Biology subjects

Liu, Q.

Publications and source records attributed to Liu, Q..

At least 451 records · Page 25Linked to original sources

bioRxiv2022

Structural basis of peptidomimetic agonism revealed by small molecule GLP-1R agonists Boc5 and WB4-24

Glucagon-like peptide-1 receptor (GLP-1R) agonists are effective in treating type 2 diabetes and obesity with proven cardiovascular benefits. However, most of them are peptides and require subcutaneous injection except for orally available semaglutide. Boc5 was identified as the first orthosteric non-peptidic agonist of GLP-1R that mimics a broad spectrum of bioactivities of GLP-1 in vitro and in vivo. Here, we report the cryo-electron microscopy structures of Boc5 and its analog WB4-24 in complex with the human GLP-1R and Gs protein. Bound to the extracellular domain, extracellular loop 2, and transmembrane (TM) helices 1, 2, 3 and 7, one arm of both compounds inserted deeply into the bottom of the orthosteric binding pocket that is usually accessible by peptidic agonists, thereby partially overlapping with the residues A8-D15 in GLP-1. The other three arms, meanwhile, extended to the TM1-TM7, TM1-TM2, and TM2-TM3 clefts showing an interaction feature substantially similar to a previously known small molecule agonist LY3502970. Such a unique binding mode creates a distinct conformation that confers both peptidomimetic agonism and biased signaling induced by non-peptidic modulators at GLP-1R. Further, the conformational difference between Boc5 and WB4-24, two closed related compounds, provides a structural framework for fine tuning of pharmacological efficacy in the development of future small molecule therapeutics targeting GLP-1R. SignificanceGLP-1R agonists are efficacious in the treatment of type 2 diabetes and obesity. While most clinically used agents require subcutaneous injection, Boc5, as the first orthosteric non-peptidic agonist of GLP-1R, suffers from poor oral bioavailability that hinders its therapeutic development. The cryo-electron microscopy structures of Boc5 and its closely related analog WB4-24 presented here reveal a previously unknown binding pocket located deeper in the transmembrane domain for non-peptidic GLP-1R agonists. Molecular interaction with this site may facilitate a broad spectrum of in vivo agonistic activities, in addition to that with the upper helical bundles presumably responsible for biased signaling. These findings deepen our understanding of peptidomimetic agonism at GLP-1R and may help design better drug leads against this important target.

molecular biology↗

bioRxiv2022

Nanometer-Resolution Long-term Tracking of Single Cargos Reveals Dynein Motor Mechanisms

Cytoplasmic dynein is essential for intracellular transport, but because of its complexity, we still do not fully understand how this 1.5 megadalton protein works. Here, we used novel optical probes that enable single-particle tracking (SPT) of individual cargos transported by dynein motors in live neurons over 900 m. Analyses using the Fluctuation Theorem (FT) showed that the number of dynein molecules switches between 1-5 motors during the transport. Clearly resolved single-molecular steps revealed that the dwell times between individual steps were accurately described by an enzymatic cycle dominated by two equal and thermally-activated rate constants. Based on these data, we propose a new molecular model whereby each step requires the hydrolysis of 2 ATPs. The model is consistent with extensive structural, single-molecule and biochemical measurements.

biophysics↗

bioRxiv2021

A tRNA-acetylating toxin and detoxifying enzyme in Mycobacterium tuberculosis.

Toxin-antitoxin (TA) systems allow bacteria to adapt to changing environments without altering gene expression. Despite being overrepresented in Mycobacterium tuberculosis (Mtb), their individual physiological roles remain elusive. We describe a TA system in Mtb which we have named TacAT due to its homology to previously discovered systems in Salmonella. The toxin, TacT, blocks growth by acetylating glycyl-tRNAs and inhibiting translation. Its effects are reversed by the enzyme peptidyl tRNA hydrolase (Pth), which also cleaves peptidyl tRNAs that are prematurely released from stalled ribosomes. Pth is essential in most bacteria and thereby has been proposed as a promising drug target for complex pathogens like Mtb. Transposon sequencing data suggest that the tacAT operon is nonessential for Mtb growth in vitro, and premature stop mutations in this TA system present in some clinical isolates suggest that it is also dispensable in vivo. We assessed whether TacT modulates pth essentiality in Mtb, as drugs targeting Pth might be ineffective if TacAT is disrupted. We find that pth essentiality is unaffected by the absence of tacAT. These results highlight a fundamental aspect of mycobacterial biology and indicate that Pths essential role hinges on its peptidyl-tRNA hydrolase activity. Our work underscores Pths potential as a viable target for new antibiotics.

