Biology subjects

Yan, X.

Publications and source records attributed to Yan, X..

At least 163 records · Page 9Linked to original sources

bioRxiv2023

Genomic analysis of Coccomyxa viridis, a common low-abundance alga associated with lichen symbioses

Lichen symbiosis is centered around a relationship between a fungus and a photosynthetic microbe, usually a green alga. In addition to their main photosynthetic partner (the photobiont), lichen symbioses can contain additional algae present in low abundance. The biology of these algae and the way they interact with the rest of lichen symbionts remains largely unknown. Here we present the first genome sequence of a non-photobiont lichen-associated alga. Coccomyxa viridis was unexpectedly found in 12% of publicly available lichen metagenomes. With few exceptions, members of the Coccomyxa viridis clade occur in lichens as non-photobionts, potentially growing in thalli endophytically. The 45.7 Mbp genome of C. viridis was assembled into 18 near chromosome-level contigs, making it one of the most contiguous genomic assemblies for any lichen-associated algae. Comparing the C. viridis genome to its close relatives revealed the presence of traits associated with the lichen lifestyle. The genome of C. viridis provides a new resource for exploring the evolution of the lichen symbiosis, and how symbiotic lifestyles shaped evolution in green algae.

microbiology↗

bioRxiv2023

Targeting and Imaging Mitochondria with a Novel Cyanine-based Fluorescent Dye and Its Application to Whole Brain Imaging

In vivo, brain imaging poses several challenges due to the complexity of brain tissue and the requirements for effective and safe imaging. In this manuscript, we reported on developing a new fluorescent dye, Cy5-PEG2, that can selectively accumulate in mitochondria, allowing us to visualize these organelles in different cell lines. Its versatility makes it broadly applicable in various experimental conditions, including monitoring mitochondrial dynamics in living cells. Moreover, we demonstrated that the Cy5-PEG2 dye could penetrate the blood-brain barrier (BBB), making it a promising tool for in vivo brain imaging. We further examined the response of glial cells in the hippocampus and neocortex regions of the brain through biomarkers GFAP and Iba1 but found no significant increase in their expression levels. This indicates that Cy5-PEG2 dye had no noticeable adverse effects on the brains immune response or neuronal health. We anticipate such a mitochondria-targeting fluorescent dye can be used to facilitate the study of mitochondrial dynamics and function in the context of whole-brain physiology and disease progression. Further research into the safety and efficacy of this dye may be necessary.

neuroscience↗

bioRxiv2023

A Stapled Peptide Inhibitor of METTL3-METTL14 for Cancer Therapy

METTL3, a primary methyltransferase catalyzing RNA N6-methyladenosine (m6A) modification, has been identified as an oncogene in several cancer types and thus nominated as a potentially effective target for therapeutic inhibition, although current options using this strategy are limited. In this study, we targeted protein-protein interactions at the METTL3-METTL14 binding interface to inhibit complex formation and subsequent catalysis of RNA m6A modification. Among candidate peptides, RM3 exhibited the highest anti-cancer potency, inhibiting METTL3 activity while also facilitating its proteasomal degradation. We then designed a stapled peptide inhibitor (RSM3) with enhanced peptide stability and formation of the -helical secondary structure required for METTL3 interaction. Functional and transcriptomic analysis in vivo indicated that RSM3 induced upregulation of programmed cell death-related genes while inhibiting cancer-promoting signals. Furthermore, tumor growth was significantly suppressed while apoptosis was enhanced upon RSM3 treatment, accompanied by in-creased METTL3 degradation, and reduced global RNA methylation levels in two in vivo tumor models. This peptide inhibitor thus exploits a mechanism distinct from other competitive-binding small molecules to inhibit oncogenic METTL3 activity. Our findings collectively highlight the potential of targeting METTL3 in cancer therapies through peptide-based inhibition of complex formation and proteolytic degradation.

biochemistry↗

bioRxiv2023

A hybrid machine learning and regression method for cell type deconvolution of spatial barcoding-based transcriptomic data

Spatial barcoding-based transcriptomic (ST) data require cell type deconvolution for cellular-level downstream analysis. Here we present SDePER, a hybrid machine learning and regression method, to deconvolve ST data using reference single-cell RNA sequencing (scRNA-seq) data. SDePER uses a machine learning approach to remove the systematic difference between ST and scRNA-seq data (platform effects) explicitly and efficiently to ensure the linear relationship between ST data and cell type-specific expression profile. It also considers sparsity of cell types per capture spot and across-spots spatial correlation in cell type compositions. Based on the estimated cell type proportions, SDePER imputes cell type compositions and gene expression at unmeasured locations in a tissue map with enhanced resolution. Applications to coarse-grained simulated data and four real datasets showed that SDePER achieved more accurate and robust results than existing methods, suggesting the importance of considering platform effects, sparsity and spatial correlation in cell type deconvolution.

