap1/Taz KO mice, which exhibit markedly restored phenotypes in adipose tissue, resulting in tumor regression compared to that in BaKO. Further, we observed dysregulation of the BECN1-YAP/TAZ axis in the adipose tissue of mice fed a high-fat diet (HFD). Treatment with the YAP/TAZ inhibitor, verteporfin, suppressed tumor progression in BaKO and HFD-fed mice, highlighting its efficacy against mice with metabolic dysregulation. Our findings provide insights into CAA formation and its significance in determining malignant TME, thereby suggesting a potential dual therapeutic strategy simultaneously targeting adipocyte homeostasis and cancer growth.

biochemistry↗

bioRxiv2023

The transcription factor OsbZIP48 governs rice responses to zinc deficiency

Zinc deficiency is the most prevalent micronutrient disorder in rice and leads to delayed development and decreased yield. Nevertheless, despite its primary importance, how rice responds to zinc deficiency remains poorly understood. Herein, we present genetic evidence that OsbZIP48 is essential for regulating rice responses to zinc deficiency. Using the reverse genetics approach, genetic inactivation of OsbZIP48 in rice seedlings caused a hyper sensitivity to zinc deficiency, associated with a significant decrease in the root-to-shoot translocation of zinc. Consistently, OsbZIP48 was constitutively expressed in roots, slightly induced by zinc deficiency in shoots, and localized into nuclei induced by Zn deficiency. Comparative transcriptome analysis of the wild-type plants and osbzip48 mutant grown under zinc deficiency enabled the identification of OsbZIP48 target genes, including key zinc transporter genes (OsZIP4 and OsZIP8). We demonstrated that OsbZIP48 controlled the expressions of these genes by directly binding to their promoters, specifically to the zinc deficiency response element (ZDRE) motif. Collectively, we showed that the OsbZIP48 gene encodes for a transcription factor in rice, and demonstrates its critical role in the response to zinc deficiency in this crop. This knowledge is crucial for the design of rice plants that are resilient to the globally prevalent zinc limitation through zinc bio-fortification programs.

plant biology↗

bioRxiv2023

Noisy delay denoises biochemical oscillators

Genetic oscillations are generated by delayed transcriptional negative feedback loops, wherein repressor proteins inhibit their own synthesis after a temporal production delay. This delay is distributed because it arises from a sequence of noisy processes, including transcription, translation, folding, and translocation. Because the delay determines repression timing and therefore oscillation period, it has been commonly believed that delay noise weakens oscillatory dynamics. Here, we demonstrate that noisy delay can surprisingly denoise genetic oscillators. Moderate delay noise unexpectedly sharpens oscillation peaks and improves temporal peak reliability without impacting period. We show that this denoising phenomenon occurs in a variety of well-studied genetic oscillators and we use queueing theory to uncover the universal mechanisms that produce it.

systems biology↗

bioRxiv2023

Neuro-Regenerative Behavior of Adipose-Derived Stem Cells in Aligned Collagen I Hydrogels

Peripheral nerve injuries persist as a major clinical issue facing the US population and can be caused by stretch, laceration, or crush injuries. Small nerve gaps are simple to treat, and the nerve stumps can be reattached with sutures. In longer nerve gaps, traditional treatment options consist of autografts, hollow nerve guidance conduits, and, more recently, manufactured fibrous scaffolds. These manufactured scaffolds often incorporate stem cells, growth factors, and/or extracellular matrix (ECM) proteins to better mimic the native environment but can have issues with homogenous cell distribution or uniformly oriented neurite outgrowth in scaffolds without fibrous alignment. Here, we utilize a custom device to fabricate collagen I hydrogels with aligned fibers and encapsulated adipose-derived mesenchymal stem cells (ASCs) for potential use as a peripheral nerve repair graft. Analysis of these scaffolds in vitro revealed heightened therapeutic secretome from ASCs, ECM deposition, and dorsal root ganglia (DRG) neurite outgrowth along the axis of fiber alignment. Our platform serves as an in vitro testbed platform to assess neuro-regenerative potential of ASCs in aligned collagen fiber scaffolds and may provide guidance on next-generation nerve repair scaffold design.

bioengineering↗