Biology subjects

Liu, L.

Publications and source records attributed to Liu, L..

At least 433 records · Page 24Linked to original sources

bioRxiv2023

Collaborative Augmented Reconstruction for Scaled Production of 3D Neuron Morphology in Mouse and Human Brains

Digital reconstruction of the intricate 3D morphology of individual neurons from microscopic images is widely recognized as a crucial challenge in both individual research laboratories and large-scale scientific projects focusing on cell types and brain anatomy. This task often fails both conventional manual reconstruction and state-of-the-art automatic reconstruction algorithms, even many of which are based on artificial intelligence (AI). It is also critical but challenging to organize multiple neuroanatomists to produce and cross-validate biologically relevant and agreeable reconstructions in scaled data production. Here we propose an approach based on collaborative human intelligence augmented by AI. Specifically, we have developed a Collaborative Augmented Reconstruction (CAR) platform for neuron reconstruction at scale. This platform allows for immersive interaction and efficient collaborative-editing of neuron anatomy using a variety of client devices, such as desktop workstations, virtual reality headsets, and mobile phones, enabling users to contribute anytime and anywhere and take advantage of several AI-based automation tools. We have tested CARs applicability for challenging mouse and human neurons towards a scaled and faithful data production. Our data indicate that the CAR platform is suitable for generating tens of thousands of neuronal reconstructions used in our companion studies.

neuroscience↗

bioRxiv2023

Cell Typing and Sub-typing Based on Detecting Characteristic Subspaces of Morphological Features Derived from Neuron Images

MotivationRecent advances in reconstructing 3D neuron morphologies at the whole brain level offer exciting opportunities to study single cell genotyping and phenotyping. However, it remains challenging to define cell types and sub-types properly. ResultsAs morphological feature spaces are often too complicated to classify neurons, we introduce a method to detect the optimal subspace of features so that neurons can be well clustered. We have applied this method to one of the largest curated databases of morphological reconstructions that contains more than 9,400 mouse neurons of 19 cell types. Our method is able to detect the distinctive feature subspaces for each cell type. Our approach also outperforms prevailing cell typing approaches in terms of its ability to identify key morphological indicators for each neuron type and separate superclasses of these neuron types. the subclasses of neuronal types could supply information for brain connectivity and modeling, also promote other analysis including feature spaces. AvailabilityAll datasets used in this study are publicly available. All analyses were conducted with python package Scikitlearn 0.23.1 version. Source code used for data processing, analysis and figure generation is available as an open-source Python package, on https://github.com/SEU-ALLEN-codebase/ManifoldAnalysis Contactljliu@braintell.org

neuroscience↗

bioRxiv2023

Gut microbial genomes with paired isolates from China signify probiotic and cardiometabolic effects

The gut microbiome displays significant genetic differences between populations while systematic characterization of the genomic landscape of the gut microbiome in Asia populations remains limited. Here, we present the Chinese gut microbial reference (CGMR) set, comprising 101,060 high quality metagenomic assembled genomes (MAGs) of 3,707 non-redundant species paired with 1,376 live isolates from a national wide collection of 3,234 fecal samples across China. This improved reference set contains 987 novel species compared with existing resources worldwide. By associating MAGs with geographic and phenotypic characteristics, we observed regional-specific coexisting MAGs and MAGs with probiotic and cardiometabolic functionalities. We further conducted mice experiments to confirm the probiotic effects of two Faecalibacterium intestinalis isolates in alleviating constipation, the cardiometabolic influences of three Bacteroides fragilis_A isolates in obesity, and the functional potential of isolates from the two new species belonging to the genera Parabacteroides and Lactobacillus in host lipids metabolism. Our study not only expands the current microbial genomes with paired isolates but also demonstrates their probiotic and cardiometabolic effects on hosts, contributing to the mechanistic understanding of host-microbe interactions and the translation of microbiome-based personalized therapies.

