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Biology subjects

Yu, F.

Publications and source records attributed to Yu, F..

At least 127 records · Page 7Linked to original sources

Estimating temporally variable selection intensity from ancient DNA data

Novel technologies for recovering DNA information from archaeological and historical specimens have made available an ever-increasing amount of temporally spaced genetic samples from natural populations. These genetic time series permit the direct assessment of patterns of temporal changes in allele frequencies, and hold the promise of improving power for the inference of selection. Increased time resolution can further facilitate testing hypotheses regarding the drivers of past selection events such as the incidence of plant and animal domestication. However, studying past selection processes through ancient DNA (aDNA) still involves considerable obstacles such as postmortem damage, high fragmentation, low coverage and small samples. To circumvent these challenges, we introduce a novel Bayesian framework for the inference of temporally variable selection based on genotype likelihoods instead of allele frequencies, thereby enabling us to model sample uncertainties resulting from the damage and fragmentation of aDNA molecules. Also, our approach permits the reconstruction of the underlying allele frequency trajectories of the population through time, which allows for a better understanding of the drivers of selection. We evaluate its performance through extensive simulations and demonstrate its utility with an application to the ancient horse samples genotyped at the loci for coat colouration. Our results reveal that incorporating sample uncertainties can further improve the inference of selection.

genetics↗

Systematic comparison and rational design of theophylline riboswitches for efficient gene repression

Riboswitches are promising regulatory tools in synthetic biology. To date, 25 theophylline riboswitches have been developed for gene expression regulation in bacteria. However, no one has systematically evaluated their regulatory effects. To facilitate rational selection of theophylline riboswitches, we examined 25 theophylline riboswitches in Escherichia coli and surprised to find that none of the five repressive riboswitches were more than 2-fold effective. To solve this problem, we rationally designed a transcriptional repressive riboswitch and demonstrated its effect not only in various bacterial strains but also in different growth media or different temperatures. By introducing two copies of theophylline riboswitches and a RepA protein degradation tag coding sequence at the 5-end of a reporter gene, we successfully constructed a dual gene expression regulatory system with up to 150-fold potency, namely the R2-RepA system. R2-RepA system is only 218 bp in length, expression of any protein could be repressed efficiently by simply inserting this system upstream of the target protein-coding sequence. This study represented a crucial step toward harnessing theophylline riboswitches and expanding the synthetic biology toolbox.

synthetic biology↗

Ploidy variation and spontaneous haploid-diploid switching of Candida glabrata clinical isolates

The human fungal pathogen Candida glabrata is phylogenetically closely related to Saccharomyces cerevisiae, a model eukaryotic organism. Unlike S. cerevisiae with both haploid and diploid forms and a complete sexual cycle, C. glabrata has long been considered a haploid and asexual species. In this study, we analyzed the ploidy states of 500 clinical isolates of C. glabrata from four Chinese hospitals and found that approximately 4% of the isolates were in or able to spontaneously switch to an aneuploidy (genomic DNA: 1N-2N), diploidy (2N), or hyperdiploid (>2N) form under in vivo or in vitro conditions. Stable diploid-form cells were identified in 3% of the isolates (15/500). Of particular interest, one clinical strain only existed in the diploid form. Multilocus sequence typing (MLST) assays revealed two major genetic clusters (A and B) of C. glabrata isolates. Most of the isolates (70%) from China belonged to the A cluster, whereas most of the isolates from other countries (such as Iran, Japan, USA, and European countries) belonged to the B cluster. Further investigation indicated that C. glabrata cells of different ploidy forms differed in a number of aspects, including morphologies, antifungal susceptibility, virulence, and global gene expression profiles. Additionally, C. glabrata could undergo spontaneous switching between the diploid and haploid form under both in vitro and in vivo conditions. Given the absence of an apparent sexual phase, one would expect that the ploidy shifts could function as an alternative strategy that promotes genetic diversity and benefits the ability of the fungus to rapidly adapt to the changing environment. ImportanceThe human fungal pathogen Candida glabrata has long been thought to be a haploid organism. Here we report the population structure and ploidy states of 500 clinical isolates of C. glabrata from China. To our surprise, we found that the ploidy of a subset of clinical isolates varied dramatically. Some isolates were in or able to switch to an aneuploid, diploid, or hyperdiploid form. C. glabrata cells with different ploidy differed in a number of biological aspects, including morphologies, antifungal susceptibility, virulence, and global gene expression profiles. Given the absence of an apparent sexual phase in this fungus, we propose that ploidy switching could be a rapid adaption strategy to environmental changes and could function as an alternative strategy of sexual reproduction.

