Biology subjects

Chai, Y.

Publications and source records attributed to Chai, Y..

60 records · Page 4Linked to original sources

bioRxiv2020

Spectrin-based Membrane Mechanics Is Asymmetric and Remodels during Neural Development

Perturbation of spectrin-based membrane mechanics causes hereditary elliptocytosis and spinocerebellar ataxia, but the underlying cellular basis of pathogenesis remains unclear. Here, we introduced the conserved disease-associated spectrin mutations into the C. elegans genome and studied the contribution of spectrin to neuronal migration and dendrite formation in developing larvae. The loss of spectrin generates an ectopic actin polymerization outside of the existing front and secondary membrane protrusions, leading to defective neuronal positioning and dendrite morphology in adult animals. Spectrin accumulates in the lateral and the rear of migrating neuroblasts and redistributes from the soma into the newly formed dendrites, indicating that the spectrin-based membrane skeleton is asymmetric and remodels to regulate actin assembly and cell shape during development. We affinity-purified spectrin from C. elegans and showed that its binding partner ankyrin functions with spectrin. Asymmetry and remodeling of membrane skeleton may enable spatiotemporal modulation of membrane mechanics for distinct developmental events. Significance StatementThe biomechanical regulation of neural development is largely unknown. The spectrin-based membrane skeleton is essential for the structural integrity of the plasma membrane. This study addresses the function and behavior of spectrin in neuroblast migration and dendrite formation. The loss of spectrin generates an ectopic actin polymerization outside of the existing front, leading to defective neuronal positioning and dendrite morphology. Spectrin is absent from the leading edge but accumulates in the posterior of migrating neuroblasts and redistributes from the soma into the nascent dendrites, indicating that the membrane skeleton is asymmetric and remodels. Asymmetry and remodeling of the membrane skeleton may enable spatiotemporal modulation of membrane mechanics for distinct developmental events.

developmental biology↗

bioRxiv2020

Sclerotinia sclerotiorum hijacks copper from its host for infection

Sclerotinia sclerotiorum induces host reactive oxygen species (ROS) production, which leads to necrosis in the host, allowing the pathogen to absorb nutrients from the dead tissues. Here, we found that three S. sclerotiorum genes involved in copper ion import/transport, SsCTR1, SsCCS and SsATX1, were significantly up-regulated during infection of Brassica oleracea. Function analysis revealed that these genes involved in fungal ROS detoxification, oxalic acid production, pathogen establishment and virulence. On the host side, four genes putatively involved in copper ion homeostasis, BolCCS, BolCCH, BolMT2A and BolDRT112, were significantly down-regulated in susceptible B. oleracea, but stably expressed in resistant B. oleracea during infection. Their homologs were found to promote resistance to necrotrophic pathogens and increase antioxidant activity in Arabidopsis thaliana. Furthermore, copper concentration analysis indicated that copper is transported into the necrotic area from healthy area during infection. Collectively, our data suggest that S. sclerotiorum hijacks host copper to detoxify ROS, whereas the resistant hosts restrict the supply of essential copper nutrients to S. sclerotiorum by maintaining copper ion homeostasis during infection.

pathology↗

bioRxiv2019

Decreasing Serine Levels During Growth Transition Triggers Biofilm Formation in Bacillus subtilis

Biofilm development in Bacillus subtilis is regulated at multiple levels. While a number of known signals that trigger biofilm formation do so through the activation of one or more sensory histidine kinases, it was recently discovered that biofilm activation is also coordinated by sensing intracellular metabolic signals, including serine starvation. Serine starvation causes ribosomes to pause on specific serine codons, leading to a decrease in the translation rate of sinR, which encodes a master repressor for biofilm matrix genes, and ultimately biofilm induction. How serine levels change in different growth stages, how B. subtilis regulates intracellular serine levels in response to metabolic status, and how serine starvation triggers ribosomes to pause on selective serine codons remain unknown. Here we show that serine levels decrease as cells enter stationary phase and that unlike most other amino acid biosynthesis genes, expression of serine biosynthesis genes decreases upon the transition into stationary phase. Deletion of the gene for a serine deaminase responsible for converting serine to pyruvate led to a delay in biofilm formation, further supporting the idea that serine levels are a critical intracellular signal for biofilm activation. Finally, we show that levels of all five serine tRNA isoacceptors are decreased in stationary phase compared to exponential phase. Interestingly, the three isoacceptors recognizing UCN serine codons are reduced to a much greater extent than the two that recognize AGC and AGU serine codons. Our findings provide evidence for a link between serine homeostasis and biofilm development in B. subtilis. IMPORTANCEIn Bacillus subtilis, biofilm formation is triggered in response to various environmental and cellular signals. It was previously proposed that serine limitation acts as a proxy for nutrient status and triggers biofilm formation at the onset of biofilm entry through a novel signaling mechanism caused by global ribosome pausing on selective serine codons. In this study, we revealed that serine levels decrease at the biofilm entry due to catabolite control and a shunt mechanism. We also show that levels of five serine tRNA isoacceptors are differentially decreased in stationary phase compared to exponential phase; three isoacceptors recognizing UCN serine codons are reduced much greater than the two recognizing AGC and AGU codons. This indicates a possible mechanism for selective ribosome pausing.

