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Qiu, Y.

Publications and source records attributed to Qiu, Y..

At least 199 records · Page 11Linked to original sources

A deep learning framework for elucidating whole-genome chemical interaction space

Molecular interaction is the foundation of biological process. Elucidation of genome-wide binding partners of a biomolecule will address many questions in biomedicine. However, ligands of a vast number of proteins remain elusive. Existing methods mostly fail when the protein of interest is dissimilar from those with known functions or structures. We develop a new deep learning framework DISAE that incorporates biological knowledge into self-supervised learning techniques for predicting ligands of novel unannotated proteins on a genome-scale. In the rigorous benchmark studies, DISAE outperforms state-of-the-art methods by a significant margin. The interpretability analysis of DISAE suggests that it learns biologically meaningful information. We further use DISAE to assign ligands to human orphan G-Protein Coupled Receptors (GPCRs) and to cluster the human GPCRome by integrating their phylogenetic and ligand relationships. The promising results of DISAE open an avenue for exploring the chemical landscape of entire sequenced genomes.

bioinformatics↗

Population Level Variation of Transposable Elements in a Maize Diversity Panel

Intact transposable elements (TEs) account for 65% of the maize genome and can impact gene function and regulation. Although TEs comprise the majority of the maize genome and affect important phenotypes, genome wide patterns of TE polymorphisms in maize have only been studied in a handful of maize genotypes, due to the challenging nature of assessing highly repetitive sequences. We implemented a method to use short read sequencing data from 509 diverse inbred lines to classify the presence/absence of 445,418 non-redundant TEs that were previously annotated in four genome assemblies including B73, Mo17, PH207, and W22. Different orders of TEs (i.e. LTRs, Helitrons, TIRs) had different frequency distributions within the population. LTRs with lower LTR similarity were generally more frequent in the population than LTRs with higher LTR similarity, though high frequency insertions with very high LTR similarity were observed. LTR similarity and frequency estimates of nested elements and the outer elements in which they insert revealed that most nesting events occurred very near the timing of the outer element insertion. TEs within genes were at higher frequency than those that were outside of genes and this is particularly true for those not inserted into introns. Many TE insertional polymorphisms observed in this population were tagged by SNP markers. However, there were also 19.9% of the TE polymorphisms that were not well tagged by SNPs (R2 < 0.5) that potentially represent information that has not been well captured in previous SNP based marker-trait association studies. This study provides a population scale genome-wide assessment of TE variation in maize, and provides valuable insight on variation in TEs in maize and factors that contribute to this variation.

plant biology↗

Automatic Traits Extraction and Fitting for Field High-throughput Phenotyping Systems

High-throughput phenotyping is a modern technology to measure plant traits efficiently and in large scale by imaging systems over the whole growth season. Those images provide rich data for statistical analysis of plant phenotypes. We propose a pipeline to extract and analyze the plant traits for field phenotyping systems. The proposed pipeline include the following main steps: plant segmentation from field images, automatic calculation of plant traits from the segmented images, and functional curve fitting for the extracted traits. To deal with the challenging problem of plant segmentation for field images, we propose a novel approach on image pixel classification by transform domain neural network models, which utilizes plant pixels from greenhouse images to train a segmentation model for field images. Our results show the proposed procedure is able to accurately extract plant heights and is more stable than results from Amazon Turks, who manually measure plant heights from original images.

plant biology↗

A dual mechanism of enhancer activation by FOXA pioneer factors induces endodermal organ fates

FOXA pioneer transcription factors (TFs) displace nucleosomes and prime chromatin across enhancers of different endodermal organs in multipotent precursors before lineage induction. Here, we examined patterns and mechanisms of FOXA target site engagement using human pluripotent stem cell models of endodermal organ development. Unexpectedly, we find that only a subset of pancreatic, hepatic, and alveolar enhancers are FOXA-primed, whereas the majority are unprimed and engage FOXA only upon lineage induction. Analysis of sequence architecture revealed more abundant and stronger FOXA motifs at primed than unprimed enhancers and enrichment for lineage-specific TF motifs at unprimed enhancers. We show that FOXA recruitment to unprimed enhancers specifically depends on lineage-specific TFs, suggesting that regulatory DNA sequence logic governs temporal FOXA recruitment. Our findings suggest that FOXA-mediated enhancer priming broadly facilitates initiation of organ lineage programs, while secondary FOXA recruitment by lineage-specific TFs to the majority of enhancers confers organ specificity to gene expression.