microbiology↗

PanGu Drug Model: Learn a Molecule Like a Human

Recent achievements in large-scale pre-trained models like GPT-3 and PanGu- showed amazing performances in many downstream tasks, which makes AI friendlier toward industrial users. Deep learning has been recognized as the most promising technology for pharmaceuticals, a powerful molecule pre-trained model could save researchers tons of time. In chemistry classes, the students learn two molecule representations, the molecular formula and the structure formula, and learn to translate them from one way to the other. Inspired by this, we developed a novel deep learning architecture using a graph-to-sequence asymmetric conditional variational autoencoders, called PanGu Drug Model, which can appropriately characterize the molecule from both representations and improve the performance of downstream drug discovery tasks. After pretrained with 1.7 billion small molecules, our proposed model achieved the state-of-the-art results in 20 drug discovery tasks, such as molecule property prediction (predict ADMET properties, compound-target interactions, drug-drug interactions and chemical reaction productivity), molecule generation and molecule optimization. A new drug screening library of 100 million drug-like small molecules with 99.68% novelty was generated by PanGu molecule generator, which could efficiently produce novel compounds with similar physiochemical properties to given distribution, this library could be used to supplement existing compound databases. In addition, PanGu molecule optimizer could optimize the chemical structures of starting molecule with improved molecular property of interest. An automatic multi-objective optimization web application implemented by PanGu Drug Model is available at http://www.pangu-drug.com/.

biochemistry↗

The Structural and Biochemical Basis for FER Receptor Kinase Early Signaling Initiation in Arabidopsis

Accumulating evidence has indicated that receptor-like kinase (RLK) autophosphorylation and substrate phosphorylation triggered by RLK are early and essential events for RLK function. However, the structural and biochemical basis for these early events is largely unclear. Herein, we used RLK FERONIA (FER) as a model and crystallized its core kinase domain (FER-KD) in the dephosphorylated state. We found that FER-KD adopts an active conformation in its crystal structure. Moreover, FER-KD mutants with reduced or no catalytic activity also adopt an active conformation before phosphorylation. Collectively, these observations suggest that FER employs a phosphorylation-independent active state before ligand-induced phosphorylation and full activation. We further demonstrated that FER is a dual-specificity kinase and that autophosphorylation on Tyr residues lags somewhat behind Ser/Thr phosphorylation. More importantly, Tyr phosphorylation is essential for FER-KD to initiate substrate GRP7 phosphorylation. Our work provides a paradigm to study the mechanisms of the early steps of RLK signaling initiation and highlights its "active" form and Tyr phosphorylation-gated roles in response to signaling stimuli.

biochemistry↗

Plant Virus Database: a resource for exploring the diversity of plant viruses and their interactions with hosts

Plant viruses cause huge damage to commercial crops, yet the studies towards plant viruses are limited and the diversity of plant viruses are under-estimated yet. This study built an up-to-date atlas of plant viruses by computationally identifying viruses from the RNA-seq data in the One Thousand Plant Transcriptomes Initiative (1KP) and by integrating plant viruses from public databases, and further built the Plant Virus Database (PVD, freely available at http://47.90.94.155/PlantVirusBase/#/home) to store and organize these viruses. The PVD contained 3,206 virus species and 9,604 virus-plant host interactions which were more than twice that reported in previous plant virus databases. The plant viruses were observed to infect only a few plant hosts and vice versa. Analysis and comparison of the viromes in the Monocots and Eudicots, and those in the plants in tropical and temperate regions showed significant differences in the virome composition. Finally, several factors including the viral group (DNA and RNA viruses), enveloped or not, and the transmission mode of viruses, were found to have no or weak associations with the host range of plant viruses. Overall, the study not only provides a valuable resource for further studies of plant viruses, but also deepens our understanding towards the genetic diversity of plant viruses and the virus-host interactions.

microbiology↗

The Receptor Kinase FER Mediates Phase Separation of Glycine-Rich RNA-Binding Protein 7 to Confer Temperature Resilience in Arabidopsis

