Biology subjects

Song, S.

Publications and source records attributed to Song, S..

At least 127 records · Page 7Linked to original sources

bioRxiv2022

Molecular basis of broad neutralization against SARS-CoV-2 variants including Omicron by a human antibody

Omicron, a newly emerging SARS-CoV-2 variant, carried a large number of mutations in the spike protein leading to an unprecedented evasion from many neutralizing antibodies (nAbs). Here, we performed a head-to-head comparison of Omicron with other existing highly evasive variants in terms of their reduced sensitivities to antibodies, and found that Omicron variant is significantly more evasive than Beta and Mu variants. Of note, some key mutations occur in the conserved epitopes identified previously, especially in the binding sites of Class 4 nAbs, contributing to the increased Ab evasion. We also reported a broadly nAb (bnAb), VacW-209, which effectively neutralized all tested SARS-CoV-2 variants and even SARS-CoV. Finally, we determined six cryo-electron microscopy structures of VacW-209 complexed with the spike ectodomains of wild-type, Delta, Mu, C.1.2, Omicron, and SARS-CoV, and revealed the molecular basis of the broadly neutralizing activities of VacW-209 against SARS-CoV-2 variants. Overall, Omicron has once again raised the alarm over virus variation with significantly compromised neutralization. BnAbs targeting more conserved epitopes among variants will continue to play a key role in pandemic control and prevention. One sentence summaryStructural and functional analyses reveal that a human antibody named VacW-209 confers broad neutralization against SARS-CoV-2 variants including Omicron by recognizing a highly conserved epitope.

immunology↗

bioRxiv2021

Recall of B cell memory depends on relative locations of prime and boost

Re-entry of memory B cells to recall germinal centers (GCs) is essential for updating their B-cell antigen receptors (BCRs). Using single B-cell culture and fate-mapping, we have characterized BCR repertoires in recall GCs following boost immunizations at sites local or distal to the priming. Local boosts with homologous antigen recruit to recall GCs progeny of primary GC B cells more efficiently than do distal boosts. Recall GCs following local boosts contain significantly more B cells with elevated levels of Ig mutations and higher avidity BCRs. This local preference is unaffected by blockade of CD40:CD154 interaction that terminate active, primary GC responses. Local boosts with heterologous antigens elicit secondary GCs with B-cell populations enriched for cross-reactivity to the priming and boosting antigens; in contrast, cross-reactive GC B cells are rare following distal boosts. Our findings indicate the importance of locality in humoral immunity and inform serial vaccination strategies for evolving viruses. One Sentence SummaryThe participation of memory B cells in recall germinal centers depends on whether the boost is local or distal to the priming site.

immunology↗

bioRxiv2021

Potent antibody immunity to SARS-CoV-2 variants elicited by a third dose of inactivated vaccine

SARS-CoV-2 variants are still prevalent worldwide and continue to pose a challenge to the effectiveness of current vaccines. It remains unknown whether a third dose of inactivated vaccine elicits immune potential against SARS-CoV-2 variants. Here, we showed a significant decline in plasma neutralization against SARS-CoV-2 at seven months after a second dose of the inactivated vaccine in a large-scale cohort. However, we also found that a third vaccination with an inactivated vaccine largely increased plasma neutralization against variants including Beta, Delta, and Lambda. More importantly, the high-affinity anti-RBD memory B cells were also generated by the third vaccination, suggesting a more potent and longer protection. These findings highlighted the importance and effectiveness of a third dose of inactivated vaccine in conferring higher protection against the emerging variants in populations.

immunology↗

bioRxiv2021

Chemogenetic activation of Locus Coeruleus Noradrenergic Neurons Modulates the Default Mode Network