microbiology↗

bioRxiv2021

An experimental test of chronic traffic noise exposure on parental behaviour and reproduction in zebra finches

Chronic traffic noise is increasingly recognised as a potential hazard to wildlife. Several songbird species have been shown to breed poorly in traffic noise exposed habitats. However, identifying whether noise is causal in this requires experimental approaches. We tested whether experimental exposure to chronic traffic noise affected parental behaviour and reproductive success in zebra finches (Taeniopygia guttata). In a counterbalanced repeated-measures design, breeding pairs were exposed to continuous playback of one of two types of highway noise previously shown to be either neutral (control) or aversive. Parental nest attendance positively correlated with feeding effort and was higher for the aversive than the control sound and this effect was more pronounced for parents attending larger broods. However, neither noise condition affected offspring number, growth or body mass. The absence of an effect held when we combined our data with data from two other comparable studies into a meta-analysis. We discuss whether the increased nest attendance could be a compensatory strategy that alleviated detrimental noise effects on the chicks, and whether it could be caused by impaired parent-offspring or within-pair communication. Future work should test these hypotheses and investigate potential long-term costs of increased parental engagement.

animal behavior and cognition↗

bioRxiv2021

A chromosome-level reference genome of Ensete glaucum gives insight into diversity, chromosomal and repetitive sequence evolution in the Musaceae

BackgroundEnsete glaucum (2n = 2x = 18) is a giant herbaceous monocotyledonous plant in the small Musaceae family along with banana (Musa). A high-quality reference genome sequence of E. glaucum offers a vital genomic resource for functional and evolutionary studies of Ensete, the Musaceae, and more widely in the Zingiberales. FindingsUsing a combination of Illumina and Oxford Nanopore Technologies (ONT) sequencing, genome-wide chromosome conformation capture (Hi-C), and RNA survey sequence, we report a high-quality assembly of the 481.5Mb genome with 9 pseudochromosomes and 36,836 genes (BUSCO 94.7%). A total of 55% of the genome is composed of repetitive sequences with LTR-retroelements (37%) and DNA transposons (7%) predominant. The 5S and 45S rDNA were each present at one locus, and the 5S rDNA had an exceptionally long monomer length of c.1,056 bp, contrasting with the c. 450 bp monomer at multiple loci in Musa. A tandemly repeated c. 134 bp satellite, 1.1% of the genome (with no similar sequence in Musa), was present around all nine centromeres, with a LINE retroelement also found at Musa centromeres. The assembly, including centromeric positions, enabled us to characterize in detail the chromosomal rearrangements occurring between the x = 9 species and x = 11 species of Musa. Only one chromosome has the same gene content as M. acuminata (ma). Three ma chromosomes represent part of only one E. glaucum (eg) chromosome, while the remaining seven ma chromosomes are fusions of parts of two, three, or four eg chromosomes, demonstrating complex and multiple evolutionary rearrangements in the change between x = 9 and x = 11. ConclusionsThe advance towards a Musaceae pangenome including E. glaucum, tolerant of extreme environments, makes a complete set of gene alleles available for crop breeding and understanding environmental responses. The chromosome-scale genome assembly show how chromosome number evolves, and features of the rapid evolution of repetitive sequences.