Temperature fluctuations repress plant growth. Although glycine-rich RNA-binding proteins (GRPs) and cold shock proteins (CSPs) have been implicated in cold adaptation, their physiological roles in the response to temperature fluctuations are largely unknown. The receptor kinase FERONIA (FER), a master regulator of cell growth, phosphorylates GRP7 within its intrinsically disordered region to modulate mRNA alternative splicing in the nucleus. Here we show that natural variations at a GRP7 residue phosphorylated by FER influences GRP7 liquid-liquid phase separation (LLPS), aiding Arabidopsis to grow over a wider temperature range. LLPS of GRP7 in the cytoplasm leads to the formation of stress granules that recruits RNAs, along with the translation machinery component eIF4E1 and mRNA chaperones, CSP1 and CSP3, to inhibit translation. Mutations in FER and the GRP7-LLPS-recruited components attenuate root growth under temperature shift conditions. Our findings illustrate the roles of GRP7 LLPS in improving plant root capacity to withstand temperature fluctuations.

plant biology↗

Variant to function mapping at single-cell resolution through network propagation

With burgeoning human disease genetic associations and single-cell genomic atlases covering a range of tissues, there are unprecedented opportunities to systematically gain insights into the mechanisms of disease-causal variation. However, sparsity and noise, particularly in the context of single-cell epigenomic data, hamper the identification of disease- or trait-relevant cell types, states, and trajectories. To overcome these challenges, we have developed the SCAVENGE method, which maps causal variants to their relevant cellular context at single-cell resolution by employing the strategy of network propagation. We demonstrate how SCAVENGE can help identify key biological mechanisms underlying human genetic variation including enrichment of blood traits at distinct stages of human hematopoiesis, defining monocyte subsets that increase the risk for severe coronavirus disease 2019 (COVID-19), and identifying intermediate lymphocyte developmental states that are critical for predisposition to acute leukemia. Our approach not only provides a framework for enabling variant-to-function insights at single-cell resolution, but also suggests a more general strategy for maximizing the inferences that can be made using single-cell genomic data.

genomics↗

Cell surface receptor kinase FERONIA linked to nutrient sensor TORC1 signaling controls root hair growth at low temperature in Arabidopsis thaliana

Root hairs (RH) are excellent model systems for studying cell size and polarity since they elongate several hundred-fold their original size. Their tip growth is determined both by intrinsic and environmental signals. Although nutrient availability and temperature are key factors for a sustained plant growth, the molecular mechanisms underlying their sensing and downstream signaling pathways remain unclear. Here, we identified that low temperature (10{degrees}C) triggers a strong RH elongation response involving the cell surface receptor kinase FERONIA (FER) and the nutrient sensing TOR Complex 1 (TORC). In this study, we found that FER is required to perceive limited nutrient availability caused by low temperature. FER interacts with and activates TORC downstream components to trigger RH growth. In addition, the small GTPase Rho-related protein from plants 2 (ROP2) is also involved in this RH growth response linking FER and TOR. We also found that limited nitrogen nutrient availability can mimic the RH growth response at 10{degrees}C in a NRT1.1-dependent manner. These results uncover a molecular mechanism by which a central hub composed by FER-ROP2-TORC is involved in the control of RH elongation under low temperature and nitrogen deficiency.

plant biology↗

Cell transcriptomic atlas of the non-human primate Macaca fascicularis

Studying tissue composition and function in non-human primates (NHP) is crucial to understand the nature of our own species. Here, we present a large-scale single-cell and single-nucleus transcriptomic atlas encompassing over one million cells from 43 tissues from the adult NHP Macaca fascicularis. This dataset provides a vast, carefully annotated, resource to study a species phylogenetically close to humans. As proof of principle, we have reconstructed the cell-cell interaction networks driving Wnt signalling across the body, mapped the distribution of receptors and co-receptors for viruses causing human infectious diseases and intersected our data with human genetic disease orthologous coordinates to identify both expected and unexpected associations. Our Macaca fascicularis cell atlas constitutes an essential reference for future single-cell studies in human and NHP.

cell biology↗

A genetic disorder reveals a hematopoietic stem cell regulatory network co-opted in leukemia

The molecular regulation of human hematopoietic stem cell (HSC) maintenance is therapeutically important, but limitations in experimental systems and interspecies variation have constrained our knowledge of this process. Here, we have studied a rare genetic disorder due to MECOM haploinsufficiency, characterized by an early-onset absence of HSCs in vivo. By generating a faithful model of this disorder in primary human HSCs and coupling functional studies with integrative single-cell genomic analyses, we uncover a key transcriptional network involving hundreds of genes that is required for HSC maintenance. Through our analyses, we nominate cooperating transcriptional regulators and identify how MECOM prevents the CTCF-dependent genome reorganization that occurs as HSCs differentiate. Strikingly, we show that this transcriptional network is co-opted in high-risk leukemias, thereby enabling these cancers to acquire stem cell properties. Collectively, we illuminate a regulatory network necessary for HSC self-renewal through the study of a rare experiment of nature.

