Biology subjects

Sun, L.

Publications and source records attributed to Sun, L..

At least 289 records · Page 16Linked to original sources

bioRxiv2022

Neural responses to biological motion distinguish autistic and schizotypal traits in the general population

Difficulties in social interactions are common to both autism and schizophrenia, and contribute to correlated autistic and schizotypal traits in the neurotypical population. It remains unresolved whether this represents a shared etiology or a superficial phenotypic overlap. Both conditions are associated with atypical neural activity in response to the perception of social stimuli, and also decreased neural synchronization between individuals that may prohibit establishing shared experiences. This study sought to establish if neural activity and neural synchronization associated with biological motion perception are differentially associated with autistic and schizotypal traits in the neurotypical population. Participants watched an audiovisual montage of naturalistic social interactions whilst hemodynamic brain activity was measured with fMRI. A separate sample of participants provided a continuous measure of the extent of biological motion, which was used to predict hemodynamic activity. General Linear Model analysis revealed that biological motion perception was associated with neural activity across the action-observation network. However, inter-subject phase synchronization analysis revealed that neural activity synchronized between individuals in occipital and parietal areas, but de-synchronized in temporal and frontal regions. Autistic traits were associated with a decrease in neural activity (precuneus, middle cingulate gyrus) and schizotypal traits were associated with a decrease in neural synchronization (middle and inferior frontal gyri). Biological motion perception elicits convergent and divergent patterns of neural activity and neural synchronization, and are differentially associated with shared traits related with autism and schizophrenia in the general population, suggesting that they originate from different neural mechanisms.

neuroscience↗

bioRxiv2022

A potent SARS-CoV-2 antibody neutralizes Omicron variant by disassembling the spike trimer

The continuous emergence of novel SARS-CoV-2 variants poses new challenges to the fight against the COVID-19 pandemic. The newly emerging Omicron strain caused serious immune escape and raised unprecedented concern all over the world. The development of antibody targeting conserved and universal epitope is urgently needed. A subset neutralizing antibody(nAbs) against COVID-19 from convalescent patients were isolated in our previous study. Here in this study, we investigated the accommodation of these nAbs to SARS-CoV-2 variants of concerns (VOCs), revealing that IgG 553-49 neutralizes pseudovirus of SARS-CoV-2 Omicron variant. In addition, we determined the cryo-EM structure of SARS-CoV-2 spike complexed with three antibodies targeting different epitopes, including 553-49, 553-15 and 553-60. Notably, 553-49 targets a novel conserved epitope and neutralizes virus by disassembling spike trimers. 553-15, an antibody that neutralizes all the other VOCs except omicron, cross-links two spike trimers to form trimer dimer, demonstrating that 553-15 neutralizes virus by steric hindrance and virion aggregation. These findings suggest the potential to develop 49 and other antibody targeting this highly conserved epitope as promising cocktail therapeutics reagent for COVID-19. ImportanceThe newly emergence of Omicron strain caused higher immune escape, raising unprecedented concerns about the effectiveness of antibody therapies and vaccines. In this study, we identified a SARS-CoV-2 Omicron neutralizing antibody 553-49, which neutralizes Omicron variant by targeting a completely conserved novel epitope. Besides, we revealed that IgG 553-15 neutralizes SARS-CoV-2 by crosslinking virions and 553-60 functions by blocking receptor binding. Comparison of different RBD epitopes revealed that the epitope of 553-49 is hidden in the S trimer and keeps high conservation during SARS-CoV-2 evolution, making 553-49 a promising therapeutics reagent to fight against the emerging Omicron and future variant of SARS-CoV-2.

microbiology↗

bioRxiv2022

Impaired Lef1 activation accelerates iPSC-derived keratinocytes differentiation in Progeria