bioinformatics↗

bioRxiv2023

The phosphorylation landscape of infection-related development by the rice blast fungus

Many of the worlds most devastating crop diseases are caused by fungal pathogens which elaborate specialized infection structures to invade plant tissue. Here we present a quantitative mass spectrometry-based phosphoproteomic analysis of infection-related development by the rice blast fungus Magnaporthe oryzae, which threatens global food security. We mapped 8,005 phosphosites on 2,062 fungal proteins, revealing major re-wiring of phosphorylation-based signaling cascades during fungal infection. Comparing phosphosite conservation across 41 fungal species reveals phosphorylation signatures specifically associated with biotrophic and hemibiotrophic fungal infection. We then used parallel reaction monitoring to identify phosphoproteins directly regulated by the Pmk1 MAP kinase that controls plant infection by M. oryzae. We define 33 substrates of Pmk1 and show that Pmk1-dependent phosphorylation of a newly identified regulator, Vts1, is required for rice blast disease. Defining the phosphorylation landscape of infection therefore identifies potential therapeutic interventions for control of plant diseases.

plant biology↗

bioRxiv2023

Detection and characterization of a novel bat filovirus (Dehong virus, DEHV) in fruit bats

Although bats are natural hosts of most filoviruses (FiVs), with the pathogenic ones frequently causing deadly haemorrhagic fevers in Africa, the viruses are difficult to trace. Recently, multiple divergent FiVs have been uncovered in China, raising concerns about their threat to public health. Here we report the detection of bat-borne FiVs at the interface of orchards between bats and humans, eventually resulting in the discovery of a novel FiV, Dehong virus (DEHV), from Rousettus leschenaultii (R. leschenaultii) bats. DEHV has the largest genome, and the phylogeny places it between the genera Dianlovirus and Marburgvirus, suggesting its classification as a prototype of a new genus within the family Filoviridae. Our study emphasizes the importance of further understanding the distribution and potential risk of FiVs in the region.

microbiology↗

bioRxiv2023

Chemoproteomics reveals the epoxidase enzyme for the biosynthesis of camptothecin precursor strictosamide epoxide

Camptothecin and its derivatives are the third largest anticancer drugs in the world market, mainly used to treat malignant tumors such as lung, colon and cervical cancer. Camptothecin was firstly discovered in Camptotheca acuminate and extracted mainly from C. acuminate and Nothapodytes nimmoniana for medicine production (Sadre et al. 2016). However, the overharvesting of C. acuminate and N. nimmoniana has greatly reduced their populations in nature, which are currently listed as the second protected plants in China and India. It is estimated there would be 20 million new cancer cases in 2025 all over the world, meeting the growing demand for camptothecin and other anti-cancer drugs has become a daunting challenge (Seca et al. 2018). In this study we tried to elucidate the unknown biosynthetic pathway from strictosamide 1 to strictosamide epoxide 2 by unearthing the candidate enzymes from the proteome of plant Ophiorrhiza pumila using the chemoproteomic strategy.

plant biology↗

bioRxiv2023

Histone variant H2A.Z is required for plant salt response by regulating gene transcription

As a well-conserved histone variant, H2A.Z epigenetically regulates plant growth and development as well as the interaction with environmental factors. However, the role of H2A.Z in response to salt stress remains unclear, and whether nucleosomal H2A.Z occupancy work on the gene responsiveness upon salinity is obscure. Here, we elucidate the involvement of H2A.Z in salt response by analyzing H2A.Z disorder plants with impaired or overloaded H2A.Z deposition. The salt tolerance is dramatically accompanied by H2A.Z deficiency and reacquired in H2A.Z OE lines. H2A.Z disorder changes the expression profiles of large-scale of salt responsive genes, announcing that H2A.Z is required for plant salt response. Genome-wide H2A.Z mapping shows that H2A.Z level is induced by salt condition across promoter, TSS and TES (-1 kb to +1kb), the peaks preferentially enrich at promoter regions near TSS. We further show that H2A.Z deposition within TSS provides a direct role on transcriptional control, which has both repressive and activating effects, while it is found generally H2A.Z enrichment negatively correlate with gene expression level response to salt stress. This study shed light on the H2A.Z function in salt tolerance, highlighting the complex regulatory mechanisms of H2A.Z on transcriptional activity for yielding appropriate responses to particularly environmental stress.

