Biology subjects

Tao, L.

Publications and source records attributed to Tao, L..

At least 55 records · Page 3Linked to original sources

bioRxiv2024

Interplay of IGF1R and estrogen signaling regulates hematopoietic stem and progenitor cells

Tissue stem cells often exhibit developmental stage-specific and sexually dimorphic properties, but the underlying mechanism remains largely elusive. By characterizing IGF1R signaling in hematopoietic cells, here we report that its disruption exerts sex-specific effects in adult hematopoietic stem and progenitor cells (HSPCs). Loss of IGF1R decreases the HSPC population in females but not in males, in part due to a reduction in HSPC proliferation induced by estrogen. In addition, the adult female microenvironment enhances engraftment of wild-type but not Igf1r-null HSPCs. In contrast, during gestation, when both female and male fetuses are exposed to placental estrogens, loss of IGF1R reduces the numbers of their fetal liver HSPCs regardless of sex. Collectively, these data support the interplay of IGF1R and estrogen pathways in HSPCs and suggest that the proliferation-promoting effect of estrogen on HSPCs is in part mediated via IGF1R signaling.

cell biology↗

bioRxiv2024

Role of Hepatocyte RIPK1 in Maintaining Liver Homeostasis during Metabolic Challenges

As a central hub for metabolism, the liver exhibits strong adaptability to maintain homeostasis in response to food fluctuations throughout evolution. However, the mechanisms governing this resilience remain incompletely understood. In this study, we identified Receptor interacting protein kinase 1 (RIPK1) in hepatocytes as a critical regulator in preserving hepatic homeostasis during metabolic challenges, such as short-term fasting or high-fat dieting. Our results demonstrated that hepatocyte-specific deficiency of RIPK1 sensitized the liver to short-term fasting-induced liver injury and hepatocyte apoptosis in both male and female mice. Despite being a common physiological stressor that typically does not induce liver inflammation, short-term fasting triggered hepatic inflammation and compensatory proliferation in hepatocyte-specific RIPK1-deficient (Ripk1{Delta}hep) mice. Transcriptomic analysis revealed that short-term fasting oriented the hepatic microenvironment into an inflammatory state in Ripk1{Delta}hep mice, with upregulated expression of inflammation and immune cell recruitment-associated genes. Single-cell RNA sequencing further confirmed the altered cellular composition in the liver of Ripk1{Delta}hep mice during fasting, highlighting the increased recruitment of macrophages to the liver. Mechanically, our results indicated that ER stress was involved in fasting-induced liver injury in Ripk1{Delta}hep mice. Overall, our findings revealed the role of RIPK1 in maintaining liver homeostasis during metabolic fluctuations and shed light on the intricate interplay between cell death, inflammation, and metabolism.

immunology↗

bioRxiv2024

Neurons underlying aggressive actions that are shared by both males and females in Drosophila

Aggression involves both sexually monomorphic and dimorphic actions. How the brain implements these two types of actions is poorly understood. We found that a set of neurons, which we call CL062, previously shown to mediate male aggression also mediate female aggression. These neurons elicit aggression acutely and without the presence of a target. Although the same set of actions is elicited in males and females, the overall behavior is sexually dimorphic. The CL062 neurons do not express fruitless, a gene required for sexual dimorphism in flies, and expressed by most other neurons important for controlling fly aggression. Connectomic analysis suggests that these neurons have limited connections with fruitless expressing neurons that have been shown to be important for aggression, and signal to different descending neurons. Thus, CL062 is part of a monomorphic circuit for aggression that functions parallel to the known dimorphic circuits.

neuroscience↗

bioRxiv2023

Biosynthesis of H-GDGTs linked to ocean oxygen deficiency

Archaeal membrane lipids GDGTs (glycerol dialkyl glycerol tetraethers) are biomarkers used for tracking Earths historical environmental changes. Among these GDGTs, the H-shaped GDGTs (H-GDGTs, or GMGTs) represent a less-explored and often overlooked subset, with its biosynthetic pathway and geological significance remaining elusive. Here, we identified the gene responsible for biosynthesizing H-GDGTs, which encodes to a radical S-adenosyl-L-methionine (SAM) enzyme, named as H-GDGTs bridge synthase (Hbs). Heterologous expression of the gene hbs in a methanogen, as well as in vitro activity assay using the purified Hbs enzyme were performed. Additionally, we found that the genes encoding Hbs are exclusively present in obligate anaerobic archaea genomes and the metagenomes obtained from oxygen-deficient environments, but not in oxic settings. The H-GDGTs lipids were also consistently enriched in the modern oxygen-deficient environments, and remarkably accumulated in ancient sediments during oceanic anoxic event-2 (OAE-2, [~]94 million years ago) period. Our findings indicate H-GDGTs holds significant promise as a novel biomarker for studying historical ocean oxygen deficiency supported by a well-established biological basis.