Hutchinson-Gilford progeria syndrome (HGPS) is a detrimental premature aging disease caused by a point mutation in the human LMNA gene. This mutation results in the abnormal accumulation of a truncated pre-lamin A protein called progerin. Among the drastically accelerated signs of aging in HGPS patients, severe skin phenotypes such as alopecia and sclerotic skins always develop with the disease progression. Here, we study the HGPS molecular mechanisms focusing on early skin development by differentiating patient-derived induced pluripotent stem cells (iPSCs) to a keratinocyte lineage. Interestingly, HGPS iPSCs showed an accelerated commitment to the keratinocyte lineage than the normal control. To study potential signaling pathways that accelerated skin development in HGPS, we investigated the WNT pathway components during HGPS iPSCs-keratinocytes induction. Surprisingly, despite the unaffected {beta}-catenin activity, the expression of a critical WNT transcription factor LEF1 was diminished from an early stage in HGPS iPSCs-keratinocytes differentiation. Chromatin immunoprecipitation (ChIP) experiment further revealed strong bindings of LEF1 to the early-stage epithelial developmental markers K8 and K18 and that the LEF1 silencing by siRNA down-regulates the K8/K18 transcription. During the iPSCs-keratinocytes differentiation, correction of HGPS mutation by Adenine base editing (ABE), while in a partial level, rescued the phenotypes for accelerated keratinocyte lineage-commitment. ABE also reduced the cell death in HGPS iPSCs-derived keratinocytes. These findings brought new insight into the molecular basis and therapeutic application for the skin abnormalities in HGPS.

developmental biology↗

bioRxiv2022

Structural insight into the individual variability architecture of the functional brain connectome

Human cognition and behaviors depend upon the brains functional connectomes, which vary remarkably across individuals. However, whether and how the functional connectome individual variability architecture is structurally constrained remains largely unknown. Using tractography- and morphometry-based network models, we observed the spatial convergence of structural and functional connectome individual variability, with higher variability in heteromodal association regions and lower variability in primary regions. We demonstrated that functional variability is significantly predicted by a unifying structural variability pattern and that this prediction follows a primary-to-heteromodal hierarchical axis, with higher accuracy in primary regions and lower accuracy in heteromodal regions. We further decomposed group-level connectome variability patterns into individual unique contributions and uncovered the structural-functional correspondence that is associated with individual cognitive traits. These results advance our understanding of the structural basis of individual functional variability and suggest the importance of integrating multimodal connectome signatures for individual differences in cognition and behaviors.

neuroscience↗

bioRxiv2022

High-performance GPCR optogenetics based on molecular properties of animal opsins, MosOpn3 and LamPP

Optogenetics for GPCR signaling is highly valuable but still requires effective and versatile tools with performance evaluation from molecular properties. Here we investigated performance of two animal opsins, mosquito Opn3 (MosOpn3) and lamprey parapinopsin (LamPP) in optical manipulation in vivo by using C. elegans. MosOpn3 introduced in a nociceptor neurons induced avoidance responses light-dependently with a retinal isomer ubiquitously present in every tissue, like ChR2 and unlike canonical vertebrate opsins. Remarkably, the sensitivity is ~7000 times higher than the case of ChR2 in the light-induced behavior. LamPP introduced in motor neurons induced violet light-dependent stop and green light-dependent go, demonstrating color-dependent manipulation of behaviors using LamPP. Furthermore, our molecular engineering extended the usability of MosOpn3 and LamPP to different signaling cascades and kinetics. Current findings demonstrated that the availability of two animal opsins is equivalent to that of ChR2 in terms of retinal requirement, providing solid strategies for GPCR optogenetics.

biochemistry↗

bioRxiv2022

Combating the SARS-CoV-2 Omicron variant with non-Omicron neutralizing antibodies

