Biology subjects

Shi, Y.

Publications and source records attributed to Shi, Y..

At least 253 records · Page 14Linked to original sources

bioRxiv2023

Comparative Analysis of Molecular Pathogenic Mechanisms and Antiviral Development Targeting Old and New World Hantaviruses

BackgroundHantaviruses - dichotomized into New World (i.e. Andes virus, ANDV; Sin Nombre virus, SNV) and Old-World viruses (i.e. Hantaan virus, HTNV) - are zoonotic viruses transmitted from rodents to humans. Currently, no FDA-approved vaccines against hantaviruses exist. Given the recent breakthrough to human-human transmission by the ANDV, an essential step is to establish an effective pandemic preparedness infrastructure to rapidly identify cell tropism, infective potential, and effective therapeutic agents through systematic investigation. MethodsWe established human cell model systems in lung (airway and distal lung epithelial cells), heart (pluripotent stem cell-derived (PSC-) cardiomyocytes), and brain (PSC-astrocytes) cell types and subsequently evaluated ANDV, HTNV and SNV tropisms. Transcriptomic, lipidomic and bioinformatic data analyses were performed to identify the molecular pathogenic mechanisms of viruses in different cell types. This cell-based infection system was utilized to establish a drug testing platform and pharmacogenomic comparisons. ResultsANDV showed broad tropism for all cell types assessed. HTNV replication was predominantly observed in heart and brain cells. ANDV efficiently replicated in human and mouse 3D distal lung organoids. Transcriptomic analysis showed that ANDV infection resulted in pronounced inflammatory response and downregulation of cholesterol biosynthesis pathway in lung cells. Lipidomic profiling revealed that ANDV-infected cells showed reduced level of cholesterol esters and triglycerides. Further analysis of pathway-based molecular signatures showed that, compared to SNV and HTNV, ANDV infection caused drastic lung cell injury responses. A selective drug screening identified STING agonists, nucleoside analogues and plant-derived compounds that inhibited ANDV viral infection and rescued cellular metabolism. In line with experimental results, transcriptome data shows that the least number of total and unique differentially expressed genes were identified in urolithin B- and favipiravir-treated cells, confirming the higher efficiency of these two drugs in inhibiting ANDV, resulting in host cell ability to balance gene expression to establish proper cell functioning. ConclusionsOverall, our study describes advanced human PSC-derived model systems and systems-level transcriptomics and lipidomic data to better understand Old and New World hantaviral tropism, as well as drug candidates that can be further assessed for potential rapid deployment in the event of a pandemic.

microbiology↗

bioRxiv2023

Directly selecting differentially expressed genes for single-cell clustering analyses

In single-cell RNA sequencing (scRNA-seq) studies, cell-types and their associated marker genes are often identified by clustering and differential expression gene (DEG) analysis. scRNA-seq data contain many genes not relevant to cell-types and gene selection procedures are needed for more accurate clustering. An ideal gene selection procedure should select all DEGs between cell-types for best cell-type identification. However, because cell-types are unknown, gene selection and DEG analysis are performed separately using different methods. Genes are selected using surrogate criteria not directly related with clustering, which often miss important genes or select unimportant genes. Clustering accuracy could be seriously influenced because of the inferior gene selection. DEGs are often detected by comparing different clusters, leading to many false DEGs due to the selection bias problem. In this paper, we present Festem, a unified method for gene selection and DEG analysis in scRNA-seq studies. Festem investigates genes clustering information based on the observation that marginal distributions of DEGs are mixtures of their different cell-type-conditional distributions, and can directly select the clustering-informative DEGs and avoid the selection bias problem. Extensive simulation and real data analyses show that Festem achieves high precision and recall for DEG detection, and enables more accurate clustering and cell-type identification. Applications to several scRNA-seq datasets demonstrate that Festem can identify cell-types that are often missed by other methods. In a large intrahepatic cholangiocarcinoma dataset, we identify CD8+ T cell-types and find that their marker genes are novel prognostic biomarkers.