genomics↗

Formation of an Aminovinyl-Cysteine Residue in Thioviridamide Non-Lanthipeptides Occurs through a Path Independent of Known Lanthionine Synthetase Activity in Streptomyces sp. NRRL S-87

2-Aminovinyl-cysteine (AviCys) is an unusual thioether amino acid shared by a variety of ribosomally synthesized and posttranslationally modified peptides (RiPPs), as part of a macrocyclic ring system that contains the C-terminal 4 or 6 residues of a precursor peptide. This amino acid is nonproteinogenic and arises from processing the C-terminal Cys residue and an internal Ser/Thr residue to form an unsaturated thioether linkage. Enzyme activities for forming lanthionine (Lan), a distinct saturated thioether residue characteristic of lanthipeptide-related RiPPs, has long been speculated to be necessary for AviCys formation. Based on investigations into the biosynthesis of thioviridamide non-lanthipeptdes in Streptomyces sp. NRRL S-87, we here report an alternative path for AviCys formation that is independent of known Lan synthetase activity. This path relies on four dedicated enzymes for posttranslational modifications of the precursor peptide, in which TvaES-87, a phosphotransferase homolog, plays a critical role. It works with LanD-like flavoprotein TvaFS-87 to form a minimum AviCys synthetase complex that follows the combined activity of TvaCDS-87 for Thr dehydration and catalyzes Cys oxidative decarboxylation and subsequent Michael addition of the resulting enethiol nucleophile onto the newly formed dehydrobutyrine residue for cyclization. With TvaES-87, TvaFS-87 activity for Cys processing can be coordinated with TvaCDS-87 activity for minimizing competitive or unexpected spontaneous reactions and forming AviCys effectively.

biochemistry↗

Genome-wide Prediction of Small Molecule Binding to Remote Orphan Proteins Using Distilled Sequence Alignment Embedding

Endogenous or surrogate ligands of a vast number of proteins remain unknown. Identification of small molecules that bind to these orphan proteins will not only shed new light into their biological functions but also provide new opportunities for drug discovery. Deep learning plays an increasing role in the prediction of chemical-protein interactions, but it faces several challenges in protein deorphanization. Bioassay data are highly biased to certain proteins, making it difficult to train a generalizable machine learning model for the proteins that are dissimilar from the ones in the training data set. Pre-training offers a general solution to improving the model generalization, but needs incorporation of domain knowledge and customization of task-specific supervised learning. To address these challenges, we develop a novel protein pre-training method, DIstilled Sequence Alignment Embedding (DISAE), and a module-based fine-tuning strategy for the protein deorphanization. In the benchmark studies, DISAE significantly improves the generalizability and outperforms the state-of-the-art methods with a large margin. The interpretability analysis of pre-trained model suggests that it learns biologically meaningful information. We further use DISAE to assign ligands to 649 human orphan G-Protein Coupled Receptors (GPCRs) and to cluster the human GPCRome by integrating their phylogenetic and ligand relationships. The promising results of DISAE open an avenue for exploring the chemical landscape of entire sequenced genomes.

systems biology↗

AD-linked R47H-TREM2 mutation induces disease-enhancing proinflammatory microglial states in mice and humans

The hemizygous R47H variant of TREM2, a microglia-specific gene in the brain, increases risk for late-onset Alzheimers disease (AD). In this study, we identified a subpopulation of microglia with disease-enhancing proinflammatory signatures associated with the R47H mutation in human AD brains and tauopathy mouse brains. Using transcriptomic analysis at the single-nuclei level from AD patients with the R47H or the common variant (CV)-TREM2 with matched sex, pathology and APOE status, we found that the R47H mutation was associated with cell type- and sex-specific transcriptional changes in human AD brains, with microglia exhibiting the most robust alterations. Further characterization revealed that R47H-associated microglial subpopulations had enhanced inflammatory signatures including hyperactivation of Akt, one of the signaling pathways downstream of TREM2. In a newly-generated tauopathy knock-in mouse model expressing one allele of human TREM2 (hTREM2) with either the R47H mutation or CV, R47H induced and exacerbated tau-mediated spatial memory deficits in female mice. Single-cell transcriptomic analysis of microglia from these mice also revealed transcriptomic changes induced by R47H that had significant overlaps with R47H microglia in human AD brains, including robust increases in proinflammatory cytokines, activation of Syk-Akt-signaling, and elevation of a subset of disease-associated microglial signatures. Strikingly, pharmacological Akt inhibition largely reversed the enhanced inflammatory signatures induced by R47H in primary microglia treated with tau fibrils. By unraveling the disease-enhancing properties of the R47H mutation in mouse and human, our findings shed light on an immune-linked AD subtype and provide new directions for modulating microglial immune responses to treat AD.

