Biology subjects

Zhao, Z.

Publications and source records attributed to Zhao, Z..

At least 217 records · Page 12Linked to original sources

bioRxiv2024

Involvement of 5' and 3' UTRs on SARS-CoV-2 Genome Packaging

The SARS-CoV-2 virus, responsible for the COVID-19 pandemic, packages its large single-stranded RNA genome through a precise yet enigmatic mechanism. A packaging signal (PS) within its genome was proposed to facilitate the assembly of new viral particles. Here in this study, we report the role of the 5 and 3 untranslated regions (UTRs) in PS-mediated genome packaging. Utilizing proximity ligation data, we demonstrate direct interactions between the UTRs and the PS9 element, a key packaging signal within the SARS-CoV-2 genome. Multiple evidence confirmed that the presence of UTRs enhance the packaging efficiency of infectious virus-like particles (iVLPs) and recruits more nucleocapsid (N) protein, suggesting a critical role in genome compaction and packaging. These insights into the regulatory mechanisms of SARS-CoV-2 genome packaging provide novel targets for antiviral therapeutics and contribute to the broader understanding of coronavirus assembly.

microbiology↗

bioRxiv2024

Bird Name-a-thon: Categorizing English bird names using crowdsourcing

Common names of species are important for communicating with the general public. In principle, these names should provide an accessible way to engage with and identify species. The common names of species have historically been labile without standard guidelines, even within a language. Currently, there is no systematic assessment of how often common names communicate identifiable and biologically relevant characteristics about species. This is a salient issue in ornithology, where common names are used more often than scientific names for species of birds in written and spoken English, even by professional researchers. To gain a better understanding of the types of terminology used in the English-language common names of bird species, a group of 85 professional ornithologists and non-professional contributors classified unique descriptors in the common names of all recognized species of birds. In the AvianLexiconAtlas database produced by this work, each species common name is assigned to one of ten categories associated with aspects of avian biology, ecology, or human culture. Across 10,906 species of birds, 89% have names describing the biology of the species, while the remaining 11% of species have names derived from human cultural references, human names, or local non-English languages. Species with common names based on features of avian biology are more likely to be related to each other or be from the same geographic region. The crowdsourced data collection also revealed that many common names contain specialized or historic terminology unknown to many of the data collectors, and we include these terms in a glossary and gazetteer alongside the dataset. The AvianLexiconAtlas can be used as a quantitative resource to assess the state of terminology in English-language common names of birds. Future research using the database can shed light on historical approaches to nomenclature and how people engage with species through their names.

zoology↗

bioRxiv2024

EmbSAM: Cell boundary localization and Segment Anything Model for fast images of developing embryos

Cellular shape dynamics are critical for understanding cell fate determination and organogenesis during development. However, fluorescence live-cell images of cell membranes frequently suffer from a low signal-to-noise ratio, especially during long-duration imaging with high spatiotemporal resolutions. This is caused by phototoxicity and photobleaching, which limit laser power and hinder effective time-lapse cell shape reconstruction, particularly in rapidly developing embryos. Here, we devised a new computational framework, EmbSAM, that incorporates a deep-learning-based cell boundary localization algorithm and the Segment Anything Model. EmbSAM enables accurate and robust three-dimensional (3D) cell membrane segmentation for roundworm Caenorhabditis elegans embryos imaged every 10 seconds. The cell shape data prior to gastrulation quantitatively characterizes a series of cell-division-coupled morphodynamics associated with cell position, cell identity, lineage, and fate, and can be accessed locally and online. The framework also exhibits potential in segmenting and quantifying the fluorescence labeling various cell-membraned-attached molecules in both wild-type and RNAi-treated embryos.

bioinformatics↗

bioRxiv2024

A Newborn F-box Gene Blocks Gene Flow by Selectively Degrading Phosphoglucomutase in Species Hybrids