plant biology↗

bioRxiv2023

Design, Synthesis, and Biological Evaluation of Novel Mitochondria-targeting Exosomes

Mitochondrial dysfunction is implicated in both brain tumors and neurodegenerative diseases, leading to various cellular abnormalities that can promote tumor growth and resistance to thera-pies, as well as impaired energy production and compromised neuronal function. Developing targeted therapies aimed at restoring mitochondrial function and improving overall cellular health could potentially be a promising approach to treating these conditions. Brain-derived exosomes (BR-EVs) have emerged as potential drug delivery vessels for neurological conditions. Herein, we report a new method for creating mitochondria-targeting exosomes and test its application in vitro and in vivo.

neuroscience↗

bioRxiv2023

In-vivo whole-cortex estimation of excitation-inhibition ratio indexes cortical maturation and cognitive ability in youth

A balanced excitation-inhibition ratio (E/I ratio) is critical for healthy brain function. Normative development of cortex-wide E/I ratio remains unknown. Here we non-invasively estimate a putative marker of whole-cortex E/I ratio by fitting a large-scale biophysically-plausible circuit model to resting-state functional MRI (fMRI) data. We first confirm that our model generates realistic brain dynamics in the Human Connectome Project. Next, we show that the estimated E/I ratio marker is sensitive to the GABA-agonist benzodiazepine alprazolam during fMRI. Alprazolam-induced E/I changes are spatially consistent with positron emission tomography measurement of benzodiazepine receptor density. We then investigate the relationship between the E/I ratio marker and neurodevelopment. We find that the E/I ratio marker declines heterogeneously across the cerebral cortex during youth, with the greatest reduction occurring in sensorimotor systems relative to association systems. Importantly, among children with the same chronological age, a lower E/I ratio marker (especially in association cortex) is linked to better cognitive performance. This result is replicated across North American (8.2 to 23.0 years old) and Asian (7.2 to 7.9 years old) cohorts, suggesting that a more mature E/I ratio indexes improved cognition during normative development. Overall, our findings open the door to studying how disrupted E/I trajectories may lead to cognitive dysfunction in psychopathology that emerges during youth. SignificanceHealthy brain function requires a delicate balance of neural excitation (E) and inhibition (I). In animals, this balance - the E/I ratio - is known to decrease with the maturation of inhibitory circuitry during healthy development. However, in humans, the normative development of cortex-wide E/I ratio remains unclear. Here, we use a biophysical model and non-invasive brain scans to estimate a marker of E/I ratio. Spatial changes in our E/I ratio marker are consistent with a drug that decreases E/I ratio. We also find that our cortex-wide E/I ratio marker decreases during development. Furthermore, North American and Asian children with lower E/I ratio, especially in higher-order cortex, have better cognitive performance. Overall, E/I ratio is a potential index of healthy neurocognitive development.

neuroscience↗

bioRxiv2023

A low dimensional manifold of human exploration and exploitation behavior reveals behavioral states of apathy and anxiety

Exploration-exploitation decision-making is a feature of daily life that is altered in a number of neuropsychiatric conditions. Humans display a range of exploration and exploitation behaviors, which can be affected by apathy and anxiety. It remains unknown how factors underlying decision-making generate the spectrum of observed exploration-exploitation behavior and how they relate to states of anxiety and apathy. Here, we report a latent structure underlying sequential exploration and exploitation decisions that explains variation in anxiety and apathy. 1001 participants in a gender-balanced sample completed a three-armed restless bandit task along with psychiatric symptom surveys. Using dimensionality reduction methods, we found that decision sequences reduced to a low-dimensional manifold. The axes of this manifold explained individual differences in the balance between states of exploration and exploitation and the stability of those states, as determined by a statistical mechanics model of decision-making. Position along the balance axis was correlated with opposing symptoms of behavioral apathy and anxiety, while position along the stability axis correlated with the level of emotional apathy. This result resolves a paradox over how these symptoms can be correlated in samples but have opposite effects on behavior. Furthermore, this work provides a basis for using behavioral manifolds to reveal relationships between behavioral dynamics and affective states, with important implications for behavioral measurement approaches to neuropsychiatric conditions.

neuroscience↗

bioRxiv2023

UniSpec: A Deep Learning Approach for Predicting Energy-Sensitive Peptide Tandem Mass Spectra and Generating Proteomics-Wide In-Silico Spectral Libraries