neuroscience↗

Unique Proteomes Implicate Functional Specialization across Heterocysts, Akinetes, and Vegetative Cells in Anabaena cylindrica

In response to environmental changes, vegetative cells of Anabaena cylindrica can differentiate into two other cell types: a heterocyst for oxic N2-fixation, and an enlarged spore called akinete for stress survival. Akinetes normally differentiate from vegetative cells adjacent to heterocysts. Heterocysts inhibit nearby cells from differentiating into heterocysts but can induce adjacent cells to become akinetes, a rare embryogenetic induction in prokaryotes. The mechanism for a patterned differentiation in A. cylindrica has been little studied. Here, we isolated three types of cells from A. cylindrica to identify their proteomes using LC-MS/MS. A total of 1395 proteins were identified, including 664 proteins from akinetes, 751 proteins from heterocysts, and 1236 proteins from vegetative cells. There were 45 proteins (33 novel proteins) found exclusive to akinetes, 57 heterocyst-specific proteins (33 novel proteins), including nif gene products, and 485 proteins exclusively in vegetative cells. Our proteomic data suggest that akinetes, unlike the typical spores of bacteria, perform unique biochemical functions that collaborate with both heterocysts and vegetative cells. A HAVe model for collaboration among heterocysts, akinetes and vegetative cells is proposed to illustrate the metabolic network of cyanophycin and carbohydrates based on the distribution of their biosynthesis related proteins in three types of cells. Interestingly, cell division proteins, DNA replication proteins, some carboxysomal proteins including RuBisCO and proteins in photosystems I, II were found abundant in heterocysts, the non-dividing cells dedicated exclusively to oxic N2-fixation. The identification of the akinete and heterocyst proteomes enables the pursuit of genetic studies into the patterned differentiation of akinetes and heterocysts.

microbiology↗

Receptor utilization of angiotensin converting enzyme 2 (ACE2) indicates a narrower host range of SARS-CoV-2 than that of SARS-CoV

Coronavirus pandemics have become a huge threat to the public health worldwide in the recent decades. Typically, SARS-CoV caused SARS pandemic in 2003 and SARS-CoV-2 caused the COVID-19 pandemic recently. Both viruses have been reported to originate from bats. Thus, direct or indirect interspecies transmission from bats to humans is required for the viruses to cause pandemics. Receptor utilization is a key factor determining the host range of viruses which is critical to the interspecies transmission. Angiotensin converting enzyme 2 (ACE2) is the receptor of both SARS-CoV and SARS-CoV-2, but only ACE2s of certain animals can be utilized by the viruses. Here, we employed pseudovirus cell-entry assay to evaluate the receptor-utilizing capability of ACE2s of 20 animals by the two viruses and found that SARS-CoV-2 utilized less ACE2s than SARS-CoV, indicating a narrower host range of SARS-CoV-2. Meanwhile, pangolin CoV, another SARS-related coronavirus highly homologous to SARS-CoV-2 in its genome, yet showed similar ACE2 utilization profile with SARS-CoV rather than SARS-CoV-2. To clarify the mechanism underlying the receptor utilization, we compared the amino acid sequences of the 20 ACE2s and found 5 amino acid residues potentially critical for ACE2 utilization, including the N-terminal 20th and 42nd amino acids that may determine the different receptor utilization of SARS-CoV, SARS-CoV-2 and pangolin CoV. Our studies promote the understanding of receptor utilization of pandemic coronaviruses, potentially contributing to the virus tracing, intermediate host screening and epidemic prevention for pathogenic coronaviruses.