The establishment of reproductive barriers such as postzygotic hybrid incompatibility (HI) remains the key to speciation. Gene duplication followed by differential functionalization has long been proposed as a major model underlying HI, but few supporting evidence exists. Here, we demonstrate that a new-born F-box gene, Cni-neib-1, of the nematode Caenorhabditis nigoni specifically inactivates an essential phosphoglucomutase encoded by Cbr-shls-1 in its sister species C. briggsae and their hybrids. Zygotic expression of Cni-neib-1 specifically depletes Cbr-SHLS-1, but not Cni-SHLS-1, in approximately 40 minutes starting from gastrulation, causing embryonic death. Cni-neib-1 is one of thirty-three paralogues emerging from a recent surge in F-box gene duplication events within C. nigoni, all of which are evolving under positive selection. Cni-neib-1 undergoes turnover even among C. nigoni populations. Differential expansion of F-box genes between the two species could reflect their distinctive innate immune responses. Collectively, we demonstrate how recent duplication of genes involved in protein degradation can cause unintended destruction of targets in hybrids that leads to HI, providing an invaluable insight into mechanisms of speciation. Significance statementUnderstanding how reproductive isolation forms and triggers speciation remains a central topic in evolutionary biology. In this study, the authors reveal a novel molecular mechanism that obstructs gene flow between the nematodes Caenorhabditis briggsae and C. nigoni. A recently evolved, species-specific F-box gene in C. nigoni selectively depletes an essential phosphoglucomutase enzyme in C. briggsae, leading to embryonic lethality in hybrids. This mechanism effectively prevents gene flow from C. nigoni to C. briggsae. This discovery underscores how a newborn gene, arising from recent gene duplication, can contribute to reproductive isolation by inadvertently disrupting a functionally important protein in hybrid offspring.

evolutionary biology↗

bioRxiv2024

Biomolecular condensation of ERC1 recruits ATG8 and NBR1 to drive autophagosome formation for plant heat tolerance

Macroautophagy (hereafter autophagy) is essential for cells to respond to nutrient stress by delivering cytosolic contents to vacuoles for degradation via the formation of a multi-layer vesicle named autophagosome. A set of autophagy-related (ATG) regulators are recruited to the phagophore assembly site for the initiation of phagophore, as well as its expansion and closure and subsequent delivery into the vacuole. However, it remains elusive that how the phagophore assembly is regulated under different stress conditions. Here, we described an unknown Arabidopsis (Arabidopsis thaliana) cytosolic ATG8-interaction protein family (ERC1/2), that binds ATG8 and NBR1 to promote autophagy. ERC1 proteins translocate to the phagophore membrane and develop into classical ring-like autophagosomes upon autophagic induction. However, ERC1 proteins form large droplets together with ATG8e proteins when in the absence of ATG8 lipidation activity. We described the property of these structures as phase-separated membraneless condensates by solving the in vivo organization with spatial and temporal resolution. Moreover, ERC1 condensates elicits a strong recruitment of the autophagic receptor NBR1. Loss of ERC1 suppressed NBR1 turnover and attenuated plant tolerance to heat stress condition. This work provides novel insights into the mechanical principle of phagophore initiation via an unreported ERC1-mediated biomolecular condensation for heat tolerance in Arabidopsis.

plant biology↗

bioRxiv2024

Mapping HIV-1 RNA Structure, Homodimers, Long-Range Interactions and persistent domains by HiCapR