microbiology↗

bioRxiv2023

SARS-CoV-2 Omicron BA.2.86: less neutralization evasion compared to XBB sub-variants

The continual emergence and circulation of new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants have caused a great challenge for the coronavirus disease 2019 (COVID-19) pandemic control. Recently, Omicron BA.2.86 was identified with more than 30 amino acid changes on the spike (S) protein, compared to Omicron BA.2 or XBB.1.5. The immune evasion potential of BA.2.86 is of great concern. In this study, we evaluated the neutralizing activities of sera collected from participants and mice. Participants were divided into five groups according to their vaccination (inactivated vaccine, protein subunit vaccine ZF2001 or ZF2202-A) and infection (Omicron BF.7/BA.5.2) status. ZF2202-A is ZF2001 vaccines next-generation COVID-19 vaccine with updated bivalent Delta-BA.5 RBD-heterodimer immunogen. BALB/c mice were immunized with XBB.1.5 RBD-homodimer, BA.5-BA.2, Delta-XBB.1.5 or BQ.1.1-XBB.1.5 RBD-heterodimers protein vaccine candidates for evaluating the neutralizing responses. We found that Omicron BA.2.86 shows stronger immune evasion than BA.2 due to >30 additional mutations on S protein. Compared to XBB sub-variants, BA.2.86 does not display more resistance to the neutralizing responses induced by ZF2001-vaccination, BF.7/BA.5.2 breakthrough infection or a booster dose of ZF2202-A-vaccination. In addition, the mouse experiment results showed that BQ.1.1-XBB.1.5 RBD-heterodimer and XBB.1.5 RBD-homodimer induced high neutralizing responses against XBB sub-variants and BA.2.86, indicating that next-generation COVID-19 vaccine should be developed to enhance the protection efficacy against the circulating strains in the future.

immunology↗

bioRxiv2023

Neutralization of SARS-CoV-2 EG.5/EG.5.1 by sera from ZF2001 RBD-dimer and its next-generation vaccines

SARS-CoV-2 Omicron EG.5 and EG.5.1 are surging in several areas of the world, including China. Compared with XBB.1, EG.5 contains additional mutations of F456L and S486P in the spike protein receptor binding domain (RBD) and its subvariant EG.5.1 carries a further spike mutation Q52H. The immune escape potential of EG.5/EG.5.1 is of great concern. In this study, we evaluated the neutralization activities of sera from participants who received COVID-19 inactivated vaccines, protein subunit vaccine ZF2001 or a booster vaccination of Delta-BA.5 RBD-heterodimer protein vaccine, and participants who had a breakthrough infection during a wave of BF.7/BA.5.2 circulation in December 2022. Neutralization profiles elicited by bivalent RBD-heterodimer vaccine candidates containing XBB.1.5 antigen were evaluated in a murine model. We found that EG.5 and EG.5.1 displayed similar immune evasion potential to XBB.1 and XBB.1.5. The Delta-BA.5 RBD-heterodimer booster induced higher neutralizing titers against the tested XBB subvariants, including EG.5 and EG.5.1, than breakthrough infection by BF.7 or BA.5.2. In addition, Delta-XBB.1.5 and BQ.1.1-XBB.1.5 RBD-heterodimer vaccines induced high neutralizing activities against XBB sub-variants in a murine model, suggesting that next-generation COVID-19 vaccines with updated components must be developed to enhance the protection efficacy against the circulating SARS-CoV-2 strains.

immunology↗

bioRxiv2023

SAD-1 kinase controls presynaptic phase separation by relieving SYD-2/Liprin-α autoinhibition

Neuronal development orchestrates the formation of an enormous number of synapses that connect the nervous system. In developing presynapses, the core active zone structure has been found to assemble through a liquid-liquid phase separation. Here, we find that the phase separation of SYD-2/Liprin-, a key active zone scaffold, is controlled by phosphorylation. Using phosphoproteomics, we identify the SAD-1 kinase to phosphorylate SYD-2 and a number of other substrates. Presynaptic assembly is impaired in sad-1 mutants and increased by overactivation of SAD-1. We determine SAD-1 phosphorylation of SYD-2 at three sites is critical to activate its phase separation. Mechanistically, phosphorylation relieves a binding interaction between two folded SYD-2 domains that inhibits phase separation by an intrinsically disordered region. We find synaptic cell adhesion molecules localize SAD-1 to nascent synapses upstream of active zone formation. We conclude that SAD-1 phosphorylates SYD-2 at developing synapses, enabling its phase separation and active zone assembly.

neuroscience↗

bioRxiv2022

Neural mechanisms of musical syntax and tonality, and the effect of musicianship.