bioinformatics↗

bioRxiv2023

ZBTB48 is a pioneer factor regulating B-cell-specific CIITA expression

CIITA is the master regulator of MHC II gene expression and hence the adaptive immune response. CIITA expression itself is tightly regulated by three cell type-specific promoters, pI, pIII, and by pIV, and can also be induced by IFN{gamma} in non-immune cells. While key regulatory elements have been identified within these promoters, knowledge of transcription factors regulating CIITA is incomplete. Here, we demonstrate that the telomere-binding protein and transcriptional activator ZBTB48 directly binds to both the critical activating elements within CIITA pIII and is essential for its gene expression. ZBTB48 establishes open chromatin at CIITA pIII upstream of activating H3K4me3 modifications both priming CIITA transcription for IFN{gamma}-induction and ensuring constitutive expression in primary murine B cells. Hence, ZBTB48 acts as a molecular on-off-switch for B-cell-specific CIITA expression.

immunology↗

bioRxiv2023

The Role and Mechanism of TEAD4 in Preimplantation Embryonic Development in Mice and Cattle

Tead4, a critical transcription factor expressed during preimplantation development, is essential for the expression of trophectoderm-specific genes in mice. However, the functional mechanism of Tead4 in mouse preimplantation development and its conservation across mammals remain unclear. Here, we report that Tead4 is a crucial transcription factor necessary for blastocyst formation in mice. Disruption of Tead4 through base editing results in developmental arrest at the morula stage. Additionally, RNA-seq analysis reveals dysregulation of 670 genes in Tead4 knockout embryos. As anticipated, Tead4 knockout leads to a decrease in trophectoderm genes Cdx2 and Gata3. Intriguingly, we observed a reduction in Krt8, suggesting that Tead4 influences the integrity of the trophectoderm epithelium in mice. More importantly, we noted a dramatic decrease in nuclear Yap in outside cells for Tead4-deficient morula, indicating that Tead4 directly regulates Hippo signaling. In contrast, bovine embryos with TEAD4 depletion could still develop to blastocysts with normal expression of CDX2, GATA3, and SOX2, albeit with a decrease in total cell number and ICM cell number. In conclusion, we propose that Tead4 regulates mouse blastocyst formation via Krt8 and Yap, both of which are critical regulators of mouse preimplantation development.

developmental biology↗

bioRxiv2023

MicroRNA-375 is induced during astrocyte-to-neuron reprogramming and promotes survival of reprogrammed neurons when overexpressed

While astrocyte-to-neuron (AtN) reprogramming holds great promise in regenerative medicine, the molecular mechanisms that govern this unique biological process remain elusive. MicroRNAs (miRNAs), as post-transcriptional regulators of gene expression, play crucial roles during development and under various pathological conditions. To understand the function of miRNAs during AtN reprogramming process, we performed RNA-seq of both mRNAs and miRNAs on human astrocyte (HA) cultures upon NeuroD1 overexpression. Bioinformatics analyses showed that NeuroD1 not only activates essential neuronal genes to initiate reprogramming process but also induces miRNA changes in HA. Among the upregulated miRNAs, we identified miR-375 and its targets, neuronal ELAVL genes (nELAVLs), which encode a family of RNA-binding proteins and are also upregulated by NeuroD1. We further showed that manipulating miR-375 level regulates nELAVLs expression during NeuroD1-mediated reprogramming. Interestingly, miR-375/nELAVLs are also induced by reprogramming factors Neurog2 and ASCL1 in HA suggesting a conserved function to neuronal reprogramming, and by NeuroD1 in the mouse astrocyte culture and spinal cord. Functionally, we showed that miR-375 overexpression improves NeuroD1-mediated reprogramming efficiency by promoting cell survival at early stages in HA even in cultures treated with the chemotherapy drug Cisplatin. Moreover, miR-375 overexpression doesnt appear to compromise maturation of the reprogrammed neurons in long term HA cultures. Lastly, overexpression of miR-375-refractory ELAVL4 induces apoptosis and reverses the cell survival-promoting effect of miR-375 during AtN reprogramming. Together, we demonstrate a neuro-protective role of miR-375 during NeuroD1-mediated AtN reprogramming and suggest a strategy of combinatory overexpression of NeuroD1 and miR-375 for improving neuronal reprogramming efficiency.