microbiology↗

bioRxiv2018

Structural insight into the mechanism of neuraminidase inhibitor-resistant mutations in human-infecting H10N8 Influenza A virus

The emergence of drug resistance in avian influenza virus (AIV) is a serious concern for public health. Neuraminidase (NA) isolated from a fatal case of avian-origin H10N8 influenza virus infection was found to carry a drug-resistant mutation, NA-Arg292Lys (291 in N8 numbering). In order to understand the full potential of H10N8 drug resistance, the virus was first passaged in the presence of the most commonly used neuraminidase inhibitors (NAIs), oseltamivir and zanamivir. As expected, the Arg292Lys substitution was detected after oseltamivir treatment, however a novel Val116Asp substitution (114 in N8 numbering) was selected by zanamivir treatment. Next generation sequencing (NGS) confirmed that the mutations arose early (after passages 1-3) and became dominant in the presence of the NAI inhibitors. Extensive crystallographic studies revealed that N8-Arg292Lys resistance results mainly from loss of interactions with the inhibitor carboxylate, while rotation of Glu276 was not impaired as observed in the N9-Arg292Lys, a group 2 NA structure. In the case of Val116Asp, the binding mode between oseltamivir and zanamivir is different. Asp151 forms stabilized hydrogen bond to guanidine group of zanamivir, which may compensate the resistance caused by Val116Asp. By contrast, the amino group of oseltamivir is too short to maintain this hydrogen bond, which result in resistant. Moreover, the oseltamivir-zanamivir hybrid inhibitor MS-257 displays higher effectiveness to Val116Asp than oseltamivir, which support this notion.\n\nAuthor SummaryAside from vaccination, NAIs are currently the only alternative for the clinical treatment and prophylaxis of influenza. Understanding the mechanisms of resistance is critical to guide in drug development. In this study, two drug-resistant NA substitutions, Val116Asp and Arg292Lys, were discovered from oseltamivir and zanamivir treatment of H10N8 virus. Crystal structural analyses revealed two distinct mechanisms of these two resistant mutations and provide the explanation for the difference in susceptibility of different NAIs. Zanamivir and laninamivir were more effective against the resistant variants than oseltamivir, and Arg292Lys results in more serious oseltamivir resistance in N9 than N8 subtype. This study is well-correlated to influenza pandemic/epidemic pre-warning, as the discovery of inhibitor resistant viruses will help for new drug preparedness.

microbiology↗

bioRxiv2017

Rapid Whole Brain Imaging Of Neural Activities In Freely Behaving Larval Zebrafish

The internal brain dynamics that link sensation and action are arguably better studied during natural animal behaviors. Here we report on a novel volume imaging and 3D tracking technique that monitors whole brain neural activity in freely swimming larval zebrafish (Danio rerio). We demonstrated the capability of our system through functional imaging of neural activity during visually evoked and prey capture behaviors in larval zebrafish.

neuroscience↗

bioRxiv2017

BMP signaling orchestrates a transcriptional network to control the fate of mesenchymal stem cells (MSCs)

Signaling pathways are used reiteratively in different developmental processes yet produce distinct cell fates through activating specific downstream transcription factors. In this study, we used tooth root development as a model to investigate how the BMP signaling pathway regulates specific downstream transcriptional complexes to direct the fate determination of multipotent mesenchymal stem cells (MSCs). We first identified the MSC population supporting mouse molar root growth as Gli1+ cells. Using a Gli1-mediated transgenic animal model, our results provide the first in vivo evidence that BMP signaling activity is required for the odontogenic differentiation of MSCs. Specifically, we identified transcription factors that are downstream of BMP signaling and are expressed in a spatially restricted pattern consistent with their potential involvement in determining distinct cellular identities within the dental mesenchyme. Finally, we found that overactivation of one key transcription factor, Klf4, associated with the odontogenic region, promotes odontogenic differentiation of MSCs. Collectively, our results demonstrate the functional significance of BMP signaling in regulating the fate of MSCs during root development and shed light on how BMP signaling can achieve functional specificity in regulating diverse organ development.\n\nSummary StatementBMP signaling activity is required for the lineage commitment of MSCs and transcription factors downstream of BMP signaling may determine distinct cellular identities within the dental mesenchyme.

developmental biology↗