Human Immunodeficiency Virus (HIV) persists as a leading global health issue. A significant gap in knowledge exists in our understanding of long-range interactions within the HIV-1 RNA genome. To bridge this gap, we introduce HiCapR, incorporating a psoralen crosslinking RNA proximity ligation and post-library hybridization for capturing HIV RNA-RNA interactions. Leveraging HiCapR, we confirm the presence of stem structures in the key regions, such as the 5-untranslated region(5-UTR) and Rev Response Element (RRE) stems, and dimer sites in 5-UTR region, which is responsible for HIV packaging. Importantly, we reveal multiple previously unknown homodimers along the HIV genome, which may have important implications for viral RNA splicing and packaging processes. Also, we uncover a wealth of unprecedented long-range interactions, particularly within the 5-UTR of infected cells. Intriguingly, our findings indicate a pronounced reduction in long-range RNA-RNA interactions, signifying a transition from a state of abundant interactions, hence a relative loose state within infected cells to a condensed structure within virions. Concurrently, we have demonstrated the presence of stable genomic domains within virions that are instrumental in the dimerization process. These domains are preserved throughout the packaging process. Our findings shed light on the functional significance of RNA organization, including stable and persistent genomic domains, homodimerization, and long-range RNA-RNA interactions, in the splicing, packaging as well as assembly of HIV. HighlightsHiCapR is a new proximity ligation method for mapping RNA structures and homodimers in the HIV genome with sufficient reliability and efficiency. Multiple homodimers were discovered along the genome, with potential implications for splicing and packaging processes. Long-range RNA-RNA interactions are abundant in infected cells but significantly reduced in virions. Stable genomic domains encluding homodimer sites are persistent in virions and are involved in dimerization.

genomics↗

bioRxiv2024

Integer topological defects provide a new way to quantify and classify cell sheets

Sheets of confluent cells are often considered as active nematics, with accumulation at [Formula] topological defects and escape from [Formula] defects being widely recognized. However, collective dynamics surrounding integer-charge defects remain poorly understood, despite its biological importance. By using microfabricated patterns, we induce diverse +1 topological defects (aster, spirals, and target) within monolayers of neural progenitor cells. Remarkably, cells are consistently attracted to the core of +1 defects regardless of their type, challenging existing theories and the conventional extensile/contractile dichotomy. We trace back the origin of this accumulation behavior to previously overlooked nonlinear active forces using a combination of experiments and a continuous theory derived from a cell-level model. Our findings demonstrate that +1 topological defects can reveal key features of active nematic systems and offer a new way to characterize and classify cell layers.

biophysics↗

bioRxiv2024

SARS-CoV-2 nsp16 is regulated by host E3 ubiquitin ligases, UBR5 and MARCHF7

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19), remains a global public health threat with considerable economic consequences. The non-structural protein 16 (nsp16), in complex with nsp10, facilitates the final viral mRNA capping step through its 2'-O-methylase activity, helping the virus to evade host immunity and prevent mRNA degradation. However, nsp16 regulation by host factors remains poorly understood. While various E3 ubiquitin ligases interact with SARS-CoV-2 proteins, their roles in targeting nsp16 for degradation are unclear. In this study, we demonstrate that nsp16 undergoes ubiquitination and proteasomal degradation mediated by the host E3 ligases UBR5 and MARCHF7. UBR5 induces K48-linked ubiquitination, whereas MARCHF7 promotes K27-linked ubiquitination, independently suppressing SARS-CoV-2 replication in cell cultures and in mice. Notably, UBR5 and MARCHF7 also degrade nsp16 variants from different viral strains, exhibiting broad-spectrum antiviral activity. Our findings reveal novel antiviral mechanisms of the ubiquitin-proteasome system (UPS) and highlight their potential therapeutic targets against COVID-19.

microbiology↗

bioRxiv2024

Olfactory receptor coexpression and co-option in the dengue mosquito

The olfactory sensory neurons of vinegar flies and mice tend to express a single ligand-specific receptor. While this one neuron-one receptor motif has long been expected to apply broadly across insects, recent evidence suggests it may not extend to mosquitoes. We sequenced and analyzed the transcriptomes of 46,000 neurons from antennae of the dengue mosquito Aedes aegypti to resolve all olfactory, thermosensory, and hygrosensory neuron subtypes and identify the receptors expressed therein. We find that half of all olfactory subtypes coexpress multiple receptors. However, coexpression occurs almost exclusively among genes from the same family--among odorant receptors (ORs) or among ionotropic receptors (IRs). Coexpression of ORs with IRs is exceedingly rare. Many coexpressed receptors are recent duplicates. In other cases, the recruitment or co-option of single receptors by multiple neuron subtypes has placed these genes together in the same cells with distant paralogs. Close examination of data from Drosophila reveal rare cases of both phenomena, indicating that the olfactory systems of these two species are not fundamentally different, but instead fall at different locations along a continuum likely to encompass diverse insects.