neuroscience↗

bioRxiv2023

A Brain-Wide Map of Neural Activity during Complex Behaviour

A key challenge in neuroscience is understanding how neurons in hundreds of interconnected brain regions integrate sensory inputs with prior expectations to initiate movements and thereby make decisions. It is difficult to meet this challenge if different laboratories apply different analyses to different recordings in different regions during different behaviours. Here, we report a comprehensive set of recordings from 621733 neurons across 139 mice in 12 labs performing a decision-making task with sensory, motor, and cognitive components, obtained with 699 Neuropixels probe insertions covering 279 brain areas in the left forebrain and midbrain and the right hindbrain and cerebellum. We provide an initial appraisal of this brain-wide map, assessing how neural activity encoded key task variables. Representations of visual stimuli appeared transiently in classical visual areas after stimulus onset and then spread to ramp-like activity in a collection of mid- and hindbrain regions that also encoded choices. Neural responses correlated with motor action almost everywhere in the brain. Responses to reward delivery and consumption versus negative feedback were also widespread. This publicly available dataset represents an unprecedented resource for understanding how computations distributed across and within brain areas drive behaviour.

neuroscience↗

bioRxiv2023

Srcap Haploinsufficiency Induced Autistic-Like Behaviors in Mice through Disruption of Satb2 Expression

Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder with significant genetic predispositions. Among these, loss-of-function mutations of the chromatin remodeling gene SRCAP have been identified in individuals with ASD, but their pathogenic mechanisms have yet to be fully elucidated. In this study, we established a germline mutant mouse model harboring a heterozygous frameshift mutation in the Srcap gene (Srcap+/-). The Srcap+/- mice exhibited notable impairments in social novelty, repetitive and stereotyped behaviors, anxiety, and learning and memory deficits. We observed a decreased number of parvalbumin (PV)-expressing neurons in their retrosplenial cortex (RSC) and dentate gyrus (DG). Furthermore, abnormalities in dendritic structure, synaptic density, and synaptic transmission were noted in the DG of Srcap+/- mice. RNA sequencing revealed that the expression of 27 genes, implicated in ASD, was dysregulated in the Srcap haploinsufficiency mice. Among these genes, we found that Srcap haploinsufficiency resulted in decreased Satb2 expression due to diminished H2A.z-binding within the promoter region of Satb2. Remarkably, intervention through retro-orbital injection of AAV vectors expressing Satb2 in newborn Srcap+/- mice reversed autistic-like behaviors and developmental defects in the RSC and DG regions. Similarly, in adolescent Srcap+/- mice, stereotactic injection of AAV expressing Satb2 into the RSC ameliorated deficits in social novelty. Collectively, these findings highlight the crucial role of the Srcap in neurodevelopment by regulating Satb2 expression, particularly impacting the development of RSC and DG regions.

neuroscience↗

bioRxiv2023

WBSCR16 Determines Metabolic Flexibility Via Regulating Mitochondrial 16S rRNA Maturation