plant biology↗

bioRxiv2021

Tom70-based transcriptional regulation of mitochondrial biogenesis and aging

Mitochondrial biogenesis has two major steps: the transcriptional activation of nuclear genome-encoded mitochondrial proteins and the import of nascent mitochondrial proteins that are synthesized in the cytosol. These nascent mitochondrial proteins are aggregation-prone and can cause cytosolic proteostasis stress. The transcription factor-dependent transcriptional regulations and the TOM-TIM complex-dependent import of nascent mitochondrial proteins have been extensively studied. Yet, little is known regarding how these two steps of mitochondrial biogenesis coordinate with each other to avoid the cytosolic accumulation of these aggregation-prone nascent mitochondrial proteins. Here we show that in budding yeast, Tom70, a conserved receptor of the TOM complex, moonlights to regulate the transcriptional activity of mitochondrial proteins. Tom70s transcription regulatory role is conserved in Drosophila. The dual roles of Tom70 in both transcription/biogenesis and import of mitochondrial proteins allow the cells to accomplish mitochondrial biogenesis without compromising cytosolic proteostasis. The age-related reduction of Tom70, caused by reduced biogenesis and increased degradation of Tom70, is associated with the loss of mitochondrial membrane potential, mtDNA, and mitochondrial proteins. While loss of Tom70 accelerates aging and age-related mitochondrial defects, overexpressing TOM70 delays these mitochondrial dysfunctions and extends the replicative lifespan. Our results reveal unexpected roles of Tom70 in mitochondrial biogenesis and aging.

cell biology↗

bioRxiv2021

The different brain areas occupied for integrating information of hierarchical linguistic units: a study based on EEG and TMS

Human linguistic units are hierarchical, and our brain responds differently when processing linguistic units during sentence comprehension, especially when the modality of the received signal is different (auditory, visual, or audio-visual). However, it is unclear how the brain processes and integrates language information at different linguistic units (words, phrases, and sentences) provided simultaneously in audio and visual modalities. To address the issue, we presented participants with sequences of short Chinese sentences through auditory or visual or combined audio- visual modalities, while electroencephalographic responses were recorded. With a frequency tagging approach, we analyzed the neural representations of basic linguistic units (i.e., characters/monosyllabic words) and higher-level linguistic structures (i.e., phrases and sentences) across the three modalities separately. We found that audio-visual integration occurs at all linguistic units, and the brain areas involved in the integration varied across different linguistic levels. In particular, the integration of sentences activated the local left prefrontal area. Therefore, we used continuous theta-burst stimulation (cTBS) to verify that the left prefrontal cortex plays a vital role in the audio-visual integration of sentence information. Our findings suggest the advantage of bimodal language comprehension at hierarchical stages in language-related information processing and provide evidence for the causal role of the left prefrontal regions in processing information of audio-visual sentences.

neuroscience↗

bioRxiv2021

DETIRE: A Hybrid Deep Learning Model for identifying Viral Sequences from Metagenomes

A metagenome contains all DNA sequences from an environmental sample, including viruses, bacteria, fungi, actinomycetes and so on. Since viruses are of huge abundance and have caused vast mortality and morbidity to human society in history as a kind of major pathogens, detecting viruses from metagenomes plays a crucial role in analysing the viral component of samples and is the very first step for clinical diagnosis. However, detecting viral fragments directly from the metagenomes is still a tough issue because of the existence of huge number of short sequences. In this paper, a hybrid Deep lEarning model for idenTifying vIral sequences fRom mEtagenomes (DETIRE), is proposed to solve the problem. Firstly, the graph-based nucleotide sequence embedding strategy is utilized to enrich the expression of DNA sequences by training an embedding matrix. Then the spatial and sequential features are extracted by trained CNN and BiLSTM networks respectively to improve the feature expression of short sequences. Finally, the two set of features are weighted combined for the final decision. Trained by 220,000 sequences of 500bp subsampled from the Virus and Host RefSeq genomes, DETIRE identifies more short viral sequences (<1,000bp) than three latest methods, DeepVirFinder, PPR-Meta and CHEER. DETIRE is freely available at https://github.com/crazyinter/DETIRE.

bioinformatics↗

bioRxiv2021

Resting-state functional connectivity of social brain regions predicts motivated dishonesty