The highly mutated and transmissible Omicron variant has provoked serious concerns over its decreased sensitivity to the current coronavirus disease 2019 (COVID-19) vaccines and evasion from most anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) neutralizing antibodies (NAbs). In this study, we explored the possibility of combatting the Omicron variant by constructing bispecific antibodies based on non-Omicron NAbs. We engineered ten IgG-like bispecific antibodies with non-Omicron NAbs named GW01, 16L9, 4L12, and REGN10987 by fusing the single-chain variable fragments (scFvs) of two antibodies through a linker and then connecting them to the Fc region of IgG1. Surprisingly, eight out of ten bispecific antibodies showed high binding affinity to the Omicron receptor-binding domain (RBD) and exhibited extreme breadth and potency against pseudotyped SARS-CoV-2 variants of concern (VOCs) including Omicron, as well as authentic Omicron(+R346K) variants. Six bispecific antibodies containing the cross-NAb GW01 neutralized Omicron variant and retained their abilities to neutralize other sarbecoviruses. Bispecific antibodies inhibited Omicron infection by binding to the ACE2 binding site. A cryo-electron microscopy (cryo-EM) structure study of the representative bispecific antibody FD01 in complex with the Omicron spike (S) revealed 5 distinct trimers and one unique bi-trimer conformation. The structure and mapping analyses of 34 Omicron S variant single mutants elucidated that two scFvs of the bispecific antibody synergistically induced the RBD-down conformation into 3-RBD-up conformation, enlarged the interface area, accommodated the S371L mutation, improved the affinity between a single IgG and the Omicron RBD, and hindered ACE2 binding by forming bi-trimer conformation. Our study offers an important foundation for anti-Omicron NAb design. Engineering bispecific antibodies based on non-Omicron NAbs may provide an efficient solution to combat the Omicron variant.

microbiology↗

bioRxiv2022

SELINA: Single-cell Assignment using Multiple-Adversarial Domain Adaptation Network with Large-scale References

The rapid accumulation of single-cell RNA-seq data has provided rich resources to characterize various human cell types. Cell type annotation is the critical step in analyzing single-cell RNA-seq data. However, accurate cell type annotation based on public references is challenging due to the inconsistent annotations, batch effects, and poor characterization of rare cell types. Here, we introduce SELINA (single cELl identity NAvigator), an integrative annotation transferring framework for automatic cell type annotation. SELINA optimizes the annotation for minority cell types by synthetic minority over-sampling, removes batch effects among reference datasets using a multiple-adversarial domain adaptation network (MADA), and fits the query data with reference data using an autoencoder. Finally, SELINA affords a comprehensive and uniform reference atlas with 1.7 million cells covering 230 major human cell types. We demonstrated the robustness and superiority of SELINA in most human tissues compared to existing methods. SELINA provided a one-stop solution for human single-cell RNA-seq data annotation with the potential to extend for other species.

bioinformatics↗

bioRxiv2022

Asymmetric Pendrin Homodimer Reveals its Molecular Mechanism as Anion Exchanger

Pendrin SLC26A4 is an anion exchanger expressed in apical membranes of selected epithelia. Pendrin ablation causes Pendred syndrome, a genetic disorder disease associated with sensorineural hearing loss, hypothyroid goiter, and reduced blood pressure. However, its molecular structure has remained unknown limiting our understanding. Here, we determined the structures of mouse pendrin with symmetric and characteristically asymmetric homodimer conformations by cryo-electron microscopy. The asymmetric homodimer consists of an inward-facing protomer and an intermediate-state protomer, representing the coincident uptake and secretion process, and exhibits the unique state of pendrin as an electroneutral exchanger. This previously unrevealed conformation, together with other conformations we captured, provides an inverted alternate-access mechanism for anion exchange. Furthermore, our structural and functional data disclosed the properties of anion exchange cleft and interpreted the important pathogenetic mutations. These investigations shed light on the pendrin exchange mechanism and extend our structure-guided understanding of pathogenetic mutations. One-Sentence SummaryCryo-EM asymmetric Pendrin homodimer cracks its exchange mechanism and guides our understanding for pathogenetic mutations.