In this report, we present UniSpec, an attention-based deep neural network designed to predict complete collision-induced fragmentation of tryptic peptides, aimed at enhancing peptide and protein identification in shotgun proteomics studies. We preprocessed spectral data from peptide tandem mass spectral libraries, compiled by the National Institute of Standards and Technology (NIST), utilizing a data approach tailored for model development, resulting in high-quality, energy-consistent spectral datasets. By analyzing all the annotated fragment ions present in these libraries, we constructed an extensive peptide fragment dictionary containing 7919 isotopic ions from sequence ions, neutral loss, internal, iminium, and amino acid fragment ions. The streamlined dictionary-based spectral training data enables UniSpec to efficiently learn the complex intensity patterns of various product ions, resulting in reliable spectral predictions for a wide range of unmodified and modified peptides. We evaluated the models accuracy by comparing its performance across training and testing data, considering diverse peptide characteristics like peptide classes, charge states, and sequence lengths. Our model attained a median cosine similarity score of 0.951 and 0.923 on the training and test data respectively. Contrary to existing deep learning models that often overlook a substantial part of peptide tandem mass spectra beyond the sequence b and y ion series, UniSpec can predict up to 75% of all measured fragment intensities (including unknown signals) in the raw experimental spectra. This represents a marked advancement from the 43.5% coverage achieved solely by b and y sequence ions in the NIST library spectra. For the evaluation of our models practical utility in predicting proteome-wide in-silico spectral libraries, we executed a benchmark test using a dataset of HeLa cells. UniSpec displayed a significant overlap of peptide identifications with the widely used search engine MS-GF+ and the NIST experimental spectral library, demonstrating its robust performance as a standalone peptide identification tool.

bioinformatics↗

bioRxiv2023

High-resolution structure of mouse radial spoke and its in-situ structure in ependymal cilia revealed by cryo-EM and cryo-ET

Radial spokes (RS) transmit mechanochemical signals between the central pair (CP) and axonemal dynein arms to coordinate ciliary motility. However, the high-resolution structure of mammalian RS remains missing. Here, we present the high-resolution cryo-EM structure of mouse RS head-neck complex in both monomer and dimer forms and reveal the intrinsic dynamics of the dimer. We also map the genetic mutations related to primary ciliary dyskinesia and asthenospermia on the head-neck complex. Moreover, we present the unprecedented cryo-ET and sub-tomogram averaging map of mouse ependymal cilia, whose beating creates unidirectional cerebrospinal fluid flow, and build the models for RS1-3, IDAs, and N-DRC. Strikingly, our cryo-ET map reveals the lack of IDA-b/c/e and the absence of tektin filaments within the A-tubule of doublet microtubules in ependymal cilia compared with mammalian respiratory cilia and sperm flagella. This tissue-specific feature may represent an evolutionary choice driven by the functional requirements on ependymal cilia. Our findings reveal the RS head-neck assembly mechanism, shed light on the coordinated rigid and elastic RS-CP interaction modes beneficial for the regulation of asymmetric ciliary beating, and also facilitate understandings on the etiology of ciliary dyskinesia-related ciliopathies.

biophysics↗

bioRxiv2023

Gene prediction and evolutionary characterization of heat shock transcription factors in Salvia miltiorrhiza

BackgroundHeat shock transcription factors (HSFs) serve as central regulators in plants and enable adaptations to dynamic environmental changes, such as heat stress. Salvia miltiorrhiza is an important medicinal plant model. However, various biotic and abiotic stresses, pathogen infections, and degeneration of elite cultivars limit the yield and quality of S. miltiorrhiza. Therefore, it is important to predict and characterize the stress resistance genes of S. miltiorrhiza and clarify potential molecular mechanisms for genetic improvement. However, the knowledge of HSF genes in S. miltiorrhiza is limited. MethodsThus, we performed a genome-wide analysis of HSF genes in S. miltiorrhiza. ResultsUsing high-quality genome sequences, we predicted 34 HSF genes distributed unevenly across eight chromosomes. Twenty-three genes were segmentally duplicated, suggesting that in S. miltiorrhiza, segmental duplications have significantly contributed to the expansion of the HSF gene family. The predicted genes were divided into 15 phylogenetic groups, among which the sequence characteristics were relatively well conserved. The Ka/Ks ratios indicated that duplicated HSF genes underwent negative selection. Most of the HSF genes displayed different expression characteristics under drought stress and salicylic acid induction. This study provides valuable data that may inform further functional studies of HSF genes in S. miltiorrhiza.

bioinformatics↗

bioRxiv2023

Living cell mTORC1 inhibition reporter mTIR reveals nutrient-sensing targets of histone deacetylase inhibitor