microbiology↗

bioRxiv2023

Antigenicity and receptor affinity of SARS-CoV-2 BA.2.86 spike

Although the COVID-19 pandemic has officially ended1, SARS-CoV-2 continues to spread and evolve. Recent infections have been dominated by XBB.1.5 and EG.5.1 subvariants2. A new subvariant designated BA.2.86 has just emerged, spreading to 21 countries in 5 continents3. This virus contains 34 spike mutations compared to its BA.2 predecessor, thereby raising concerns about its propensity to evade existing antibodies. We examined its antigenicity using human sera and monoclonal antibodies (mAbs). Reassuringly, BA.2.86 was not more resistant to human sera than XBB.1.5 and EG.5.1, indicating that the new subvariant would not have a growth advantage in this regard. Importantly, sera from patients who had XBB breakthrough infection exhibited robust neutralizing activity against all viruses tested, suggesting that upcoming XBB.1.5 monovalent vaccines could confer added protection. The finding that the longer genetic distance of BA.2.86 did not yield a larger antigenic distance was partially explained by the mAb data. While BA.2.86 showed greater resistance to mAbs to subdomain 1 (SD1) and receptor-binding domain (RBD) class 2 and 3 epitopes, it was more sensitive to mAbs to class 1 and 4/1 epitopes in the "inner face" of RBD that is exposed only when this domain is in the "up" position. We also identified six new spike mutations that mediate antibody resistance, including E554K that threatens SD1 mAbs in clinical development. The BA.2.86 spike also had a remarkably high receptor affinity. The ultimate trajectory of this new SARS-CoV-2 variant will soon be revealed by continuing surveillance, but its worldwide spread is worrisome.

microbiology↗

bioRxiv2023

Connectome Operations For FSL ExEcution (COFFEE): a turnkey pipeline for preprocessing of fMRI data

Volumetric analysis methods continue to enjoy great popularity in the analysis of task-related functional MRI (fMRI) data. Among these methods, the software package FSL (FMRIB, Oxford, UK) is omnipresent throughout the field. However, it remains unknown what advantages might be gained by integrating FSL with alternative preprocessing tools. Here we developed the One-step General Registration and Extraction (OGRE) pipeline to apply FreeSurfer brain extraction for simultaneous registration and motion correction ("one-step resampling"), for FSL volumetric analysis of fMRI data. We compared three preprocessing approaches (OGRE, FSL, and fMRIPrep) in a dataset wherein adult human volunteers (N=39) performed a precision drawing task during fMRI scanning. The three approaches produced grossly similar results, but OGREs preprocessing led to lower inter-individual variability across the brain and greater detected activation in primary motor cortex contralateral to movement. This demonstrates that FreeSurfer tools and one-step resampling can improve FSLs volumetric analysis of fMRI data. The OGRE pipeline provides an off-the-shelf method to apply FreeSurfer-based brain extraction and one-step resampling of motion correction and registration for FSL analysis of task fMRI data.

neuroscience↗

bioRxiv2023

MMD-DTA: A multi-modal deep learning framework for drug-target binding affinity and binding region prediction

AbstractThe prediction of drug-target affinity (DTA) plays an important role in the development of drugs and the discovery of potential drug targets. In recent years, computer-assisted DTA prediction has become an important method in this field. In this work, we propose a multi-modal deep learning framework for drug-target binding affinity and binding region prediction, namely MMD-DTA. The model can predict DTA while unsupervised learning of drug-target binding regions. The experimental results show that MMD-DTA performs better than the existing models on the main evaluation metrics. In addition, external validation results show that MMD-DTA improves the generalization ability of the model by integrating sequence information and structural information of drugs and targets, and the model trained on the benchmark dataset can be well generalized to independent virtual screening tasks. Visualization of drug-target binding region prediction shows the powerful interpretability of MMD-DTA, which has important implications for exploring the functional regions of drug molecules acting on proteins.

bioinformatics↗

bioRxiv2023

Multi-omics analysis reveals signatures of selection and loci associated with complex traits in pigs