microbiology↗

Cross-neutralization antibodies against SARS-CoV-2 and RBD mutations from convalescent patient antibody libraries

The emergence of coronavirus disease 2019 (COVID-19) pandemic led to an urgent need to develop therapeutic interventions. Among them, neutralizing antibodies play crucial roles for preventing viral infections and contribute to resolution of infection. Here, we describe the generation of antibody libraries from 17 different COVID-19 recovered patients and screening of neutralizing antibodies to SARS-CoV-2. After 3 rounds of panning, 456 positive phage clones were obtained with high affinity to RBD (receptor binding domain). Then the positive clones were sequenced and reconstituted into whole human IgG for epitope binning assays. After that, all 19 IgG were classified into 6 different epitope groups or Bins. Although all these antibodies were shown to have ability to bind RBD, the antibodies in Bin2 have more superiority to inhibit the interaction between spike protein and angiotensin converting enzyme 2 receptor (ACE2). Most importantly, the antibodies from Bin2 can also strongly bind with mutant RBDs (W463R, R408I, N354D, V367F and N354D/D364Y) derived from SARS-CoV-2 strain with increased infectivity, suggesting the great potential of these antibodies in preventing infection of SARS-CoV-2 and its mutations. Furthermore, these neutralizing antibodies strongly restrict the binding of RBD to hACE2 overexpressed 293T cells. Consistently, these antibodies effectively neutralized pseudovirus entry into hACE2 overexpressed 293T cells. In Vero-E6 cells, these antibodies can even block the entry of live SARS-CoV-2 into cells at only 12.5 nM. These results suggest that these neutralizing human antibodies from the patient-derived antibody libraries have the potential to become therapeutic agents against SARS-CoV-2 and its mutants in this global pandemic.

immunology↗

Characterization of the substitution hotspots in SARS-CoV-2 genome using BioAider and detection of a SR-rich region in N protein providing further evidence of its animal origin

The novel human coronavirus (SARS-CoV-2) causes the coronavirus disease 2019 (COVID-19) pandemic worldwide. The increasing sequencing data have shown abundant single nucleotide variations in SARS-CoV-2 genome. However, it is difficult to quickly analyze genomic variation and screen key mutations of SARS-CoV-2. In this study, we developed a visual program, named BioAider, for quick and convenient sequence annotation and mutation analysis on multiple genome-sequencing data. Using BioAider, we conducted a comprehensive genome variation analysis on 3,240 sequences of SARS-CoV-2 genome. Herein, we detected 14 substitution hotspots within SARS-CoV-2 genome, including 10 non-synonymous and 4 synonymous ones. Among these hotspots, NSP13-Y541C was predicted to be a crucial substitution which might affect the unwinding activity of NSP13, a key protein for viral replication. Besides, we also found 3 groups of potentially linked substitution hotspots which were worth further study. In particular, we discovered a SR-rich region (aa 184-204) on the N protein of SARS-CoV-2 distinct from SARS-CoV, indicating more complex replication mechanism and unique N-M interaction of SARS-CoV-2. Interestingly, the quantity of SRXX repeat fragments in the SR-rich region well reflected the evolutionary relationship among SARS-CoV-2 and SARS-CoV-2 related animal coronaviruses, providing further evidence of its animal origin. Overall, we developed an efficient tool for rapid identification of mutations, identified substitution hotspots in SARS-CoV-2 genomes, and detected a distinctive polymorphism SR-rich region in N protein. This tool and the detected hotspots could facilitate the viral genomic study and may contribute for screening antiviral target sites.

genomics↗

Pancreatic progenitor epigenome maps prioritize type 2 diabetes risk genes with roles in development

Genetic variants associated with type 2 diabetes (T2D) risk affect gene regulation in metabolically relevant tissues, such as pancreatic islets. Here, we investigated contributions of regulatory programs active during pancreatic development to T2D risk. Generation of chromatin maps from developmental precursors throughout pancreatic differentiation of human embryonic stem cells (hESCs) identifies enrichment of T2D variants in pancreatic progenitor-specific stretch enhancers that are not active in islets. Genes associated with progenitor-specific stretch enhancers are predicted to regulate developmental processes, most notably tissue morphogenesis. Through gene editing in hESCs, we demonstrate that progenitor-specific enhancers harboring T2D-associated variants regulate cell polarity genes LAMA1 and CRB2. Knockdown of lama1 or crb2 in zebrafish embryos causes a defect in pancreas morphogenesis and impairs islet cell development. Together, our findings reveal that a subset of T2D risk variants specifically affects pancreatic developmental programs, suggesting that dysregulation of developmental processes can predispose to T2D.