The neural basis for the processing of musical syntax has previously been examined almost exclusively in classical tonal music, which is characterized by strictly organized hierarchical structure. The present study investigated the neural mechanisms for processing musical syntax across genres varying in tonality - classical, impressionist, and atonal music - and, in addition, examined how musicianship modulates such processing. Results showed that, first, the dorsal stream, including bilateral inferior frontal gyrus and superior temporal gyrus, plays a key role in the perception of tonality. Second, right fronto-temporal regions were crucial in allowing musicians to outperform non-musicians in musical syntactic processing; musicians also benefit from a cortical-subcortical network including pallidum and cerebellum, suggesting more auditory-motor interaction in musicians than in non-musicians. Third, left pars triangularis carries out on-line computations independently of tonality and musicianship, whereas right pars triangularis is sensitive to tonality and partly dependent on musicianship. Finally, unlike tonal music, processing of atonal music could not be differentiated from that of scrambled notes, both behaviorally and neurally, even among musicians. The present study highlights the importance of studying varying music genres and experience levels, and provides a better understanding of musical syntax and tonality processing and how such processing is modulated by music experience.

neuroscience↗

bioRxiv2022

Programming super DNA-enzyme molecules for on-demand enzyme activity modulation

Dynamic interactions of enzymes, including programmable configuration and cycling of enzymes, play important roles in the regulation of cellular metabolism. Here, we construct a super DNA-enzymes molecule (SDEM) that comprises at least two cascade enzymes and linked DNA strands to control and detect metabolism. We find that the programmable SDEM which comprises glucose oxidase (GOx) and horseradish peroxidase (HRP) has a 50-fold lower detection of limit and a 1.6-fold higher reaction rate than free enzymes. SDEM can be assembled and disassembled using a hairpin structure and a displacement DNA strand to complete multiple cycles. An entropically driven catalytic assembly (catassembly) enables different SDEMs to switch from SDEM with GOx and HRP cascades to SDEM with sarcosine oxidase (SOX) and HRP cascades by over six orders of magnitude less time than no catassembly to detect different metabolisms (glucose and sarcosine) on demand.

biochemistry↗

bioRxiv2022

RGA1 alleviates low-light-repressed pollen tube growth by improving the metabolism and allocation of sugars and energy

Low-light stress compromises photosynthetic and energy efficiency and leads to spikelet sterility; however, the effect of low-light stress on pollen tube elongation in the pistil remains poorly understood. The gene RGA1, which encodes a G subunit of the heterotrimeric G protein, enhanced low-light tolerance in rice plants at anthesis by preventing the cessation of pollen tube elongation in the pistil. The levels of reactive oxygen species were higher and the content of ATP and ATPase was lower in RGA1 mutant (d1) plants compared with wild-type and RGA1-overexpressing (OE-1) plants under low-light conditions. Energy deficits, rather than interference with signaling transduction pathways, were the main contributors to the inhibition of pollen tube elongation in the pistil by low-light stress. In this process, marked increases in the activities of acid invertase (INV), sucrose synthase (SUS), and mitochondrial respiratory electron transport chain complexes, as well as the relative expression levels of SUTs, SWEETs, SUSs, INVs, CINs, SnRK1A, and SnRk1B, were observed in OE-1 plants. INV and ATPase activators (sucrose and Na2SO3, respectively) increased spikelet fertility by improving the energy status in the pistil under low-light conditions, and the ATPase inhibitor Na2VO4 induced spikelet sterility and decreased ATPase activity. Therefore, RGA1 could alleviate the low-light stress-induced impairment of pollen tube elongation to increase spikelet fertility by promoting sucrose unloading in the pistil and improving the metabolism and allocation of energy.

plant biology↗

bioRxiv2022

Topological Links in Predicted Protein Complex Structures Reveal Limitations of AlphaFold