Selection signatures that contribute to phenotypic diversity, especially morphogenesis in pigs, remain to be further elucidated. To reveal the regulatory role of genetic variations in phenotypic differences between Eastern and Western pig breeds, we performed a systematic analysis based on seven high-quality de novo assembled genomes, 1,081 resequencing data representing 78 domestic breeds, 162 methylomes, and 162 transcriptomes of skeletal muscle from Tongcheng (Eastern) and Landrace (Western) pigs at 27 developmental stages. Selective sweep uncovers different genetic architectures behind divergent selection directions for the Eastern and Western breeds. Notably, two loci showed functional alterations by almost fixed missense mutations. By integrating time-course transcriptome and methylome, we revealed differences in developmental timing during myogenesis between Eastern and Western breeds. Genetic variants under artificial selection have critical regulatory effects on progression patterns of heterochronic genes like GHSR and BDH1, by the interaction of local DNA methylation status, particularly during embryonic development. Altogether, our work not only provides valuable resources for understanding pig complex traits, but also contributes to human biomedical research.

genomics↗

bioRxiv2023

HILAMA: High-dimensional multi-omic mediation analysis with latent confounding

MotivationThe increasingly available multi-omic datasets have posed both new opportunities and challenges to the development of quantitative methods for discovering novel mechanisms in biomedical research. One natural approach to analyzing such datasets is mediation analysis originated from the causal inference literature. Mediation analysis can help unravel the mechanisms through which exposure(s) exert the effect on outcome(s). However, existing methods fail to consider the case where (1) both exposures and mediators are potentially high-dimensional and (2) it is very likely that some important confounding variables are unmeasured or latent; both issues are quite common in practice. To the best of our knowledge, however, no methods have been developed to address these challenges with statistical guarantees. ResultsIn this article, we propose a new method for HIgh-dimensional LAtent-confounding Mediation Analysis, abbreviated as "HILAMA", that considers both high-dimensional exposures and mediators, and more importantly, the possible existence of latent confounding variables. HILAMA achieves false discovery rate (FDR) control under finite sample size for multiple mediation effect testing. The proposed method is evaluated through extensive simulation experiments, demonstrating its improved stability in FDR control and superior power in finite sample size compared to existing competitive methods. Furthermore, our method is applied to the proteomics-radiomics data from ADNI, identifying some key proteins and brain regions relating to Alzheimers disease. The results show that HILAMA can effectively control FDR and provide valid statistical inference for high dimensional mediation analysis with latent confounding variables. AvailabilityThe R package HILAMA is publicly available at https://github.com/Cinbo-Wang/HILAMA. Contactcinbo_w@sjtu.edu.cn

bioinformatics↗

bioRxiv2023

Bet hedging in a unicellular microalga

AbstractUnderstanding how organisms adapt to unpredictable future environments is a fundamental goal in biology, which becomes even more urgent in an era of rapid climate change. One evolutionary adaptation to randomly fluctuating environments is bet hedging, a strategy that successfully facilitates reproduction and population persistence and has been widely reported from microbes to humans. Empirical evidence for its presence in microalga, one of Earths most important primary producers and carbon sinks, is lacking. Here, we report a bet-hedging strategy in the unicellular microalga Haematococcus pluvialis. In a series of experiments, we show that an isogenic H. pluvialis population reversibly diversifies into hetero-phenotypic mobile and non-mobile subunits, independent of environmental conditions. Mobile cells grow faster but are more susceptible to external stressors, while non-mobile cells hardly grow but are more stress-resistant. This is attributed to dramatic shifts from growth-promoting activities (cell division, photosynthesis) to resilience-promoting cellular metabolic processes, including cell enlargement and aggregation, and accumulation of antioxidant and energy-storaging compounds. Our results provide experimental evidence for bet hedging in microalga, which has implications for their potential to adapt to current and predicted future conditions, and thus for the conservation of ecosystem functions.