Motivated dishonesty is a typical social behavior varying from person to person. Resting-state fMRI (rsfMRI) is capable of identifying unique patterns from functional connectivity (FC) between brain networks. To identify the relevant neural patterns and build an interpretable model to predict dishonesty, we scanned 8-min rsfMRI before an information-passing task. In the task, we employed monetary rewards to induce dishonesty. We applied both connectome-based predictive modeling (CPM) and region-of-interest (ROI) analysis to examine the association between FC and dishonesty. CPM indicated that the stronger FC between fronto-parietal and default mode networks can predict a higher dishonesty rate. The ROIs were set in the regions involving four cognitive processes (self-reference, cognitive control, reward valuation, and moral regulation). The ROI analyses showed that a stronger FC between these regions and the prefrontal cortex can predict a higher dishonesty rate. Our study offers an integrated model to predict dishonesty with rsfMRI, and the results suggest that the frequent motivated dishonest behavior may require a higher engagement of social brain regions.

neuroscience↗

bioRxiv2021

Chitin and cuticle proteins form the cuticular layer in the spinning duct of silk-spinning arthropods

Chitin is found in the exoskeleton and peritrophic matrix of arthropods, but recent studies have also identified chitin in the spinning duct of silk-spinning arthropods. Here, we report the presence and function of chitin and cuticle proteins ASSCP1 and ASSCP2 in the spinning duct of silkworms. We show that chitin and these proteins are co-located in the cuticular layer of the spinning duct. Ultrastructural analysis indicates that the cuticular layer has a multilayer structure by layered stacking of the chitin laminae. After knocking down ASSCP1 and ASSCP2, the fine structure of this layer was disrupted, which had negative impacts on the mechanical properties of silk. This work clarifies the function of chitin in the spinning duct of silk-spinning arthropods. Chitin and cuticle proteins are the main components of the hard and rigid cuticular layer, providing the shearing stress during silk fibrillogenesis and regulating the final mechanical properties of silk.

molecular biology↗

bioRxiv2021

Variations in EEG predicts the individual differences in social tasks

People experience events and form an impression of others in a way that is affected by social influence every day. In the present study, we designed a series of tasks centered on social influence to investigate peoples bias in following others opinions and its underlying neural predictors. Our results showed social conformity and proved that social influence-induced change can be predicted by the amount of inter-trial electroencephalogram (EEG) variations when people view others faces. This prediction effect is robust in the alpha-band over the right frontal and left occipital electrodes for negative influence. Inter-trial EEG variations can also predict the subsequent trust difference between negatively and positively influenced faces. Our findings suggest that higher Inter-trial EEG variations in the pre-influence task may serve as a predictor of high vulnerability to social influence. The present study provides a novel approach that considers both the stability of ones endogenous EEG and the variations in external task components to predict human social behaviors.

neuroscience↗

bioRxiv2021

Bicolor angelfish (Centropyge bicolor) provides the first chromosome-level genome of the Pomacanthidae family

The Bicolor Angelfish, Centropyge bicolor, is a tropical coral reef fish. It is named for its striking two-color body. However, a lack of high-quality genomic data means little is known about the genome of this species. Here, we present a chromosome-level C. bicolor genome constructed using Hi-C data. The assembled genome is 650 Mbp in size, with a scaffold N50 value of 4.4 Mbp, and a contig N50 value of 114 Kbp. Protein-coding genes numbering 21,774 were annotated. Our analysis will help others to choose the most appropriate de novo genome sequencing strategy based on resources and target applications. To the best of our knowledge, this is the first chromosome-level genome for the Pomacanthidae family, which might contribute to further studies exploring coral reef fish evolution, diversity and conservation.

genomics↗

bioRxiv2021

Spatiotemporal mapping of gene expression landscapes and developmental trajectories during zebrafish embryogenesis

Vertebrate embryogenesis is a remarkably dynamic process during which numerous cell types of different lineages generate, change, or disappear within a short period of time. A major challenge in understanding this process is the lack of topographical transcriptomic information that can help correlate microenvironmental cues within the hierarchy of cell fate decisions. Here, we employed Stereo-seq, a high-definition spatially resolved transcriptomic technology, to dissect the spatiotemporal dynamics of gene expression and regulatory networks in the developing zebrafish embryos. We profiled 91 embryo sections covering six critical time points during the first 24 hours of development, obtaining a total of 139,391 spots at cellular size ([~]100 m2) with spatial coordinates. Meanwhile, we identified spatial modules and co-varying genes for specific tissue organizations. By performing the integrative analysis of the Stereo-seq and scRNA-seq data from each time point, we reconstructed the spatially resolved developmental trajectories of cell fate transitions and molecular changes during zebrafish embryogenesis. We further investigated the spatial distribution of ligand-receptor pairs for major signaling pathways and identified novel interactions that potentially crosstalk with the Notch signaling pathway during zebrafish development. Our study constitutes a fundamental reference for further studies aiming to understand vertebrate development.