The default mode network (DMN) of the brain is involved in cognition, emotion regulation, impulsivity, and balancing between internally and externally focused states. DMN dysregulation has been implicated in several neurological and neuropsychiatric disorders. In this study, we used functional magnetic resonance imaging (fMRI), positron emission tomography (PET), and spectral fiber-photometry to investigate the selective neuromodulatory effect of norepinephrine (NE)-releasing noradrenergic neurons in the locus coeruleus (LC) on the DMN in mice. Chemogenetic-induced tonic LC-NE activity decreased cerebral blood volume (CBV) and glucose uptake, and increased synchronous low frequency fMRI activity within the frontal cortices of the DMN. Fiber-photometry results corroborated these findings, showing that LC-NE activation induced NE release, enhanced calcium-weighted neuronal spiking, and reduced CBV in the anterior cingulate cortex. These data suggest that LC-NE alters conventional stimulus-evoked coupling between neuronal activity and CBV in the frontal DMN. We also demonstrated that chemogenetic activation of LC-NE neurons strengthened functional connectivity within the frontal DMN, and this effect was causally mediated by reduced modulatory inputs from retrosplenial and hippocampal regions to the association cortices of the DMN.

neuroscience↗

bioRxiv2021

LungCancer3D: A Comprehensive Database for Integrating Lung Cancer Chromatin Architecture with Other Multi-omics

With the breakthrough of chromatin conformation capture technologies in recent years, the importance of three-dimensional (3D) genome structure in gene expression, cell function regulation, disease occurrence, and development has been gradually recognized. To provide a comprehensive visualization of chromatin architecture and other multi-omics data for lung cancer research, we have constructed a comprehensive database, LungCancer3D (http://www.lungcancer3d.net). This web-based tool focuses on displaying human lung cancer-related HiC data along with a variety of other publicly available data, such as RNA-seq, scRNA-seq, ATAC-seq, ChIP-seq, DNA methylation, DNA mutation, and copy number variations. Researchers can visualize these diverse multi-omics data directly through the genome browser and discover how the genes expression is regulated at diverse levels. For example, we have demonstrated that the high expression level of C-MYC in lung cancer may be caused by the distant enhancer introduced by the de novo chromatin loops in lung cancer cells to bind the C-MYC promoter. The integrated multi-omics analyses through the LungCancer3D website can reveal the mechanisms underlying lung cancer development and provide potential targets for lung cancer therapy.

bioinformatics↗

bioRxiv2021

A merger between compatible but divergent genomes supports allopolyploidization in the Brassicaceae family

Hybridization and polyploidization are pivotal to plant evolution. Genetic crosses between distantly related species rarely occur in nature mainly due to reproductive barriers but how such hurdles can be overcome is largely unknown. xBrassicoraphanus is a fertile intergeneric allopolyploid synthesized between Brassica rapa and Raphanus sativus in the Brassicaceae family. Genomes of B. rapa and R. sativus are diverged enough to suppress synapsis formation between non-homologous progenitor chromosomes during meiosis, and we found that both genomes reside in the single nucleus of xBrassicoraphanus without genome loss or rearrangement. Expressions of syntenic orthologs identified in B. rapa and R. sativus were adjusted to a hybrid nuclear environment of xBrassicoraphanus, which necessitates reconfiguration of transcription network by rewiring cis-trans interactions. B. rapa coding sequences have a higher level of gene-body methylation than R. sativus, and such methylation asymmetry is maintained in xBrassicoraphanus. B. rapa-originated transposable elements were transcriptionally silenced in xBrassicoraphanus, rendered by gain of CHG methylation in trans via small RNAs derived from the same sequences of R. sativus subgenome. Our work proposes that not only transcription compatibility but also a certain extent of genome divergence supports hybrid genome stabilization, which may explain great diversification and expansion of angiosperms during evolution.