biophysics↗

bioRxiv2022

EPSTEIN-BARR VIRUS LMP1 ENHANCES LEVELS OF MICROVESICLE-ASSOCIATED PD-L1

Extracellular vesicles (EVs) circulate throughout the body and carry cargo that can be conferred to proximal or distant cells, making them major delivery vehicles for cellular communication. Epstein-Barr virus (EBV) infected cells release EVs that contain viral proteins such as the major viral oncogene, latent membrane protein 1 (LMP1). LMP1 has been shown to regulate the cellular gene expression of programmed cell death protein 1 ligand (PD-L1). PD-L1, a protein that suppresses the immune system by binding to PD-1, (a receptor found on cytotoxic T cells). PD-L1 has been recently found to be packaged into small EVs contributing to immune evasion of lung cancer cells. Recent studies establish that MVs are shed in very large amounts by tumor cells, and that elevated levels of MVs correlate to disease metastasis and cancers being more aggressive. Here, we demonstrate PD-L1 enrichment in MVs released from nasopharyngeal carcinoma cells and an important function of EBV LMP1 in regulating PD-L1 levels in MVs. These PD-L1+ MVs containing LMP1 likely contribute to the immunosuppressive microenvironment found in EBV-associated cancers. ImportanceAccumulating evidence over the past decade supports that viruses utilize EVs and associated pathways to incorporate viral products to evade eliciting an immune response, while concurrently enabling viral spread or persistence within the host. Considering that viral proteins confer very strong antigenic peptides that will be recognized by T cells, the regulation of the PD-1 pathway by the overexpression of MV-associated PD-L1 may be a strong immune evasion tactic utilized by viruses. The discovery that EBV LMP1 increases PD-L1 microvesicle secretion, identifies a new therapeutic target in immune blockade therapy. We expect that our findings will begin to clarify the mechanism of LMP1-mediated enhanced packaging of PD-L1 into MVs and may produce more specific targets to treat EBV-associated cancers. Consequently, identifying whether a disease is of viral origin through predictive MV biomarkers could further allow for more targeted therapies.

microbiology↗

bioRxiv2022

Accurate sex classification from neural responses to sexual stimuli

Sex differences in brain activity evoked by sexual stimuli remain elusive despite robust evidence for stronger enjoyment of and interest towards sexual stimuli in men than in women. To test whether visual sexual stimuli evoke different brain activity patterns in men and women, we measured haemodynamic brain activity induced by visual sexual stimuli in two experiments in 91 subjects (46 males). In one experiment, the subjects viewed sexual and non-sexual film clips and dynamic annotations for nudity in the clips was used to predict their hemodynamic activity. In the second experiment, the subjects viewed sexual and non-sexual pictures in an event-related design. Males showed stronger activation than females in the visual and prefrontal cortices and dorsal attention network in both experiments. Furthermore, using multivariate pattern classification we could accurately predict the sex of the subject on the basis of the brain activity elicited by the sexual stimuli. The classification generalized across the experiments indicating that the sex differences were consistent. Eye tracking data obtained from an independent sample of subjects (N = 110) showed that men looked longer than women at the chest area of the nude female actors in the film clips. These results indicate that visual sexual stimuli evoke discernible brain activity patterns in men and women which may reflect stronger attentional engagement with sexual stimuli in men than women.

neuroscience↗

bioRxiv2022

Single-cell analysis of microglial transcriptomic diversity in subarachnoid hemorrhage

BackgroundSubarachnoid hemorrhage (SAH) is a severe stroke and the advanced treatment for SAH is still limited. Recent studies have shown that microglia-mediated neuroinflammation plays a critical role in the pathogenesis of SAH. Microglia can transform their states in response to central nervous system injury. However, the transcriptomic features of microglia remained unknown in SAH. Recent developed single-cell RNA sequencing (scRNA-seq) provides a possible way to solve this problem. MethodsEndovascular perforation (EVP) murine SAH model was established to reproduce experimental SAH. Microglia states are examined with immune staining and quantitate analysis. Post-SAH microglial single-cell suspension were harvest and sequenced using 10X scRNA-seq platform. Then, the detailed single-cell transcriptomic characterization of post-SAH microglia were analyzed with bioinformatics. ResultsTranscriptional analysis revealed at least ten diverse microglial subgroups, including SAH-associated microglia (SAM), inflammatory-associated microglia (IAM) and proliferation-associated microglia (PAM), which all exhibit distinct marker gene expression patterns. Microglia subsets interaction reveals the functional relationship between elevated signaling pathways and microglial sub-populations in SAH. Receptor-ligand pair analysis revealed that complex inter-cellular interactions exist between the microglia subsets and other cell types, and indicated that microglia are important mediators of neuroinflammation after SAH. Integrated analysis with normal microglia further proved the existence of these microglia subpopulations and different gene markers associated with SAH were clarified. ConclusionsCollectively, we first report the single-cell transcriptome of post-SAH microglia and found specific biomarkers related to the neuroinflammation in SAH. These results enhanced our understanding of the pathological mechanisms of microglial response to SAH, and may guide future development of SAH monitoring methods and therapeutics.