ecology↗

bioRxiv2023

Mapping the developmental potential of mouse inner ear organoids at single-cell resolution

Inner ear organoids recapitulate development and are intended to generate cell types of the otic lineage for applications such as basic science research and cell replacement strategies. Here, we use single-cell sequencing to study the cellular heterogeneity of late-stage mouse inner ear organoid sensory epithelia, which we validated by comparison with data sets of the mouse cochlea and vestibular epithelia. We resolved supporting cell sub-types, cochlear like hair cells, and vestibular Type I and Type II like hair cells. While cochlear like hair cells aligned best with an outer hair cell trajectory, vestibular like hair cells followed developmental trajectories similar to in vivo programs branching into Type II and then Type I extrastriolar hair cells. These results highlight the transcriptional accuracy of the organoid developmental program but will also inform future strategies to improve synaptic connectivity and regional specification.

developmental biology↗

bioRxiv2023

Probucol mitigates high-fat diet-induced cognitive and social impairments through disruption of redox-inflammation association

Obesity and its detrimental metabolic consequences are commonly recognized as risk factors for impairments in the central nervous system (CNS). However, the direct link between metabolic abnormalities and brain functions during high-fat feeding remains unclear. Here, we show that treatment with probucol, a cholesterol-lowering drug, counteracts the cognitive and social impairments induced by a high-fat diet in mice, while having no effect on mood disorders. Unexpectedly, the beneficial effects of probucol do not result from rectifying obesity or restoring glucose and lipid homeostasis, as evidenced by the lack of change in body weight, blood glucose and serum cholesterol levels. Interestingly, high-fat feeding led to association among the levels of redox factors, including oxidized low-density lipoprotein, glutathione and malondialdehyde, as well as a significant negative correlation between malondialdehyde levels and behavioral performance. Probucol treatment interrupts these linkages and differentially regulates the proteins for the generation of reactive oxygen species and reactive nitrogen species in the brain. These findings prompt a reconsideration of the mechanism of action of probucol, as well as the roles of altered metabolic profiles and free radicals in brain function.

animal behavior and cognition↗

bioRxiv2023

Convergent evolution of SARS-CoV-2 XBB lineages on receptor-binding domain 455-456 enhances antibody evasion and ACE2 binding

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) XBB lineages have achieved dominance worldwide and keep on evolving. Convergent evolution of XBB lineages on the receptor-binding domain (RBD) L455F and F456L is observed, resulting in variants like EG.5, FL.1.5.1, XBB.1.5.70, and HK.3. Here, we show that neutralizing antibody (NAb) evasion drives the convergent evolution of F456L, while the epistatic shift caused by F456L enables the subsequent convergence of L455F through ACE2 binding enhancement and further immune evasion. L455F and F456L evade Class 1 NAbs, reducing the neutralization efficacy of XBB breakthrough infection (BTI) and reinfection convalescent plasma. Importantly, L455F single substitution significantly dampens receptor binding; however, the combination of L455F and F456L forms an adjacent residue flipping, which leads to enhanced NAbs resistance and ACE2 binding affinity. The perturbed receptor-binding mode leads to the exceptional ACE2 binding and NAb evasion, as revealed by structural analyses. Our results indicate the evolution flexibility contributed by epistasis cannot be underestimated, and the evolution potential of SARS-CoV-2 RBD remains high.

immunology↗

bioRxiv2023

PyHFO: Lightweight Deep Learning-poweredEnd-to-End High-Frequency Oscillations AnalysisApplication