plant biology↗

bioRxiv2021

CRISPR-Cas Controls Cryptic Prophages

The bacterial archetypal adaptive immune system, CRISPR-Cas, is thought to be repressed in the best-studied bacterium, Escherichia coli K-12. We show here that the E. coli CRISPR-Cas system is active and serves to inhibit its nine defective (i.e., cryptic) prophages. Specifically, compared to the wild-type strain, reducing the amounts of specific interfering RNAs (crRNA) decreases growth by 40%, increases cell death by 700%, and prevents persister cell resuscitation. Similar results were obtained by inactivating CRISPR-Cas by deleting the entire 13 spacer region (CRISPR array); hence, CRISPR-Cas serves to inhibit the remaining deleterious effects of these cryptic prophages, most likely through CRISPR array-derived crRNA binding to cryptic prophage mRNA, rather than through cleavage of cryptic prophage DNA; i.e., self-targeting. Consistently, four of the 13 E. coli spacers contain complementary regions to the mRNA sequences of seven cryptic prophages, and inactivation of CRISPR-Cas increases the level of mRNA for lysis protein YdfD of cryptic prophage Qin and lysis protein RzoD of cryptic prophage DLP-12. Also, lysis is clearly seen via transmission electron microscopy when the whole CRISPR-Cas array is deleted, and eliminating spacer #12, which encodes crRNA with complementary regions for DLP-12 (including rzoD), Rac, Qin (including ydfD), and CP4-57 cryptic prophages, also results in growth inhibition and cell lysis. Therefore, we report the novel results that (i) CRISPR-Cas is active in E. coli and (ii) CRISPR-Cas is used to tame cryptic prophages, likely through RNAi; i.e., unlike with active lysogens, active CRISPR-Cas and cryptic prophages may stably co-exist.

molecular biology↗

bioRxiv2021

Distributed and multifaceted effects of threat and safety

Sustained anticipation of unpredictable aversive events generates anticipatory processing that is central to anxiety. In the present functional Magnetic Resonance Study (fMRI) study, we examined how sustained threat is processed in the human brain. We used a relatively large sample (N = 109) and employed a Bayesian multilevel analysis approach to contrast threat and safe periods. Our analyses demonstrated that the effect of sustained threat is heterogeneous and distributed across the brain. Thus, the impact of threat is widespread, and not restricted to a small set of putatively emotion-related regions, such as the amygdala and the bed nucleus of the stria terminalis. Both transient and sustained, and increased and decreased responses during threat were observed. Our study reveals that transitioning between threat and safe states, and vice versa, leads to a widespread switch in brain responding that involves most of the brain.

neuroscience↗

bioRxiv2021

Epithelial-mesenchymal plasticity through loss of CTCF motif accessibility and protein expression

Epithelial-mesenchymal transition (EMT) and its reversal, mesenchymal-epithelial transition (MET) drive tissue reorganization critical for early development. In carcinomas, processing through EMT, MET or partial states promotes migration, invasion, dormancy, and metastatic colonization. As a reversible process, EMT is inherently regulated at epigenetic and epigenomic levels. To understand the epigenomic nature of reversible EMT and its partial states, we characterized chromatin accessibility dynamics, transcriptomic output, protein expression, and cellular phenotypes during stepwise reversible EMT. We found that the chromatin insulating protein machinery, including CTCF, is suppressed and re-expressed, coincident with broad alterations in chromatin accessibility, during EMT/MET and is lower in triple-negative breast cancer cell lines with EMT features. Through analysis of chromatin accessibility using ATAC-seq, we identify that early phases of EMT are characterized by enrichment for AP-1 family member binding motifs but also by diminished enrichment for CTCF binding motifs. Through loss-of-function analysis we demonstrate that suppression of CTCF alters cellular plasticity, facilitating entrance into a partial EMT state. These findings are indicative of a role of CTCF and chromatin reorganization for epithelial-mesenchymal plasticity.

cell biology↗

bioRxiv2021

The First High-Quality Reference Genome of Sika Deer Provides Insights for High-Tannin Adaptation

Sika deer are known to prefer oak leaves, which are rich in tannins and toxic to most mammals; however, the genetic mechanisms underlying their unique ability to adapt to living in the jungle are still unclear. In identifying the mechanism responsible for the tolerance of a highly toxic diet, we have made a major advancement in the elucidation of the genomics of sika deer. We generated the first high-quality, chromosome-level genome assembly of sika deer and measured the correlation between tannin intake and RNA expression in 15 tissues through 180 experiments. Comparative genome analyses showed that the UGT and CYP gene families are functionally involved in the adaptation of sika deer to high-tannin food, especially the expansion of UGT genes in a subfamily. The first chromosome-level assembly and genetic characterization of the tolerance toa highly toxic diet suggest that the sika deer genome will serve as an essential resource for understanding evolutionary events and tannin adaptation. Our study provides a paradigm of comparative expressive genomics that can be applied to the study of unique biological features in non-model animals.