cell biology↗

A human monoclonal antibody potently pan-neutralizes SARS-CoV-2 VOCs by targeting RBD invariant sites

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a global pandemic of novel corona virus disease (COVID-19). The neutralizing monoclonal antibodies (mAbs) targeting the receptor binding domain (RBD) of SARS-CoV-2 are among the most promising strategies to prevent and treat COVID-19. However, SARS-CoV-2 variants of concern (VOCs) profoundly reduced the efficacies of most of mAbs and vaccines approved for clinical use. Herein, we demonstrated mAb 35B5 efficiently neutralizes both wild-type (WT) SARS-CoV-2 and VOCs, including B.1.617.2 (delta) variant, in vitro and in vivo. Cryo-electron microscopy (cryo-EM) revealed that 35B5 neutralizes SARS-CoV-2 by targeting a unique epitope that avoids the prevailing mutation sites on RBD identified in circulating VOCs, providing the molecular basis for its pan-neutralizing efficacy. The 35B5-binding epitope could also be exploited for the rational design of a universal SARS-CoV-2 vaccine.

immunology↗

Hidden structure in disordered proteins is adaptive to intracellular changes

Intrinsically disordered proteins and protein regions (IDPs) are essential to cellular function in all proteomes. Unlike folded proteins, IDPs exist in an ensemble of rapidly interchanging conformations. IDP sequences encode interactions that create structural biases within the ensemble. Such structural biases determine the three-dimensional shape of IDP ensembles and can affect their activity. However, the plasticity and sensitivity of IDP ensembles means structural biases, often measured in vitro, may differ in the dynamic and heterogeneous intracellular environment. Here we reveal that structural biases found in vitro in well-studied IDPs persist inside human-derived cells. We further show that a subset of IDPs are able to sense changes in cellular physical-chemical composition and modulate their ensemble in response. We propose that IDP ensembles can evolve to sense and respond to intracellular physicochemical changes, or to resist them. This property can be leveraged for biological function, be the underlying cause of IDP-driven pathology, or be leveraged for the design of disorder-based biosensors and actuators.

biophysics↗

Emergence of an adaptive epigenetic cell state in human bladder urothelial carcinoma evolution

Intratumor heterogeneity (ITH) of bladder cancer (BLCA) facilitates therapy resistance and immune evasion to affect clinical prognosis directly. However, the molecular and cellular mechanism generating ITH in BLCA remains elusive. Here we show that a TM4SF1-positive cancer subpopulation (TPCS) drives ITH diversification in BLCA. By extensive profiling of the epigenome and transcriptome of BLCA from 79 donors across all stages, we elucidated the evolution trajectories of luminal and basal BLCA. TPCS emerges from the basal trajectory and shows extensive transcriptional plasticity with a distinct epigenomic landscape. Clinically, TPCS were enriched in advanced stage patients and associated with poor prognosis. Our results showed how cancer adapts to its environment by adopting a stem cell-like epigenomic landscape.

cancer biology↗

Multi-attribute Glycan Identification and FDR Control for Glycoproteomics

Rapidly improving methods for glycoproteomics have enabled increasingly large-scale analyses of complex glycopeptide samples, but annotating the resulting mass spectrometry data with high confidence remains a major bottleneck. We recently introduced a fast and sensitive glycoproteomics search method in our MSFragger search engine, which reports glycopeptides as a combination of a peptide sequence and the mass of the attached glycan. In samples with complex glycosylation patterns, converting this mass to a specific glycan composition is not straightforward, however, as many glycans have similar or identical masses. Here, we have developed a new method for determining the glycan composition of N-linked glycopeptides fragmented by collision or hybrid activation that uses multiple sources of information from the spectrum, including observed glycan B- (oxonium) and Y-type ions and mass and precursor monoisotopic selection errors to discriminate between possible glycan candidates. Combined with false discovery rate estimation for the glycan assignment, we show this method is capable of specifically and sensitively identifying glycans in complex glycopeptide analyses and effectively controls the rate of false glycan assignments. The new method has been incorporated into the PTM-Shepherd modification analysis tool to work directly with the MSFragger glyco search in the FragPipe graphical user interface, providing a complete computational pipeline for annotation of N-glycopeptide spectra with FDR control of both peptide and glycan components that is both sensitive and robust against false identifications.