Mitochondria play significant roles in energy homeostasis by dissipating excess calories. However, the key proteins in mitochondrial govern metabolically flexibility remain poorly understand. Herein, we generated adipose specific Wbscr16-/-mice and cells, both of which exhibited a preference for fat utilization and displayed dramatic mitochondrial changes. We demonstrated that WBSCR16 is essential for the specific cleavage of 16S rRNA-tRNALeu, leading to the production of maturated 16S rRNA, which in turn controls mitochondrial large ribosomal assembly. Importantly, WBSCR16 was identified as a 16S rRNA-binding protein that directly interacts with RNase P subunit MRPP3. Furthermore, evidence showed that WBSCR16 ablation promotes energy wasting via lipid cycling in BAT, leading to excess energy expenditure and resistance to obesity. Conversely, cells and mice with WBSCR16 overexpression preferred to glucose utilization. These findings suggest that WBSCR16 is the key mitochondrial switch protein between glucose and lipid metabolism, making it a promising target for the development of fat busting drug.

cell biology↗

bioRxiv2023

Sustained store-operated calcium entry utilizes activated chromatin state leads to instability in iTregs

Thymus-originated tTregs and in vitro induced iTregs are subsets of regulatory T cells. While they share the capacity of immune suppression, their stabilities are different, with iTregs losing their phenotype upon stimulation or under inflammatory milieu. Epigenetic differences, particularly methylation state of Foxp3 CNS2 region, provide an explanation for this shift. Whether additional regulations, including cellular signaling, could directly lead phenotypical instability requires further analysis. Here we show that upon TCR triggering, store-operated calcium entry (SOCE) and NFAT nuclear translocation are blunted in tTregs, yet fully operational in iTregs, similar to Tconvs. On the other hand, tTregs show minimal changes in their chromatin accessibility upon activation, in contrast to iTregs that demonstrate an activated chromatin state with highly accessible T cell activation and inflammation related genes. Assisted by several cofactors, NFAT driven by strong SOCE signaling in iTregs preferentially binds to primed opened T helper (TH) genes, resulting in their activation normally observed only in Tconv activation, ultimately leads to instability. Conversely, suppression of SOCE in iTregs can partially rescue their phenotype. Thus our study adds two new layer, cellular signaling and chromatin accessibility, of understanding in Treg stability, and may provide a path for better clinical applications of Treg cell therapy.

immunology↗

bioRxiv2023

Community-based Reconstruction and Simulation of a Full-scale Model of Region CA1 of Rat Hippocampus

The CA1 region of the hippocampus is one of the most studied regions of the rodent brain, thought to play an important role in cognitive functions such as memory and spatial navigation. Despite a wealth of experimental data on its structure and function, it has been challenging to reconcile information obtained from diverse experimental approaches. To address this challenge, we present a community-driven, full-scale in silico model of the rat CA1 that integrates a broad range of experimental data, from synapse to network, including the reconstruction of its principal afferents, the Schaffer collaterals, and a model of the effects that acetylcholine has on the system. We tested and validated each model component and the final network model, and made input data, assumptions, and strategies explicit and transparent. The unique flexibility of the model allows scientists to address a range of scientific questions. In this article, we describe the methods used to set up simulations that reproduce and extend in vitro and in vivo experiments. Among several applications in the article, we focus on theta rhythm, a prominent hippocampal oscillation associated with various behavioral correlates and use our computer model to reproduce and reconcile experimental findings. Finally, we make data, code and model available through the hippocampushub.eu portal, which also provides an extensive set of analyses of the model and a user-friendly interface to facilitate adoption and usage. This neuroscience community-driven model represents a valuable tool for integrating diverse experimental data and provides a foundation for further research into the complex workings of the hippocampal CA1 region.

neuroscience↗

bioRxiv2023

Carotenoid assembly regulates quinone diffusion and the Roseiflexus castenholzii reaction center-light harvesting complex architecture