In the context of epilepsy studies, intracranially-recorded interictal high-frequency oscillations (HFOs) in EEG signals are emerging as promising spatial neurophysiological biomarkers for epileptogenic zones. While significant efforts have been made in identifying and understanding these biomarkers, deep learning is carving novel avenues for biomarker detection and analysis. Yet, transitioning such methodologies to clinical environments is difficult due to the rigorous computational needs of processing EEG data via deep learning. This paper presents our development of an advanced end to end software platform, PyHFO, aimed at bridging this gap. PyHFO provides an integrated and user-friendly platform that includes time-efficient HFO detection algorithms such as short-term energy (STE) and Montreal Neurological Institute and Hospital (MNI) detectors and deep learning models for artifact and HFO with spike classification. This application functions seamlessly on conventional computer hardware. Our platform has been validated to adeptly handle datasets from 10-minute EEG recordings captured via grid/strip electrodes in 19 patients. Through implementation optimization, PyHFO achieves speeds up to 50 times faster than the standard HFO detection method. Users can either employ our pre-trained deep learning model for their analyses or use their EEG data to train their model. As such, PyHFO holds great promise for facilitating the use of advanced EEG data analysis tools in clinical practice and large-scale research collaborations.

neuroscience↗

bioRxiv2023

Genomic insights into post-domestication expansion and selection of body size in ponies

Horses domestication revolutionized human civilization by changing transportation, farming, and warfare patterns. Despite extensive studies on modern domestic horse origins, the intricate demographic history and genetic signatures of pony size demand further exploration. Here, we present a high-quality genome of the Chinese Debao pony and extensively analyzed 385 individuals from 49 horse breeds. We reveal the conservation of ancient components in East Asian horses and close relationships between Asian horses and specific European pony lineages. Genetic analysis uncovers Asian paternal origin for European pony breeds, and these pony-sized horses share a close genetic affinity due to the presence of a potential ancestral ghost pony population. Additionally, we identify promising cis-regulatory elements influencing horse withers height by regulating genes like RFLNA and FOXO1. Overall, our study provides insightful perspectives into the development history and genetic determinants underlying body size in ponies and offers broader implications for horse population management and improvement. TeaserDecoding pony genetics: exploring origins and size determinants sheds light on their historical and biological impacts.

genomics↗

bioRxiv2023

Antibody Neutralization of Emerging SARS-CoV-2: EG.5.1 and XBC.1.6

SARS-CoV-2 variants EG.5.1 and XBC.1.6 have recently emerged, attracting increased attention due to their rapid expansion globally and in Australia, respectively. EG.5.1 evolved from Omicron subvariant XBB.1.9, harboring additional Q52H and F456L spike substitutions. The F456L mutation is located within the epitopes of many class-1 monoclonal antibodies (mAbs) directed to the receptor-binding domain (RBD), raising concerns about further antibody evasion. XBC.1.6, a descendant of a Delta-BA.2 recombinant, carries 15 additional spike mutations. The extent to which antibody evasion contributes to the growth advantage of XBC.1.6 in Australia remains to be determined. To assess the antibody evasion properties of the emergent variants, we conducted pseudovirus neutralization assays using sera from individuals who received three doses of COVID-19 mRNA monovalent vaccines plus one dose of a BA.5 bivalent vaccine, as well as from patients with BQ or XBB breakthrough infection. The assays were also performed using a panel of 14 mAbs that retained neutralizing activity against prior XBB subvariants. Our data suggested that EG.5.1 was slightly but significantly more resistant (< 2-fold) to neutralization by BQ and XBB breakthrough sera than XBB.1.16, which is known to be antigenically similar to XBB.1.5. Moreover, the F456L mutation in EG.5.1 conferred heightened resistance to certain RBD class-1 mAbs. In contrast, XBC.1.6 was more sensitive to neutralization by sera and mAbs than the XBB subvariants. Notably, XBB breakthrough sera retained only weak neutralization activity against XBB subvariants. In summary, EG.5.1 and XBC.1.6 exhibited distinct antibody evasion properties. The recent global expansion of EG.5.1 might be attributable, in part, to its enhanced neutralization resistance. That XBB breakthrough infections did not elicit a robust antibody neutralization response against XBB subvariants is indicative of immunological imprinting. The high prevalence of XBC.1.6 in Australia is not due to enhanced antibody evasion.