neuroscience↗

bioRxiv2024

A single-molecule nanopore sequencing platform

Nanopore sequencing, a third-generation sequencing technology, has revolutionized the gene sequencing industry with its advantages of long reads, fast speed, real-time sequencing and analysis, and potential in detecting base modifications. This technology allows researchers to sequence longer DNA fragments in a single read, providing more comprehensive genomic information compared to previous methods. Nanopore sequencing operates on electrical signals generated by a nanopore embedded in a membrane separating two electrolyte-filled chambers. When single-stranded DNA (ssDNA) passes through the nanopore, it creates variations in the current that correspond to different DNA bases. By analyzing these current fluctuations with machine learning algorithms, the DNA sequence can be determined. In this study, we introduced several improvements to nanopore sequencing, including nanopore local chemistry sequencing, novel motor and pore proteins, chip design, and basecalling algorithms. Our new nanopore sequencing platform, CycloneSEQ, demonstrated long-duration sequencing (107 hours) on a single chip with high yield (>50 Gb). In human genomic DNA sequencing, CycloneSEQ was able to produce long reads with N50 33.6 kb and modal identity 97.0%. Preliminary findings on human whole-genome de novo assembly, variant calling, metagenomics sequencing, and single-cell RNA sequencing have further highlighted CycloneSEQs potential across different areas of genomics.

genomics↗

bioRxiv2024

Scupa: Single-cell unified polarization assessment of immune cells using the single-cell foundation model

Immune cells undergo cytokine-driven polarization in respond to diverse stimuli. This process significantly modulates their transcriptional profiles and functional states. Although single-cell RNA sequencing (scRNA-seq) has advanced our understanding of immune responses across various diseases or conditions, currently there lacks a method to systematically examine cytokine effects and immune cell polarization. To address this gap, we developed Single-cell unified polarization assessment (Scupa), the first computational method for comprehensive immune cell polarization analysis. Scupa is trained on data from the Immune Dictionary, which characterizes 66 cytokine-driven polarization states across 14 immune cell types. By leveraging the cell embeddings from the Universal Cell Embeddings model, Scupa effectively identifies polarized cells in new datasets generated from different species and experimental conditions. Applications of Scupa in independent datasets demonstrated its accuracy in classifying polarized cells and further revealed distinct polarization profiles in tumor-infiltrating myeloid cells across cancers. Scupa complements conventional single-cell data analysis by providing new insights into immune cell polarization, and it holds promise for assessing molecular effects or identifying therapeutic targets in cytokine-based therapies.

bioinformatics↗

bioRxiv2024

Genesis and regulation of C-terminal cyclic imides from protein damage

C-Terminal cyclic imides are post-translational modifications (PTMs) that can arise from spontaneous intramolecular cleavage of asparagine or glutamine residues resulting in a form of irreversible protein damage. These protein damage events are recognized and removed by the E3 ligase substrate adapter cereblon (CRBN), indicating that these aging-related modifications may require cellular quality control mechanisms to prevent deleterious effects. However, the factors that determine protein or peptide susceptibility to C-terminal cyclic imide formation or their effect on protein stability have not been explored in detail. Here, we characterize the primary and secondary structures of peptides and proteins that promote intrinsic formation of C-terminal cyclic imides in comparison to deamidation, a related form of protein damage. Extrinsic effects from solution properties and stressors on the cellular proteome additionally promote C-terminal cyclic imide formation on proteins like glutathione synthetase (GSS) that are susceptible to aggregation if the protein damage products are not removed by CRBN. This systematic investigation provides insight to the regions of the proteome that are prone to these unexpectedly frequent modifications, the effects of this form of protein damage on protein stability, and the biological role of CRBN.