Carotenoid (Car) pigments perform central roles in photosynthesis-related light harvesting (LH), photoprotection, and assembly of functional pigment-protein complexes. However, the relationships between Car depletion in the LH, assembly of the prokaryotic reaction center (RC)-LH complex, and quinone exchange are not fully understood. Here, we analyzed native RC-LH (nRC-LH) and Car-depleted RC-LH (dRC-LH) complexes in Roseiflexus castenholzii, a chlorosome-less filamentous anoxygenic phototroph that forms the deepest branch of photosynthetic bacteria. Newly identified exterior Cars functioned with the bacteriochlorophyll B800 to block the proposed quinone channel between LH{beta} subunits in the nRC-LH, forming a sealed LH ring that was disrupted by transmembrane helices from cytochrome c and subunit X to allow quinone shuttling. dRC-LH lacked subunit X, leading to an exposed LH ring with a larger opening, which together accelerated the quinone exchange rate. We also assigned amino acid sequences of subunit X and two hypothetical proteins Y and Z that functioned in forming the quinone channel and stabilizing the RC-LH interactions. This study reveals the structural basis by which Cars assembly regulates the architecture and quinone exchange of bacterial RC-LH complexes. These findings mark an important step forward in understanding the evolution and diversity of prokaryotic photosynthetic apparatus.

biochemistry↗

bioRxiv2023

Diffusion MRI Harmonization via Personalized Template Mapping

One fundamental challenge in diffusion MRI (dMRI) harmonization is to disentangle the contributions of scanner-related effects from the variable brain anatomy for the observed imaging signals. Conventional harmonization methods rely on establishing an atlas space to resolve anatomical variability and generate a unified inter-site mapping function. However, this approach is limited in accounting for the misalignment of neuroanatomy that still widely persists even after registration, especially in regions close to cortical boundaries. To overcome this challenge, we propose a personalized framework in this paper to more effectively address the confounding from the misalignment of neuroanatomy in dMRI harmonization. Instead of using a common template representing site-effects for all subjects, the main novelty of our method is the adaptive computation of personalized templates for both source and target scanning sites to estimate the inter-site mapping function. We integrate our method with the rotation invariant spherical harmonics (RISH) features to achieve the harmonization of dMRI signals between sites. In our experiments, the proposed approach is applied to harmonize the dMRI data acquired from two scanning platforms: Siemens Prisma and GE MR750 from the Adolescent Brain Cognitive Development (ABCD) dataset and compared with a state-of-the-art method based on RISH features. Our results indicate that the proposed harmonization framework achieves superior performance not only in reducing inter-site variations due to scanner differences but also in preserving sex-related biological variability in original cohorts. Moreover, we assess the impact of harmonization on the estimation of fiber orientation distributions (FOD) and show the robustness of the personalized harmonization procedure in preserving the fiber orientation of original dMRI signals.

bioinformatics↗

bioRxiv2023

Structural and functional damage to neuronal nuclei caused by extracellular tau oligomers

INTRODUCTIONNeuronal nuclei are normally smoothly surfaced. In Alzheimers disease (AD) and other tauopathies, though, they often develop invaginations. We investigated mechanisms and functional consequences of neuronal nuclear invagination in tauopathies. METHODSNuclear invagination was assayed by immunofluorescence in brain, and in cultured neurons before and after extracellular tau oligomers (xcTauO) exposure. Nucleocytoplasmic transport was assayed in cultured neurons. Gene expression was investigated using nanoString nCounter technology and qRT-PCR. RESULTSInvaginated nuclei were twice as abundant in human AD as in cognitively normal adults, and were increased in mouse neurodegeneration models. In cultured neurons, nuclear invagination was induced by xcTauOs by an intracellular tau-dependent mechanism. xcTauOs impaired nucleocytoplasmic transport, increased histone H3 trimethylation at lysine 9 and altered gene expression, especially by increasing tau mRNA. DISCUSSIONxcTauOs may be a primary cause of nuclear invagination in vivo, and by extension, impair nucleocytoplasmic transport and induce pathogenic gene expression changes.

neuroscience↗

bioRxiv2023

Tau Filaments from Amyotrophic Lateral Sclerosis/Parkinsonism-Dementia Complex (ALS/PDC) adopt the CTE Fold