genomics↗

bioRxiv2021

DELAY OF GERMINATION 6, encoding the ANAC060 transcription factor, inhibits seed dormancy

The timing of seed germination is regulated by seed dormancy. There is ample natural variation for seed dormancy among as well as within plant species. In Arabidopsis several DELAY OF GERMINATION quantitative trait loci have been identified, of which DOG1 is best studied. Here we report the identification of DOG6, a quantitative trait locus with a similar strong effect on seed dormancy as DOG1. DOG6 affects the timing of germination both in laboratory as well as in field conditions. Complementation cloning revealed that DOG6 encodes the membrane bound transcription factor ANAC060. The absence of the ANAC060 protein or its sequestration outside the nucleus results in increased seed dormancy levels. The different natural variants of ANAC060 differ for the presence of the membrane binding domain, either due to the fact that this domain is absent in the genomic sequence or because the cDNA is alternatively spliced. Our data indicates that ANAC060 regulates seed dormancy by among others binding to and regulating the expression of protein phosphatases 2C class A proteins including PROTEIN PHOSPHATASE 2CA (PP2CA), ABI FIVE BINDING PROTEIN 3 (AFP3) and HIGHLY ABA-INDUCED PP2C GENE 3 (HAI3). Significance StatementANAC transcription factors are known to effect plant development as well as the response of plants to their environment. Here, we present the identification of DELAY OF GERMINATION 6 (DOG6), a seed dormancy quantitative trait locus that encodes the ANAC060 transcription factor. We have identified different natural alleles of ANAC060 and show that these genetic variants determine the localization of the protein. ANAC060 alleles that lack the membrane binding domain end up in the nucleus. Hence they affect transcription and as such attenuate seed dormancy.

plant biology↗

bioRxiv2021

Ultrapotent SARS-CoV-2 neutralizing antibodies with protective efficacy against newly emerged mutational variants

Accumulating mutations in the SARS-CoV-2 Spike (S) protein can increase the possibility of immune escape, challenging the present COVID-19 prophylaxis and clinical interventions. Here, 3 receptor binding domain (RBD) specific monoclonal antibodies (mAbs), 58G6, 510A5 and 13G9, with high neutralizing potency blocking authentic SARS-CoV-2 virus displayed remarkable efficacy against authentic B.1.351 virus. Each of these 3 mAbs in combination with one neutralizing Ab recognizing non-competing epitope exhibited synergistic effect against authentic SARS-CoV-2 virus. Surprisingly, structural analysis revealed that 58G6 and 13G9, encoded by the IGHV1-58 and the IGKV3-20 germline genes, both recognized the steric region S470-495 on the RBD, overlapping the E484K mutation presented in B.1.351. Also, 58G6 directly bound to another region S450-458 in the RBD. Significantly, 58G6 and 510A5 both demonstrated prophylactic efficacy against authentic SARS-CoV-2 and B.1.351 viruses in the transgenic mice expressing human ACE2 (hACE2), protecting weight loss and reducing virus loads. These 2 ultrapotent neutralizing Abs can be promising candidates to fulfill the urgent needs for the prolonged COVID-19 pandemic.

immunology↗

bioRxiv2021

Escherichia coli Cryptic Prophages Sense Nutrients to Control Persister Cell Resuscitation