developmental biology↗

bioRxiv2021

Severe fever with thrombocytopenia syndrome virus and parthenogenetic Asian longhorned tick Haemaphysalis longicornis (Acari: Ixodidae)

Severe fever with thrombocytopenia syndrome virus (SFTSV) is spreading rapidly in Asia. It is transmitted by Haemaphysalis longicornis (Asian longhorned tick, ALT), which has both parthenogenetically and sexually reproducing populations. Parthenogenetic populations were found in at least 15 provinces in China and strongly correlated with the distribution of SFTS. The distribution of SFTS cases was however poorly correlated with the distribution of populations of bisexual ALTs. Phylogeographic analysis suggested that the parthenogenetic population spread much faster than bisexual population because colonization is independent of sexual reproduction. A higher proportion of parthenogenetic ALTs were collected from migratory birds captured at an SFTS endemic area, implicating the contribution to the long-range movement of ALTs in China. The SFTSV susceptibility of parthenogenetic females was like that of bisexual females under laboratory conditions. These results suggest that parthenogenetic ALT, probably transported by migratory birds, play a major role in the rapid spread of SFTSV. Article Summary LineThe parthenogenetic population of Asian longhorned tick is broadly distributed in China and plays a major role in the long-distance spread of SFTSV and perhaps future invasion of countries outside of Asia.

evolutionary biology↗

bioRxiv2021

A New Mouse Model of Diffuse Midline Glioma to Test Targeted Immunotherapies

BACKGROUNDDiffuse midline gliomas remain incurable, with consistently poor outcomes in children despite radiotherapy. Immunotherapeutic approaches hold promise, with the integration of the hosts immune system fundamental to their design. Here, we describe a new, genetically engineered immunocompetent model that incorporates interleukin 13 receptor alpha 2 (IL13R2), a tumor-associated antigen, which is suitable for further evaluation of the antitumor activity of IL13R2-targeted immunotherapeutics in preclinical studies. METHODSThe RCAS-Tv-a delivery system was used to induce gliomagenesis through overexpression of PDGFB and p53 deletion with and without human IL13R2 in Nestin-Tva; p53fl/fl mice. Hindbrain or cerebral cortex nestin progenitors of neonatal pups were infected with Cre recombinase and PDGFB+IL13R2 or Cre recombinase and PDGFB to model diffuse midline glioma and supratentorial high-grade glioma, respectively. Immunoblotting and flow cytometry was used to confirm target expression. Kaplan-Meier survival curves were established to compare tumor latency in both models. Tumor tissue was analyzed through immunohistochemistry and H&E staining. Cell lines generated from tumor-bearing mice were used for in vitro studies and orthotopic injections. RESULTSThe protein expression of PDGFB and IL13R2 was confirmed by flow cytometry and western blot. In both groups, de novo tumors developed without significant difference in median survival between PDGFB and p53 loss (n=25, 40 days) and PDGFB, IL13R2, and p53 loss (n=33, 38 days, p=0.62). Tumors demonstrated characteristics of high-grade glioma such as infiltration, palisading necrosis, microvascular proliferation, high Ki-67 index, heterogeneous IL13R2 expression, and CD11b+ macrophages, along with a low proportion of CD3+ T cells. Orthotopic tumors developed from cell lines retained histopathological characteristics of de novo tumors. Mice orthotopically implanted with cells in the hindbrain or right cortex showed a median survival of 42 days and 41 (p=0.56) days, respectively. CONCLUSIONGeneration of de novo tumors using the RCAS-Tv-a delivery system was successful, with tumors possessing histopathologic features common to pediatric diffuse gliomas. The development of these models opens the opportunity for preclinical assessment of IL13R2-directed immunotherapies with the potential for clinical translation.