The amyotrophic lateral sclerosis/parkinsonism-dementia complex (ALS/PDC) of the island of Guam and the Kii peninsula of Japan is a fatal neurodegenerative disease of unknown cause that is characterised by the presence of abundant filamentous tau inclusions in brains and spinal cords. Here we used electron cryo-microscopy (cryo-EM) to determine the structures of tau filaments from the cerebral cortex of three cases of ALS/PDC from Guam and eight cases from Kii, as well as from the spinal cord of two of the Guam cases. Tau filaments had the chronic traumatic encephalopathy (CTE) fold, with variable amounts of Type I and Type II filaments. Paired helical tau filaments were also found in two Kii cases. We also identified a novel Type III CTE tau filament, where protofilaments pack against each other in an anti-parallel fashion. ALS/PDC is the third known tauopathy with CTE-type filaments and abundant tau inclusions in cortical layers II/III, the others being CTE and subacute sclerosing panencephalitis. Because these tauopathies are believed to have environmental causes, our findings support the hypothesis that ALS/PDC is caused by exogenous factors. SIGNIFICANCEA neurodegenerative disease of unknown cause on the island of Guam and the Kii peninsula of Japan has been widely studied, because patients can suffer from the combined symptoms of motor neuron disease, parkinsonism and dementia. Abnormal filamentous inclusions made of tau protein characterise this amyotrophic lateral sclerosis/parkinsonism-dementia complex (ALS/PDC) and their formation closely correlates with neurodegeneration. Here we have used electron cryo-microscopy (cryo-EM) to show that tau filaments from ALS/PDC are identical to those from chronic traumatic encephalopathy (CTE), a disease caused by repetitive head impacts or blast waves. CTE tau filaments are also found in subacute sclerosing panencephalitis, which is a rare consequence of measles infection. ALS/PDC may therefore also be caused by environmental factors.

neuroscience↗

bioRxiv2023

Integrin beta4 promotes DNA damage drug resistance in triple-negative breast cancer via TNFAIP2/IQGAP1/Rac1

Anti-tumor drug resistance is a challenge for human triple-negative breast cancer treatment. Our previous work demonstrated that TNFAIP2 activates RAC1 to promote triple-negative breast cancer cell proliferation and migration. However, the mechanism by which TNFAIP2 activates RAC1 is unknown. In this study, we found that TNFAIP2 interacts with IQGAP1 and Integrin {beta}4. Integrin {beta}4 activates RAC1 through TNFAIP2 and IQGAP1 and confers DNA damage-related drug resistance in triple-negative breast cancer. These results indicate that the Integrin {beta}4/TNFAIP2/IQGAP1/RAC1 axis provides potential therapeutic targets to overcome DNA damage-related drug resistance in triple-negative breast cancer.

cancer biology↗

bioRxiv2023

The anti-cancer compound JTE-607 reveals hidden sequence specificity of the mRNA 3' processing machinery

JTE-607 is a small molecule compound with anti-inflammation and anti-cancer activities. Upon entering the cell, it is hydrolyzed to Compound 2, which directly binds to and inhibits CPSF73, the endonuclease for the cleavage step in pre-mRNA 3' processing. Although CPSF73 is universally required for mRNA 3' end formation, we have unexpectedly found that Compound 2- mediated inhibition of pre-mRNA 3' processing is sequence-specific and that the sequences flanking the cleavage site (CS) are a major determinant for drug sensitivity. By using massively parallel in vitro assays, we have measured the Compound 2 sensitivities of over 260,000 sequence variants and identified key sequence features that determine drug sensitivity. A machine learning model trained on these data can predict the impact of JTE-607 on poly(A) site (PAS) selection and transcription termination genome-wide. We propose a biochemical model in which CPSF73 and other mRNA 3' processing factors bind to RNA of the CS region in a sequence-specific manner and the affinity of such interaction determines the Compound 2 sensitivity of a PAS. As the Compound 2-resistant CS sequences, characterized by U/A-rich motifs, are prevalent in PASs from yeast to human, the CS region sequence may have more fundamental functions beyond determining drug resistance. Together, our study not only characterized the mechanism of action of a compound with clinical implications, but also revealed a previously unknown and evolutionarily conserved sequence-specificity of the mRNA 3' processing machinery.