bioinformatics↗

CAR modulates plasma membrane nano-organization and immune signaling downstream of RALF1-FERONIA ligand-receptor signaling system

O_LIThe receptor-like kinase (RLK) FERONIA (FER) senses peptide ligands in the plasma membrane (PM), modulates plant growth and development, and integrates biotic and abiotic stress signaling for downstream adaptive response. However, the molecular interplay of these diverse processes is largely unknown. C_LIO_LIHere, we show that FER, the receptor of Rapid Alkalinization Factor 1 (RALF1), physically interacts with C2 domain ABA-related (CAR) proteins to control the nano-organization of the PM in Arabidopsis. C_LIO_LIDuring this process, the RALF1-FER pathway upregulates CAR protein translation, and then more CAR proteins are recruited to PM. This acts as a rapid feedforward loop to stabilize PM liquid-ordered phase. FER interacts with and phosphorylates CARs, and reducing their lipid-binding ability, which breaks the feedback regulation CAR activity at latter time point. C_LIO_LISimilar to FER mutant, pentuple car14569 mutants inhibit flg22-induced FLS2-BAK1 immune complex formation, which depends on the integrity of nanodomains. O_LITogether, we propose that the FER-CAR module controls the formation of the PM nano-organization during RALF signaling through a self-contained amplifying loop including both positive and negative feedbacks. C_LI C_LI

plant biology↗

Molecular Swiss Army Knives: Tardigrade CAHS Proteins Mediate Desiccation Tolerance Through Multiple Mechanisms

Tardigrades, also known as water bears, make up a phylum of small but extremely hardy animals, renowned for their ability to survive extreme stresses, including desiccation. How tardigrades survive desiccation is one of the enduring mysteries of animal physiology. Here we show that CAHS D, an intrinsically disordered protein belonging to a unique family of proteins possessed only by tardigrades, undergoes a liquid-to-gel phase transition in a concentration dependent manner. Unlike other gelling proteins, such as gelatin, our data support a mechanism in which gel formation of CAHS D is driven by intermolecular {beta}-{beta} interactions. We find that gel formation corresponds with strong coordination of water and slowing of water diffusion. The degree of water coordination correlates with the ability of CAHS D to protect lactate dehydrogenase from unfolding when dried. This implies that the mechanism for unfolding protection can be attributed to a combination of hydration and slowed molecular motion. Conversely, rapid diffusion leading to efficient molecular shielding appears to be the predominant mechanism preventing protein aggregation. Our study demonstrates that distinct mechanisms are required for holistic protection during desiccation, and that protectants, such as CAHS D, can act as molecular Swiss Army Knives capable of providing protection through several different mechanisms simultaneously.

biophysics↗

Modulation of the renin-angiotensin system inhibits memory advantage for negative emotional material via decreasing hippocampus activation and its coupling with the amygdala

Exaggerated arousal and dysregulated emotion-memory interactions are key pathological dysregulations that accompany the development of post-traumatic stress disorder (PTSD). Current treatments for PTSD are of moderate efficacy and preventing the dysregulations already during exposure to threatening events may attenuate the development of PTSD-symptomatology. In a preregistered double-blind, between-subject, placebo-controlled pharmaco-fMRI design, the present proof-of-concept study examined the potential of a single dose of angiotensin II type 1 receptor (AT1R) antagonist losartan (LT) to attenuate the mnemonic advantage of threatening stimuli and the underlying neural mechanism via combining an emotional subsequent memory paradigm with LT (n=29) or placebo treatment (n=30) and a surprise memory test after 24h washout. LT generally improved memory performance and abolished emotional memory enhancement for negative yet not positive material while emotional experience during encoding remained intact. LT further suppressed hippocampus activity during encoding of subsequently remembered negative stimuli. On the network level LT reduced coupling between hippocampus and basolateral amygdala during successful memory formation of negative stimuli. Our findings suggest that LT may have the potential to attenuate memory formation for negative yet not positive information by decreasing hippocampus activity and its functional coupling strength with amygdala. These findings suggest a promising potential of LT to prevent preferential encoding and remembering of negative events, a mechanism that could prevent the emotion-memory dysregulations underlying the development of PTSD-symptomatology.

neuroscience↗