biochemistry↗

bioRxiv2024

Learning in single cells: biochemically-plausible models of habituation

The ability to learn is typically attributed to animals with brains. However, the apparently simplest form of learning, habituation, in which a steadily decreasing response is exhibited to a repeated stimulus, is found not only in animals but also in single-cell organisms and individual mammalian cells. Habituation has been codified from studies in both invertebrate and vertebrate animals, as having ten characteristic hallmarks, seven of which involve a single stimulus. Here, we show by mathematical modelling that simple molecular networks, based on plausible biochemistry with common motifs of negative feedback and incoherent feedforward, can robustly exhibit all single-stimulus hallmarks. The models reveal how the hallmarks arise from underlying properties of timescale separation and reversal behaviour of memory variables and they reconcile opposing views of frequency and intensity sensitivity expressed within the neuroscience and cognitive science traditions. Our results suggest that individual cells may exhibit habituation behaviour as rich as that in multi-cellular animals with central nervous systems and that the relative simplicity of the biomolecular level may enhance our understanding of the mechanisms of learning.

systems biology↗

bioRxiv2024

How do we imagine a speech? A triple network model for situationally simulated inner speech

Inner speech is a silent verbal experience and plays central roles in human consciousness and cognition. Despite impressive studies over the past decades, the neural mechanisms of inner speech remain largely unknown. In this study, we adopted an ecological paradigm called situationally simulated inner speech. Unlike mere imaging speech of words, situationally simulated inner speech involves the dynamic integration of contextual background, episodic and semantic memories, and external events into a coherent structure. We conducted dynamic activation and network analyses on fMRI data, where participants were instructed to engage in inner speech prompted by cue words across 10 different contextual backgrounds. Our seed-based co-activation pattern analyses revealed dynamic involvement of the language network, sensorimotor network, and default mode network in situationally simulated inner speech. Additionally, frame-wise dynamic conditional correlation analysis uncovered four temporal-reoccurring states with distinct functional connectivity patterns among these networks. We proposed a triple network model for deliberate inner speech, including language network for a truncated form of overt speech, sensorimotor network for perceptual simulation and monitoring, and default model network for integration and sense-making processing. HighlightsO_LIIn ten contextual backgrounds, subjects were instructed to perform situationally simulated inner speech based on cue words. C_LIO_LIThe ventral parts of the bilateral somatosensory areas and middle superior temporal gyrus were as centers for seed-based co-activation pattern analyses. C_LIO_LIA triple network model of language network, sensorimotor network, and default mode network was proposed for deliberate inner speech. C_LI

neuroscience↗

bioRxiv2024

Cognitive hyperplasticity drives insomnia

Sleep is vital for maintenance of cognitive functions and lifespan across the animal kingdom. Here, we report our surprising findings that insomniac (inc) Drosophila short sleep mutants, which lack a crucial adaptor protein for the autism-associated Cullin-3 ubiquitin ligase, exhibited excessive olfactory memory. Through a genetic modifier screen, we find that a mild attenuation of Protein Kinase A (PKA) signaling specifically rescued the sleep and longevity phenotypes of inc mutants. Surprisingly, this mild PKA signaling reduction further boosted the excessive memory in inc mutants, coupled with further exaggerated mushroom body overgrowth phenotypes. We propose that an intrinsic hyperplasticity scenario genuine to inc mutants enhances cognitive functions. Elevating PKA signaling seems to serve as a checkpoint which allows to constrain the excessive memory and mushroom body overgrowth in these animals, albeit at the sacrifice of sleep and longevity. Our data offer a mechanistic explanation for the sleep deficits of inc mutants, which challenges traditional views on the relation between sleep and memory, and suggest that behavioral hyperplasticity, e.g., prominent in autistic patients, can provoke sleep deficits.

neuroscience↗

bioRxiv2024

F-CPI: Prediction of activity changes induced by fluorine substitution using multimodal deep learning