molecular biology↗

bioRxiv2023

Comparative Phylogenomics and Phylotranscriptomics Provide Insights into the Genetic Complexity of Nitrogen Fixing Root Nodule Symbiosis

Plant root nodule symbiosis (RNS) with mutualistic nitrogen-fixing bacteria is restricted to a single clade of angiosperms, the Nitrogen-Fixing Nodulation Clade (NFNC), and is best understood in the legume family. It is widely accepted that nodulation originated through the assembly of modules recruited from existing functions, such as mycorrhizal symbiosis, polar growth, and lateral root development. Because nodulating species are scattered within the NFNC, the number of times nodulation has evolved or has been lost has been a matter of considerable speculation. This interesting evolutionary question has practical implications concerning the ease with which nodulation might be engineered in non-nodulating crop plants. Nodulating species share many commonalities, due either to divergence from a common ancestor over 100 million years ago or to convergence or deep homology following independent origins over that same time period. In either case, comparative analyses of diverse nodulation syndromes can provide insights into constraints on nodulation--what must be acquired or cannot be lost for a functional symbiosis--and what the latitude is for variation in the symbiosis. However, much remains to be learned about nodulation, especially outside of legumes. Here we present new information across the spectrum of nodulating groups. We find no evidence for convergence at the level of amino acid residues or gene family expansion across the NFNC. Our phylogenomic analyses further emphasize the uniqueness of the transcription factor, NIN, as a master regulator of nodulation, and identify key mutations affecting its function across the NFNC. We find that nodulation genes are over-represented among orthologous gene groups (OGs) present in the NFNC common ancestor, but that lineage-specific OGs play major roles in nodulation. We identified over 900,000 conserved noncoding elements (CNEs), of which over 300,000 were unique to NFNC species. A significant proportion of these are associated with nodulation-related genes and thus are candidates for transcriptional regulators.

evolutionary biology↗

bioRxiv2023

PGAR-Zernike: an ultra-fast, accurate and fully open-sourcestructure retrieval toolkit for convenient structural database construction

With the release of AlphaFold2, protein model databases are growing at an unprecedented rate. Efficient structure retrieval schemes are becoming more and more important to quickly analyze structure models. The core problem in structural retrieval is how to measure the similarity between structures. Some structure alignment algorithms can solve this problem but at a substantial time cost. At present, the state-of-the-art method is to convert protein structures into 3D Zernike descriptors and evaluate the similarity between structures by Euclidean distance. However, methods for computing 3D Zernike descriptors of protein structures are almost always based on structural surfaces and most are web servers, which is not conducive for users to analyze customized datasets. To overcome this limitation, we propose PGAR-Zernike, a convenient toolkit for computing different types of Zernike descriptors of structures: the user simply needs to enter one line of command to calculate the Zernike descriptors of all structures in a customized datasets. Compared with the state-of-the-art method based on 3D Zernike descriptors and an efficient structural comparison tool, PGAR-Zernike achieves higher retrieval accuracy and binary classification accuracy on benchmark datasets with different attributes. In addition, we show how PGA-Zernike completes the construction of the descriptor database and the protocol used for the PDB dataset so as to facilitate the local deployment of this tool for interested readers. We construct a demonstration containing 590685 structures; at this scale, our retrieval system takes only 4 ~ 9 seconds to complete a retrieval, and experiments show that it reaches the state-of-the-art level in terms of accuracy. PGAR-Zernike is an open-source toolkit, whose source code and related data are accessible at https://github.com/junhaiqi/PGAR-Zernike/.

bioinformatics↗