cancer biology↗

bioRxiv2021

Automated skull stripping in mouse fMRI analysis using 3D U-Net

Skull stripping is an initial and critical step in the pipeline of mouse fMRI analysis. Manual labeling of the brain usually suffers from intra- and inter-rater variability and is highly time-consuming. Hence, an automatic and efficient skull-stripping method is in high demand for mouse fMRI studies. In this study, we investigated a 3D U-Net based method for automatic brain extraction in mouse fMRI studies. Two U-Net models were separately trained on T2-weighted anatomical images and T2*-weighted functional images. The trained models were tested on both interior and exterior datasets. The 3D U-Net models yielded a higher accuracy in brain extraction from both T2-weighted images (Dice > 0.984, Jaccard index > 0.968 and Hausdorff distance < 7.7) and T2*-weighted images (Dice > 0.964, Jaccard index > 0.931 and Hausdorff distance < 3.3), compared with the two widely used mouse skull-stripping methods (RATS and SHERM). The resting-state fMRI results using automatic segmentation with the 3D U-Net models are identical to those obtained by manual segmentation for both the seed-based and group independent component analysis. These results demonstrate that the 3D U-Net based method can replace manual brain extraction in mouse fMRI analysis.

neuroscience↗

bioRxiv2021

PAX3-FOXO1 coordinates enhancer architecture, eRNA transcription, andRNA polymerase pause release at select gene targets

Transcriptional control is a highly dynamic process that changes rapidly in response to various cellular and extracellular cues1. Thus, it is difficult to achieve a mechanistic understanding of transcription factor function using traditional genetic deletion or RNAi methods, because these slow approaches make it challenging to distinguish direct from indirect transcriptional effects. Here, we used a chemical-genetic approach to rapidly degrade a canonical transcriptional activator, PAX3-FOXO12-6 to define how the t(2;13)(q35;q14) disrupts normal gene expression programs to trigger cancer. By coupling rapid protein degradation with the analysis of nascent transcription over short time courses, we identified a core transcriptional network that rapidly collapsed upon PAX3-FOXO1 degradation. Moreover, loss of PAX3-FOXO1 impaired RNA polymerase pause release and transcription elongation at regulated gene targets. The activity of PAX3-FOXO1 at enhancers controlling this core network was surprisingly selective and often only a single element within a complex super-enhancer was affected. In addition, fusion of the endogenous PAX3-FOXO1 with APEX2 identified proteins in close proximity with PAX3-FOXO1, including ARID1A and MYOD1. We found that continued expression of PAX3-FOXO1 was required to maintain chromatin accessibility and allow neighboring DNA binding proteins and chromatin remodeling complexes to associate with this small number of regulated enhancers. Overall, this work provides a detailed mechanism by which PAX3-FOXO1 maintains an oncogenic transcriptional regulatory network.

molecular biology↗

bioRxiv2021

Dr. Sim: Similarity Learning for Transcriptional Phenotypic Drug discovery

Transcriptional phenotypic drug discovery has achieved great success, and various compound perturbation-based data resources, such as Connectivity Map (CMap) and Library of Integrated Network-Based Cellular Signatures (LINCS), have been presented. Computational strategies fully mining these resources for phenotypic drug discovery have been proposed, and among them, a fundamental issue is to define the proper similarity between the transcriptional profiles to elucidate the drug mechanism of actions and identify new drug indications. Traditionally, this similarity has been defined in an unsupervised way, and due to the high dimensionality and the existence of high noise in those high-throughput data, it lacks robustness with limited performance. In our study, we present Dr. Sim, which is a general learning-based framework that automatically infers similarity measurement rather than being manually designed and can be used to characterize transcriptional phenotypic profiles for drug discovery with generalized good performance. We evaluated Dr. Sim on comprehensively publicly available in vitro and in vivo datasets in drug annotation and repositioning using high-throughput transcriptional perturbation data and indicated that Dr. Sim significantly outperforms the existing methods and is proved to be a conceptual improvement by learning transcriptional similarity to facilitate the broad utility of high-throughput transcriptional perturbation data for phenotypic drug discovery. The source code and usage of Dr. Sim is available at https://github.com/bm2-lab/DrSim/.

bioinformatics↗