genomics↗

An Atlas of Gene Regulatory Elements in Adult Mouse Cerebrum

The mammalian cerebrum performs high level sensory, motor control and cognitive functions through highly specialized cortical networks and subcortical nuclei. Recent surveys of mouse and human brains with single cell transcriptomics1-3 and high-throughput imaging technologies4,5 have uncovered hundreds of neuronal cell types and a variety of non-neuronal cell types distributed in different brain regions, but the cell-type-specific transcriptional regulatory programs responsible for the unique identity and function of each brain cell type have yet to be elucidated. Here, we probe the accessible chromatin in >800,000 individual nuclei from 45 regions spanning the adult mouse isocortex, olfactory bulb, hippocampus and cerebral nuclei, and use the resulting data to define 491,818 candidate cis regulatory DNA elements in 160 distinct sub-types. We link a significant fraction of them to putative target genes expressed in diverse cerebral cell types and uncover transcriptional regulators involved in a broad spectrum of molecular and cellular pathways in different neuronal and glial cell populations. Our results provide a foundation for comprehensive analysis of gene regulatory programs of the mammalian brain and assist in the interpretation of non-coding risk variants associated with various neurological disease and traits in humans. To facilitate the dissemination of information, we have set up a web portal (http://catlas.org/mousebrain).

neuroscience↗

SARS-CoV-2 Spike Glycoprotein Receptor Binding Domain is Subject to Negative Selection with Predicted Positive Selection Mutations

COVID-19 is a highly contagious disease caused by a novel coronavirus SARS-CoV-2. The interaction between SARS-CoV-2 spike protein and the host cell surface receptor ACE2 is responsible for mediating SARS-CoV-2 infection. By analyzing the spike-hACE2 interacting surface, we predicted many hot spot residues that make major contributions to the binding affinity. Mutations on most of these residues are likely to be deleterious, leading to less infectious virus strains that may suffer from negative selection. Meanwhile, several residues with mostly advantageous mutations have been predicted. It is more probable that mutations on these residues increase the transmission ability of the virus by enhancing spike-hACE2 interaction. So far, only a limited number of mutations has been reported in this region. However, the list of hot spot residues with predicted downstream effects from this study can still serve as a tracking list for SARS-CoV-2 evolution studies. Coincidentally, one advantageous mutation, p.476G>S, started to surge in the last couple of weeks based on the data submitted to the public domain, indicating that virus strains with increased transmission ability may have already spread.

bioinformatics↗

Mosquito defensins enhance Japanese encephalitis virus infection by facilitating virus adsorption and entry within mosquito

Japanese encephalitis virus (JEV) is a viral zoonosis which can cause viral encephalitis, death and disability. Culex is the main vector of JEV, but little is known about JEV transmission by this kind of mosquito. Here, we found that mosquito defensin facilitated the adsorption of JEV on target cells via both direct and indirect pathways. Mosquito defensin bound the ED III domain of viral E protein and directly mediated efficient virus adsorption on the target cell surface, Lipoprotein receptor-related protein 2 expressed on the cell surface is the receptor affecting defensin dependent adsorption. Mosquito defensin also indirectly down-regulated the expression of an antiviral protein, HSC70B. As a result, mosquitos defensin enhances JEV infection in salivary gland while increasing the possibility of viral transmission by mosquito. These findings demonstrate that the novel effects of mosquito defensin in JEV infection and the mechanisms through which the virus exploits mosquito defensin for infection and transmission.

microbiology↗

Building a Reference Transcriptome for the Hexaploid Hard Fescue Turfgrass (Festuca brevipila) Using a Combination of PacBio IsoSeq and Illumina Sequencing