We determined previously that some cryptic prophages are not genomic junk but instead enable cells to combat myriad stresses as part of an active stress response. However, how these phage fossils affect the extreme stress response of dormancy; i.e., how cryptic prophages affect persister cell formation and resuscitation, has not been fully explored. Persister cells form as a result of stresses such as starvation, antibiotics, and oxidative conditions, and resuscitation of these persister cells likely causes recurring infections such as those associated with tuberculosis, cystic fibrosis, and Lyme disease. Unlike for the active stress response, here we find that deletion of each of the nine Escherichia coli cryptic prophages has no effect on persister cell formation. Strikingly, elimination of each cryptic prophage results in an increase in persister cell resuscitation with a dramatic increase in resuscitation upon deleting all nine prophages. This increased resuscitation includes eliminating the need for a carbon source and is due to activation of the phosphate import system as a result of inactivating transcriptional regulator AlpA of the CP4-57 cryptic prophage, since we found {Delta}alpA increases persister resuscitation, and AlpA represses phosphate regulator PhoR. Therefore, we report a novel cellular stress mechanism controlled by cryptic prophages: regulation of phosphate uptake which controls the exit of the cell from dormancy and prevents premature resuscitation in the absence of nutrients.

microbiology↗

bioRxiv2021

Optimized hip-knee-ankle exoskeleton assistance at a range of walking speeds

BackgroundEffective autonomous exoskeletons will need to be useful at a variety of walking speeds, but we do not know how optimal exoskeleton assistance should change with speed. Optimal exoskeleton assistance may increase with speed similar to biological torque changes or a well-tuned assistance profile may be effective at a variety of speeds. MethodsWe optimized hip-knee-ankle exoskeleton assistance to reduce metabolic cost for three participants walking at 1.0 m/s, 1.25 m/s and 1.5 m/s. We measured metabolic cost, muscle activity, exoskeleton assistance and kinematics. We performed two tailed paired t-tests to determine significance. ResultsExoskeleton assistance reduced the metabolic cost of walking compared to wearing the exoskeleton with no torque applied by 26%, 47% and 50% at 1.0, 1.25 and 1.5 m/s, respectively. For all three participants, optimized exoskeleton ankle torque was the smallest for slow walking, while hip and knee torque changed slightly with speed in ways that varied across participants. Total applied positive power increased with speed for all three participants, largely due to increased joint velocities, which consistently increased with speed. ConclusionsExoskeleton assistance is effective at a range of speeds and is most effective at medium and fast walking speeds. Exoskeleton assistance was less effective for slow walking, which may explain the limited success in reducing metabolic cost for patient populations through exoskeleton assistance. Exoskeleton designers may have more success when targeting activities and groups with faster walking speeds. Speed-related changes in optimized exoskeleton assistance varied by participant, indicating either the benefit of participant-specific tuning or that a wide variety of torque profiles are similarly effective.

bioengineering↗

bioRxiv2021

Comprehensive evaluation of ACE2 expression in female ovary by single-cell RNA-seq analysis

Pneumonia induced by severe acute respiratory coronavirus 2 (SARS-CoV-2) via ACE2 receptor may affect many organ systems like lung, heart and kidney. An autopsy report revealed positive SARS-Cov-2 detection results in ovary, however, the developmental-stage-specific and cell-type-specific risk in fetal primordial germ cells (PGCs) and adult women ovary remained unclear. In this study, we used single-cell RNA-sequencing (scRNA-seq) datasets spanning several developmental stages of ovary including PGCs and cumulus-oocyte complex (COC) to investigate the potential risk of SARS-CoV-2 infection. We found that PGCs and COC exhibited high ACE2 expression. More importantly, the ratio of ACE2-positive cells was sharply up-regulated in primary stage and ACE2 was expressed in all oocytes and cumulus cells in preovulatory stage, suggesting the possible risk of SARS-CoV-2 infection in follicular development. CatB/L, not TMPRSS2, was identified to prime for SARS-CoV-2 entry in follicle. Our findings provided insights into the potential risk of SARS-CoV-2 infection during folliculogenesis in adulthood and the possible risk in fetal PGCs.