neuroscience↗

bioRxiv2021

Broad neutralization of SARS-CoV-2 variants by an inhalable bispecific single-domain antibody

The effectiveness of SARS-CoV-2 vaccines and therapeutic antibodies has been limited by the continuous emergence of viral variants, and by the restricted diffusion of antibodies from circulation into the sites of respiratory virus infection. Here, we report the identification of two highly conserved regions on Omicron variant RBD recognized by broadly neutralizing antibodies. Based on this finding, we generated a bispecific single-domain antibody that was able to simultaneously and synergistically bind these two regions on a single Omicron variant RBD as revealed by Cryo-EM structures. This inhalable antibody exhibited exquisite neutralization breadth and therapeutic efficacy in mouse models of SARS-CoV-2 infections. The structures also deciphered an uncommon cryptic epitope within the spike trimeric interface that may have implications for the design of broadly protective SARS-CoV-2 vaccines and therapeutics.

immunology↗

bioRxiv2021

m7G cap-eIF4E interaction stimulates polysome formation by enhancing first-round initiation kinetics

Translation in eukaryotic cells occurs predominantly through a 7-methylguanosine (m7G) cap-dependent mechanism. m7G cap interactions with eukaryotic initiation factor 4E (eIF4E) facilitates 43S recruitment to the mRNA 5 end and enhances the translation efficiency of mRNA. However, it remains poorly understood how m7G cap-eIF4E interactions affect polysome formation kinetics. Here, we examine the role of the m7G cap in polysome formation by utilizing a single-molecule approach to track individual ribosomes during active translation. Translation was monitored in wheat germ extract with capped and uncapped synthetic mRNAs and in HeLa extract with purified human eIF4E titration. The presence of the m7G cap and the supplementation of eIF4E to eIF4E-deficient extract enhanced the kinetics of the first initiation event of polysomes. Subsequent to the first initiation event, efficient polysome-forming initiation events occurred independent of mRNA m7G capping status and eIF4E concentration. Our results indicate that m7G cap-eIF4E interactions in wheat germ and HeLa extracts promote polysome formation by enhancing first-round initiation kinetics. The dynamics of individual translation events on polysomal mRNAs suggest that first-round initiation events activate mRNAs for efficient subsequent rounds of polysome-forming initiation.

biophysics↗

bioRxiv2021

Two doses of mRNA vaccine elicit cross-neutralizing memory B-cells against SARS-CoV-2 Omicron variant

SARS-CoV-2 Beta and Omicron variants have multiple mutations in the receptor-binding domain (RBD) allowing antibody evasion. Despite the resistance to circulating antibodies in those who received two doses of mRNA vaccine, the third dose prominently recalls cross-neutralizing antibodies with expanded breadth to these variants. Herein, we longitudinally profiled the cellular composition of persistent memory B-cell subsets and their antibody reactivity against these variants following the second vaccine dose. The vaccination elicited a memory B-cell subset with resting phenotype that dominated the other subsets at 4.9 months. Notably, most of the resting memory subset retained the ability to bind the Beta variant, and the memory-derived antibodies cross-neutralized the Beta and Omicron variants at frequencies of 59% and 29%, respectively. The preservation of cross-neutralizing antibody repertoires in the durable memory B-cell subset likely contributes to the prominent recall of cross-neutralizing antibodies following the third dose of the vaccine. One Sentence SummaryFully vaccinated individuals preserve cross-neutralizing memory B-cells against the SARS-CoV-2 Omicron variant.

immunology↗

bioRxiv2021

Human embryos arrest in a quiescent-like state characterized by metabolic and zygotic genome activation problems

Around 60% of in vitro fertilized (IVF) human embryos irreversibly arrest before compaction between the 3-8-cell stage, posing a significant clinical problem. The mechanisms behind this arrest are unclear. Here, we show that the arrested embryos enter a quiescent-like state, marked by cell cycle arrest, the downregulation of ribosomes and histones and downregulation of MYC and p53 activity. Mechanistically, the arrested embryos can be divided into three types. Type I embryos fail to complete the maternal-zygotic transition, and type II/III embryos have erroneously low levels of glycolysis and variable levels of oxidative phosphorylation. Treatment with resveratrol or nicotinamide riboside (NR) can partially rescue the arrested phenotype. The mechanism of reactivation involves the upregulation of SIRT1, and activation of glycolysis and fatty acid oxidation which forces the embryos out of a quiescent state. Overall, our data reveal how human embryo arrest can be overcome by modulating metabolic pathways.