Mammalian or mechanistic target of rapamycin complex 1 (mTORC1) is a clinically effective therapeutic target for diseases such as cancer, diabetes, aging, and neurodegeneration, yet an efficient tool to monitor mTORC1 inhibition in living cells or tissues is still lacking. Here we devised a genetically encoded mTORC1 inhibition reporter termed mTIR that exhibits a highly contrasted fluorescence puncta pattern in response to mTORC1 inhibition. mTIR specifically senses physiological, pharmacological and genetic inhibition of mTORC1 signaling in living cells and tissues. Importantly, mTIR can be applied as an powerful tool for imaging-based visual screening of mTORC1 inhibitors. By this method, we identified histone deacetylase inhibitors (HDACi) that selectively inhibit mTORC1 by inducing nutrient-sensing gene expression. Thus, mTIR is a unique living cell reporter efficiently detecting the inhibition of mTORC1 activity, and the HDACi Panobinostat transcriptionally target mTORC1 signaling via amino acids sensing.

cell biology↗

bioRxiv2023

When Do Visual Category Representations Emerge in Infants' Brains?

Organizing the continuous stream of visual input into categories like places or faces is important for everyday function and social interactions. However, it is unknown when neural representations of these and other visual categories emerge. Here we used steady state evoked potential electroencephalography to measure cortical responses in infants at 3-4 months, 4-6 months, 6-8 months, and 12-15 months, when they viewed controlled, gray-level images of faces, limbs, corridors, characters, and cars. We found that distinct responses to these categories emerge at different ages. Reliable brain responses to faces emerge first, at 4-6 months, followed by limbs and places around 6-8 months. Between 6-15 months response patterns become more distinct, such that a classifier can decode what an infant is looking at from their brain responses. These findings have important implications for assessing typical and atypical cortical development as they not only suggest that category representations are learned, but also that representations of categories that may have innate substrates emerge at different times during infancy.

neuroscience↗

bioRxiv2023

A Multi-omic Analysis of the Human Lung Reveals Distinct Cell Specific Aging and Senescence Molecular Programs

Age is a major risk factor for lung disease. To understand the mechanisms underlying this association, we characterized the changing cellular, genomic, transcriptional, and epigenetic landscape of lung aging using bulk and single-cell RNAseq (scRNAseq) data. Our analysis revealed age-associated gene networks that reflected hallmarks of aging, including mitochondrial dysfunction, inflammation, and cellular senescence. Cell type deconvolution revealed age-associated changes in the cellular composition of the lung: decreased alveolar epithelial cells and increased fibroblasts and endothelial cells. In the alveolar microenvironment, aging is characterized by decreased AT2B cells and reduced surfactant production, a finding that was validated by scRNAseq and IHC. We showed that a previously reported senescence signature, SenMayo, captures cells expressing canonical senescence markers. SenMayo signature also identified cell-type specific senescence-associated co-expression modules that have distinct molecular functions, including ECM regulation, cell signaling, and damage response pathways. Analysis of somatic mutations showed that burden was highest in lymphocytes and endothelial cells and was associated with high expression of senescence signature. Finally, aging and senescence gene expression modules were associated with differentially methylated regions, with inflammatory markers such as IL1B, IL6R, and TNF being significantly regulated with age. Our findings provide new insights into the mechanisms underlying lung aging and may have implications for the development of interventions to prevent or treat age-related lung diseases.

genomics↗

bioRxiv2023

Cell targeting and immunostimulatory properties of a novel Fcγ-receptor independent agonistic anti-CD40 antibody in rhesus macaques

Targeting CD40 by agonistic antibodies used as vaccine adjuvants or for cancer immunotherapy is a strategy to stimulate immune responses. The majority of studied agonistic anti-human CD40 antibodies require crosslinking of their Fc region to inhibitory Fc{gamma}RIIb to induce immune stimulation although this has been associated with toxicity in previous studies. Here we introduce an agonistic anti-human CD40 monoclonal IgG1 antibody (MAB273) unique in its specificity to the CD40L binding site of CD40 but devoid of Fc{gamma}-receptor binding, we demonstrate rapid binding of MAB273 to B cells and dendritic cells resulting in strong activation in vitro on human cells and in vivo in rhesus macaques. Dissemination of fluorescently labeled MAB273 after subcutaneous administration was found predominantly at the site of injection and specific draining lymph nodes. Phenotypic cell differentiation and upregulation of genes associated with immune activation were found in the targeted tissues. Antigen-specific T cell responses were enhanced by MAB273 when given in a prime-boost regimen and for boosting low preexisting responses. MAB273 may therefore be a promising immunostimulatory adjuvant that warrants future testing for therapeutic and prophylactic vaccination strategies.

immunology↗