developmental biology↗

bioRxiv2021

ESD1 Affects Seed Setting Rate in Rice by Controlling Embryo Sac Development

Seed setting rate is one of the critical factors that determine rice yield. Grain formation is a complex biological process, whose molecular mechanism is yet to be improved. Here we investigated the function of an OVATE family protein, Embryo Sac Development 1 (ESD1), in the regulation of seed setting rate in rice (Oryza sativa) by examining its loss-of-function mutants generated via CRISPR/Cas9 technology. ESD1 was predominantly expressed at stage 6 of panicle development, especially in the ovules. esd1 mutants displayed reduced seed setting rates with normal stamen development and pollen tube growth but abnormal pistil group. Investigation of embryo sacs revealed that during the mitosis of functional megaspores, some egg cells degraded during differentiation in esd1 mutants, thereby hindering subsequent fertilization process and reducing seed setting rate. In addition, the transcriptional level of OsAPC6, a reported embryo sac developing gene, was found to be significantly reduced in esd1 mutants. These results support that ESD1 is an important modulator of embryo sac development and seed setting rate in rice. Together, this finding demonstrates that ESD1 positively regulates the seed setting rate by controlling embryo sac development in rice, and has implications for the improvement of rice yield.

plant biology↗

bioRxiv2021

Inhibition of HSP90 reversed STAT3 mediated muscle wasting induced by cancer cachexia

Cancer cachexia is one of the most common causes of death among cancer patients, no effective anti-cachectic treatment is currently available. In experimental cachectic models, aberrant activation of STAT3 in skeletal muscle has been found to contribute to muscle wasting. However, its clinical association, the factors regulating STAT3 activation, and the molecular mechanisms of STAT3-induced muscle atrophy in cancer cachexia remain incompletely understood. Here, we show that an enhanced interaction between STAT3 and HSP90, which causes the persistent STAT3 activation in the skeletal muscle of cancer cachexia patients, is the crucial event for the development of cachectic muscle wasting. Administration of HSP90 inhibitors alleviated the muscle wasting in C26 tumor-bearing cachetic mice model or C26 conditional medium induced C2C12 myotube atrophy. A mechanistic study indicated that in cachectic skeletal muscle, prolonged STAT3 activation triggered muscle wasting in a FOXO1-dependent manner, STAT3 activated FOXO1 by binding directly to its promoter. Our results provide key insights into the role of the HSP90/STAT3/FOXO1 axis in cachectic muscle wasting, which shows promising therapeutic potential as a target for the treatment of cancer cachexia.

pathology↗

bioRxiv2021

Correcting statistical bias in correlation-based kinship estimators

Accurate estimate of relatedness is important for genetic data analyses, such as association mapping and heritability estimation based on data collected from genome-wide association studies. Inaccurate relatedness estimates may lead to spurious associations and biased heritability estimations. Individual-level genotype data are often used to estimate kinship coefficient between individuals. The commonly used sample correlation-based genomic relationship matrix (scGRM) method estimates kinship coefficient by calculating the average sample correlation coefficient among all single nucleotide polymorphisms (SNPs), where the observed allele frequencies are used to calculate both the expectations and variances of genotypes. Although this method is widely used, a substantial proportion of estimated kinship coefficients are negative, which are difficult to interpret. In this paper, through mathematical derivation, we show that there indeed exists bias in the estimated kinship coefficient using the scGRM method when the observed allele frequencies are regarded as true frequencies. This leads to negative bias for the average estimate of kinship among all individuals, which explains the estimated negative kinship coefficients. Based on this observation, we propose an unbiased estimation method, UKin, which can reduce the bias. We justify our improved method with rigorous mathematical proof. We have conducted simulations as well as two real data analyses to demonstrate that both bias and root mean square error in kinship coefficient estimation can be reduced by using UKin. Further simulations indicate that the power in association mapping can also be improved by using our unbiased kinship estimates to adjust for cryptic relatedness. Author summaryInference of relatedness plays an important role in genetic data analysis. Many methods have been proposed to estimate kinship coefficients, including the commonly used genomic relationship matrix method. However, a substantial proportion of the kinship coefficients estimated by this method are negative, which is difficult to interpret. In this paper, through mathematical derivation, we show that there indeed exists a negative bias in this approach. To correct for this bias, we propose a new kinship coefficient estimation method, UKin, which is unbiased without requiring extra genetic information nor added computational complexity. The better performance of UKin in reducing bias and root mean squared error is demonstrated through theory, simulations and analysis of data from the young-onset breast cancer and familial intracranial aneurysm studies.

genetics↗