developmental biology↗

bioRxiv2021

Functional organization of social perception in the human brain

Humans rapidly extract diverse and complex information from ongoing social interactions, but the perceptual and neural organization of the different aspects of social perception remains unresolved. We showed short film clips with rich social content to 97 healthy participants while their haemodynamic brain activity was measured with fMRI. The clips were annotated moment-to-moment for 112 social features. Cluster analysis revealed that 13 dimensions were sufficient for describing the social perceptual space. Regression analysis was used to map regional neural response profiles to different social features. Multivariate pattern analysis was then utilized to establish the spatial specificity of these responses. The results revealed a gradient in the processing of social information in the brain. Posterior temporal and occipital regions were broadly tuned to most social dimensions and the classifier revealed that these responses showed spatial specificity for social dimensions; in contrast Heschl gyri and parietal areas were also broadly associated with different social signals, yet the spatial patterns of responses did not differentiate social dimensions. Frontal and subcortical regions responded only to a limited number of social dimensions and the spatial response patterns did not differentiate social dimension. Altogether these results highlight the distributed nature of social processing in the brain.

neuroscience↗

bioRxiv2021

Generating Electricity from Water Evaporation Through Microbial Biofilms

Sustainable strategies for energy production are required to reduce reliance on fossil fuels and to power electronics without generating toxic waste.1-7 Generating electricity from water evaporation through engineered materials is a promising approach,8,9 but power outputs have been low and the materials employed were not sustainably produced. Microorganisms can be mass produced with renewable feedstocks. Here, we demonstrate that it is possible to engineer microbial biofilms as a cohesive, flexible material for long-term continuous electricity production from evaporating water. The biofilm sheets were the functional component in devices that continuously produced power densities ([~]1 W/cm2) higher than that achieved with non-biological materials. Current production scaled directly with biofilm-sheet size and skin-patch devices harvested sufficient electricity from the moisture on skin to continuously power wearable devices. The results demonstrate that appropriately engineered biofilms can perform as robust functional materials without the need for further processing or maintaining cell viability. Biofilm-based hydroelectric current production was comparable to that achieved with similar sized biofilms catalyzing current production in microbial fuel cells,10,11 without the need for an organic feedstock or maintaining cell viability. The ubiquity of biofilms in nature suggests the possibility of additional sources of biomaterial for evaporation-based electricity generation and the possibility of harvesting electricity from diverse aqueous environments.

microbiology↗

bioRxiv2021

Isolation and characterization of fucosylated extracellular vesicles based on a novel GlyExo-Capture technique

Owing to their diagnostic and therapeutic potential, extracellular vesicles (EVs) derived from tumour cells have recently garnered great interest. The presence of different glycosylation sites at the EV surface supports the need for efficient glycosylated EV isolation. Here, we developed a GlyExo-Capture technique for robustly capturing fucosylated EVs from sera and cell supernatants. Lens culinaris lectin (LCA)-immobilized magnetic complexes were found to capture approximately 60% of the total EVs from HepG2 cells. The capture efficiency was reduced to less than 40% in nontumorigenic MIHA cells. Notably, the cellular uptake pattern of highly fucosylated EVs was markedly different from that of EVs with low fucosylation. The unearthing of enriched fucosylated EV miRNA cargos by next-generation deep sequencing (NGS) revealed 75 differentially expressed miRNAs (DEMs) in hepatocellular carcinoma (HCC). Among them, a 4-miRNA panel was chosen and yielded an area under the ROC curve (AUC) of 0.86 and 0.84 for the detection of HCC from non-HCC controls in testing samples and independent validation samples, respectively. The 4-miRNA signature was independent of alpha-fetoprotein (AFP), and a combined model with AFP yielded an increased AUC of 0.92. In conclusion, we developed a high-throughput method for capturing fucosylated EVs efficiently and shed light on the use of fucosylated EVs as potential sources of miRNAs for cancer biomarker detection.

cancer biology↗