BackgroundHard fescue (Festuca brevipila Tracey, 2n=6x=42) is a cool season turfgrass with a fine leaf texture that performs well under low-input management. Breeding and genetics studies of F. brevipila have been limited due to the complexity of its hexaploid genome. To advance our knowledge of F. brevipila genomics, we used PacBio isoform sequencing to develop a reference transcriptome for this species. ResultsHere, we report the F. brevipila reference transcriptome generated from root, crown, leaf, and inflorescence tissues. We obtained 59,510 full-length transcripts, of which 38,556 were non-redundant full-length transcripts. The longest and shortest transcripts were 11,487 and 58 bp, respectively. Distribution of synonymous distances among paralogs within F. brevipila suggested highly similar subgenomes that are difficult to distinguish from sequencing errors. To evaluate the phylogenetic relationships among F. brevipila and close relatives, we sequenced three additional transcriptomes using closely related species on an Illumina platform. The results of our phylotranscriptomic analysis supported the close relationships among F. brevipila (6x), Festuca ovina (4x), Festuca ovina subsp. ovina (2x), and Festuca valesiaca (2x), with high levels of discordance among gene trees. ConclusionsOverall, the F. brevipila PacBio Isoseq reference transcriptome provided the foundation for transcriptome studies and allowed breeders a resource for gene discovery in this important turfgrass species.

plant biology↗

LanD-like Flavoprotein-Catalyzed Aminovinyl-Cysteine Formation through Oxidative Decarboxylation and Cyclization of a Peptide at the C-Terminus

Aminovinyl-cysteine residues arise from processing the C-terminal O_SCPLOWLC_SCPLOW-Cys and an internal O_SCPLOWLC_SCPLOW-Ser/O_SCPLOWLC_SCPLOW-Thr or O_SCPLOWLC_SCPLOW-Cys of a peptide. Formation of these nonproteinogenic amino acids, which occur in a macrocyclic ring of diverse ribosomally synthesized lanthipeptides and non-lanthipeptides, remains poorly understood. Here, we report that LanD-like flavoproteins in the biosynthesis of distinct non-lanthipeptides share an unexpected dual activity for aminovinyl-cysteine formation. Each flavoprotein catalyzes oxidative decarboxylation of the C-terminal O_SCPLOWLC_SCPLOW-Cys and couples the resulting enethiol nucleophile with the internal residue to afford a thioether linkage for peptide cyclization. The cyclization step, which largely depends on proximity effect by positioning the enethiol intermediate with a bent conformation at the active site, can be substrate-dependent, proceeding inefficiently through nucleophilic substitution for an unmodified peptide or efficiently through Michael addition for a dehydrated/dethiolated peptide. Uncovering this unusual flavin-dependent paradigm for thioether residue formation advances the understanding in the biosynthesis of aminovinyl-cysteine-containing RiPPs and renews interest in flavoproteins, particularly those involved in non-redox transformations. LanD-like flavoproteins activity, which is flexible in peptide substrate and amenable for evolution by engineering, can be combined with different post-translational modifications for structural diversity, thereby holding promise for peptide macrocyclization/functionalization in drug development by chemoenzymatic or synthetic biology approaches.

biochemistry↗

Increases in ambient temperature progressively disassemble Arabidopsis phytochrome B from individual photobodies with distinct thermostabilities

Warm temperature is postulated to induce plant thermomorphogenesis through a signaling mechanism similar to shade, as both destabilize the active form of the photoreceptor and thermosensor phytochrome B (phyB). At the cellular level, shade antagonizes phyB signaling by triggering phyB disassembly from photobodies. Here we report temperature-dependent photobody localization of fluorescent protein-tagged phyB (phyB-FP) in the epidermal cells of Arabidopsis hypocotyl and cotyledon. Our results demonstrate that warm temperature operates through different photobody dynamics from shade. Increases in temperature from 12{degrees}C to 27{degrees}C incrementally reduce photobody number by stimulating phyB-FP disassembly from selective thermo-unstable photobodies. The thermostability of photobodies relies on phyBs photosensory module. Surprisingly, elevated temperatures inflict opposite effects on phyBs functions in the hypocotyl and cotyledon despite inducing similar photobody dynamics, indicative of tissue/organ-specific temperature signaling circuitry downstream of photobody dynamics. Our results thus provide direct cell biology evidence supporting an early temperature signaling mechanism via dynamic assembly/disassembly of individual photobodies possessing distinct thermostabilities.

plant biology↗