AlphaFold is making great progress in protein structure prediction, not only for single-chain proteins but also for multi-chain protein complexes. When using AlphaFold-Multimer to predict protein-protein complexes, we observed some unusual structures in which chains are looped around each other to form topologically intertwining links at the interface. To our knowledge, such topological links are never observed in the experimental structures deposited in the Protein Data Bank (PDB). Although it is well known and has been well studied that protein structures may have topologically complex shapes such as knots and links, existing methods are hampered by the chain closure problem and show poor performance in identifying topologically linked structures in protein-protein complexes. Therefore, we address the chain closure problem by using sliding windows from a local perspective and propose an algorithm to measure the topological-geometric features that can be used to identify topologically linked structures. An application of the method to AlphaFold-Multimer-predicted protein complex structures finds that approximately 0.7% of the predicted structures contain topological links. The method presented in this work will facilitate the computational study of protein-protein interactions and help further improve the structural prediction of multi-chain protein complexes.

bioinformatics↗

bioRxiv2022

The single-cell atlas of the murine reproductive tissues during preterm labor

Preterm birth, the leading cause of perinatal morbidity and mortality worldwide, frequently results from the syndrome of preterm labor. Intra-amniotic infection is the best-established causal link to preterm labor, and involves premature activation of the parturition cascade in the reproductive tissues. Herein, we utilized single-cell RNA-sequencing (scRNA-seq) to generate a single-cell atlas of the murine uterus, decidua, and cervix in a model of infection-induced preterm labor. We show that preterm labor affects the transcriptomic profiles of specific immune and non-immune cell subsets. Shared and tissue-specific gene expression signatures were identified among affected cells. Importantly, determination of intercellular communications implicates specific cell types preterm labor-associated signaling pathways across tissues. Last, in silico comparison of murine and human uterine cell-cell interactions reveals conserved signaling pathways implicated in labor. Thus, scRNA-seq provides new insights into the preterm labor-driven cellular landscape and communications in the reproductive tissues.

immunology↗

bioRxiv2022

Multi-modal Imaging of Disease Progression in TH-MYCN Mouse Models of Neuroblastoma

MYCN is a major driver for neuroblastoma (NB) and the tyrosine hydroxylase (TH)-MYCN transgenic mouse model is extensively used for preclinical NB studies. However, spatio-temporal NB progression in the TH-MYCN model has not been studied, and questions remain about the value of implanted models as a surrogate for transgenic mice. In this work, we used magnetic resonance imaging (MRI) to study tumor progression and nanoparticle contrast-enhanced computed tomography (n-CECT) to assess tumor vascular architecture in TH-MYCN transgenic mice (2-7 weeks of age) and TH-MYCN+/+-derived orthotopic allograft and syngeneic mice (2-5 weeks post-tumor implantation). Tumors in TH-MYCN transgenic mice became evident in the abdominal paraspinal region at week 5. A delayed thoracic paraspinal mass became evident at week 6 and most mice succumbed by week 7. In allograft and syngeneic mice, single mass tumor growth was restricted to the peritoneal cavity. N-CECT revealed a predominantly microvascular network in TH-MYCN tumors while implanted tumors exhibited heterogeneous and tortuous vessels. N-CECT quantitative analysis demonstrated high vascularity (tumor fractional blood volume ~ 0.12) in all models. Multi-modal imaging of TH-MYCN transgenic and implanted models revealed differences in growth patterns and vascular architecture that should be considered in designing preclinical studies.

cancer biology↗

bioRxiv2022

Sensorimotor transformation underlying odor-modulated locomotion in walking Drosophila

Most real-world behaviors are performed with incomplete information. Odor-guided locomotion, an ecologically important behavior essential to an animals survival, is an example of such a behavior. Different odors activate different patterns of olfactory receptor neuron (ORN) classes providing information about which odor is present but does not provide any navigational information. In this study, we investigate the sensorimotor transformation that relates ORN activation to locomotion changes in Drosophila by optogenetically activating different combinations of ORN classes and measuring the resulting changes in locomotion. Three features describe this sensorimotor transformation: First, locomotion depends on both the instantaneous firing frequency (f) and its change (df); the two together serve as short-term memory that allows the fly to automatically adapt its motor program to sensory context. Second, the mapping between f-df and locomotor parameters such as speed or curvature is distinct for each pattern of activated ORNs. Finally, the sensorimotor mapping changes with time after odor exposure allowing integration of information over a longer timescale.

neuroscience↗

bioRxiv2022

Dendrites use mechanosensitive channels to proofread ligand-mediated guidance during morphogenesis.