microbiology↗

bioRxiv2023

Nitrate-driven anaerobic oxidation of ethane and butane by bacteria

The short-chain gaseous alkanes (ethane, propane and butane; SCGAs) are important components of natural gas, yet our understanding of their fate in environmental systems is poorly understood. Microbially mediated anaerobic oxidation of SCGAs coupled to nitrate reduction has been demonstrated for propane, but is yet to be shown for ethane or butane - despite being energetically feasible. Here we report two independent bacterial enrichments performing anaerobic ethane and butane oxidation, respectively, coupled to nitrate reduction to dinitrogen gas and ammonium. Isotopic 13C-and 15N-labelling experiments, mass and electron balance tests, and metabolite and meta-omics analyses collectively reveal that the recently described propane-oxidising Candidatus Alkanivorans nitratireducens was also responsible for nitrate-dependent anaerobic oxidation of the SCGAs in both these enrichments. The complete genome of this species encodes alkylsuccinate synthase genes for the activation of ethane/butane via fumarate addition. Further substrate range tests confirm Ca. A. nitratireducens is metabolically versatile, being able to degrade ethane, propane and butane under anaerobic conditions. Moreover, our study proves nitrate as an additional electron sink for ethane and butane in anaerobic environments, and for the first time demonstrates the use of the fumarate addition pathway in anaerobic ethane oxidation. These findings significantly contribute to our understanding of microbial metabolism of SCGAs in anaerobic environments.

microbiology↗

bioRxiv2023

Diversity of Bathyarchaeia viruses in metagenomes and virus-encoded CRISPR system components

Bathyarchaeia represent a class of archaea common and abundant in sedimentary ecosystems. The virome of Bathyarchaeia so far has not been characterized. Here we report 56 metagenome-assembled genomes of Bathyarchaeia viruses identified in metagenomes from different environments. Gene sharing network and phylogenomic analyses led to the proposal of four virus families, including viruses of the realms Duplodnaviria and Adnaviria, and archaea-specific spindle-shaped viruses. Genomic analyses uncovered diverse CRISPR elements in these viruses. Viruses of the proposed family Fuxiviridae harbor an atypical type IV-B CRISPR-Cas system and a Cas4 protein that might interfere with host immunity. Viruses of the family Chiyouviridae encode a Cas2-like endonuclease and two mini-CRISPR arrays, one with a repeat identical to that in the host CRISPR array, potentially allowing the virus to recruit the host CRISPR adaptation machinery to acquire spacers that could contribute to competition with other mobile genetic elements or to inhibition of host defenses. These findings present an outline of the Bathyarchaeia virome and offer a glimpse into their counter-defense mechanisms.

microbiology↗

bioRxiv2023

Thermoplasmonic modulation of cardiomyocytes activity with local temperature read-out

Cardiomyocyte beating rate modulation is required in multiple in vitro assays and it is usually done by electrical or optogenetic methods. In this work, we develop and characterize a light-based strategy to modulate the cardiomyocyte beating rate by near-infrared (NIR) controlled plasmonic stimulation. For this purpose, gold nanorods (GNRs) acting as plasmonic heaters and silica-coated quantum dots (QDs) as nanothermometers are attached to surfaces used for cardiomyocyte cultures, while the cell electrophysiological activity is visualized by monitoring calcium transients via calcium imaging. This system is capable of modulating cardiac activity with near infrared-controllable plasmonic heating while measuring local temperature changes owing to the temperature-dependent fluorescence of silica-coated QDs. Table of Contents (TOC) O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=125 SRC="FIGDIR/small/554091v1_ufig1.gif" ALT="Figure 1"> View larger version (31K): org.highwire.dtl.DTLVardef@4325fcorg.highwire.dtl.DTLVardef@72c48dorg.highwire.dtl.DTLVardef@c60849org.highwire.dtl.DTLVardef@14a1e27_HPS_FORMAT_FIGEXP M_FIG C_FIG

bioengineering↗