There are a large number of fluorine (F)-containing compounds in approved drugs, and F substitution is a common method in drug discovery and development. However, F is difficult to form traditional hydrogen bonds and typical halogen bonds. As a result, accurate prediction of the activity after F substitution is still impossible using traditional drug design methods, whereas artificial intelligence driven activity prediction might offer a solution. Although more and more machine learning and deep learning models are being applied, there is currently no model specifically designed to study the effect of F on bioactivities. In this study, we developed a specialized deep learning model, F-CPI, to predict the effect of introducing F on drug activity, and tested its performance on a carefully constructed dataset. Comparison with traditional machine learning models and popular CPI task models demonstrated the superiority and necessity of F-CPI, achieving an accuracy of approximately 89% and a precision of approximately 67%. In the end, we utilized F-CPI for the structural optimization of hit compounds against SARS-CoV-2 3CLpro. Impressively, in one case, the introduction of only one F atom resulted in a more than 100-fold increase in activity (IC50: 22.99 nM vs. 28190 nM). Therefore, we believe that F-CPI is a helpful and effective tool in the context of drug discovery and design.

bioinformatics↗

bioRxiv2024

YTHDF2 upregulation and relocation dictate CD8 T cell polyfunctionality in tumor immunity

Epigenetic traits impact the antitumor function of CD8 T cells, yet whether and how RNA methylation programs engage in T cell immunity is poorly understood. Here we show that the N6-methyladenosine (m6A) RNA reader YTHDF2 is highly expressed in early effector or effector-like CD8 T cells and is partially distributed in the nucleus. YTHDF2 loss in T cells exacerbates tumor progression and confers unresponsiveness to PD-1 blockade in mice and humans. In addition to initiating RNA decay for mitochondrial fitness, YTHDF2 can orchestrate chromatin regulation to promote T cell polyfunctionality. YTHDF2-mediatd preservation of gene transcription arises from the interaction of YTHDF2 with IKZF1/3. Accordingly, immunotherapy-induced efficacy could be largely restored in YTHDF2-deficient T cells through combinational use of lenalidomide. Moreover, m6A recognition is fundamental for YTHDF2 translocation to the nucleus and autoregulation at the RNA level. Thus, YTHDF2 coordinates epitranscriptional and transcriptional networks to potentiate T cell immunity. HighlightsO_LIYTHDF2 expression and distribution underpin the threshold for bona fide CD8 T cell effector response C_LIO_LICanonical YTHDF2-mRNA decay pathway alleviates mitochondrial stress and CD8 T cell exhaustion C_LIO_LINuclear YTHDF2 sequesters IKZF1/3-mediated transcriptional repression to safeguard CD8 T cell polyfunctionality C_LIO_LIThe tumoricidal activity of YTHDF2-deficient CD8 T cells could be repaired through the synergy of anti-PD-1 and lenalidomide C_LI

immunology↗

bioRxiv2024

Somy evolution in the honey bee infecting trypanosomatid parasite, Lotmaria passim

Lotmaria passim is a ubiquitous trypanosomatid parasite of honey bees nestled within the medically important subfamily Leishmaniinae. Although this parasite is associated with honey bee colony losses, the original draft genome--which was completed before its differentiation from the closely related Crithidia mellificae--has remained the reference for this species despite lacking improvements from newer methodologies. Here we report the updated sequencing, assembly, and annotation of the BRL type strain (ATCC PRA-422) of Lotmaria passim. The nuclear genome assembly has been resolved into 31 complete chromosomes and is paired with an assembled kinetoplast genome consisting of a maxicircle and 30 minicircle sequences. The assembly spans 33.7 Mb and contains very little repetitive content, from which our annotation of both the nuclear assembly and kinetoplast predicted 10,288 protein-coding genes. Analyses of the assembly revealed evidence of a recent chromosomal duplication event within chromosomes 5 and 6 and provides evidence for a high level of aneuploidy in this species, mirroring the genomic flexibility employed by other trypanosomatids as a means of adaptation to different environments. This high-quality reference can therefore provide insights into adaptations of trypanosomatids to the thermally regulated, acidic, and phytochemically rich honey bee hindgut niche, which offers parallels to the challenges faced by other Leishmaniinae during the challenges they undergo within insect vectors, during infection of mammals, and exposure to antiparasitic drugs throughout their multi-host life cycles. This reference will also facilitate investigations of strain-specific genomic polymorphisms, their role in pathogenicity, and the development of treatments for pollinator infection.

genomics↗