Ligand-receptor interactions guide axon navigation and dendrite arborization. Mechanical forces also influence guidance choices. However, the nature of such mechanical stimulations, the mechanosensors identity and how they interact with guidance receptors are unknown. Here, we demonstrate that mechanosensitive DEG/ENaC channels are required for dendritic arbor morphogenesis in Caenorhabditis elegans. Inhibition of DEG/ENaC channels causes reduced dendritic outgrowth and branching in vivo, a phenotype that is alleviated by overexpression of the mechanosensitive channels PEZO-1/Piezo or YVC1/TrpY1. DEG/ENaCs trigger local Ca2+ transients in growing dendritic filopodia via activation of L-type voltage-gated Ca2+ channels. Anchoring of filopodia by guidance ligand/receptor is required for the mechanical activation of DEG/ENaC channels. Therefore, mechanosensitive channels serve as a checkpoint for appropriate chemoaffinity by activating Ca2+ transients required for neurite growth.

neuroscience↗

bioRxiv2021

Boron Supply Restores Aluminum-Blocked Auxin Transport by Modulation PIN2 Trafficking in the Arabidopsis Roots

This study tested a hypothesis that boron (B) supply alleviates aluminum (Al) toxicity by modifying auxin distribution in functionally different root zones. Auxin distribution and transport at various Al and B ratios were analyzed using the range of molecular and imaging techniques. Al stress resulted in increased auxin accumulation in root apical meristem (MZ) and transition zones (TZ) while reducing its content in elongation zone (EZ). This phenomenon was explained by reduction in basipetal auxin transport caused by Al blockage of PIN2 endocytosis, regulated at posttranscriptional level. This inhibition of PIN2 endocytosis was dependent on actin filaments and microtubules. B supply facilitated the endocytosis and exocytosis of PIN2 carriers via recycling endosomes conjugated with IAA to modify Al-induced auxin depletion in the EZ. However, disruption of auxin signaling with auxinole did not alleviate Al-induced inhibition of root growth. B supply alleviates Al-induced inhibition of root growth via restoring the endocytic recycling of PIN2 proteins involved in the basipetal (shootward) auxin transport, restoring Al-induced auxin depletion in the elongation zone. Short summaryAluminum-intensified PIN2 abundance, nontranscriptional, via repressing PIN2 endocytosis to block polar auxin transport, and this adverse effect could be alleviated by boron supply.

physiology↗

bioRxiv2021

Escape Steering by Cholecystokinin Peptidergic Signaling

Escape is an evolutionarily conserved and essential avoidance response. Considered to be innate, most studies on escape responses focused on hard-wired circuits. We report here that peptidergic signaling is an integral and necessary component of the Caenorhabditis elegans escape circuit. Combining genetic screening, electrophysiology and calcium imaging, we reveal that a neuropeptide NLP-18 and its cholecystokinin receptor CKR-1 enable the escape circuit to execute a full omega ({Omega}) turn, the last motor step where the animal robustly steers away from its original trajectory. We demonstrate in vivo and in vitro that CKR-1 is a Gq protein coupled receptor for NLP-18. in vivo, NLP-18 is mainly secreted by the gustatory sensory neuron (ASI) to activate CKR-1 in the head motor neuron (SMD) and the turn-initiating interneuron (AIB). Removal of NLP-18, removal of CKR-1, or specific knockdown of CKR-1 in SMD or AIB neurons lead to shallower turns hence less robust escape steering. Consistently, elevation of head motor neuron (SMD)s Ca2+ transients during escape steering is attenuated upon the removal of NLP-18 or CKR-1. in vitro, synthetic NLP-18 directly evokes CKR-1-dependent currents in oocytes and CKR-1-dependent Ca2+ transients in SMD. Thus, cholecystokinin signaling modulates an escape circuit to generate robust escape steering.

neuroscience↗

bioRxiv2021

A genetic disorder reveals a hematopoietic stem cell regulatory network co-opted in leukemia

The molecular regulation of human hematopoietic stem cell (HSC) maintenance is therapeutically important, but limitations in experimental systems and interspecies variation have constrained our knowledge of this process. Here, we have studied a rare genetic disorder due to MECOM haploinsufficiency, characterized by an early-onset absence of HSCs in vivo. By generating a faithful model of this disorder in primary human HSCs and coupling functional studies with integrative single-cell genomic analyses, we uncover a key transcriptional network involving hundreds of genes that is required for HSC maintenance. Through our analyses, we nominate cooperating transcriptional regulators and identify how MECOM prevents the CTCF-dependent genome reorganization that occurs as HSCs differentiate. Strikingly, we show that this transcriptional network is co-opted in high-risk leukemias, thereby enabling these cancers to acquire stem cell properties. Collectively, we illuminate a regulatory network necessary for HSC self-renewal through the study of a rare experiment of nature.

cell biology↗