Biology subjects

Tao, L.

Publications and source records attributed to Tao, L..

At least 73 records · Page 4Linked to original sources

bioRxiv2021

WY14643 Increases Herpesvirus Replication Independent of PPARα Expression and Inhibits IFNβ Production

Peroxisome proliferator activated receptor (PPAR) agonists are commonly used to treat metabolic disorders in humans because they regulate fatty acid oxidation and cholesterol metabolism. In addition to their roles in controlling metabolism, PPAR agonists also regulate inflammation and are immunosuppressive in models of autoimmunity. We aimed to test whether activation of PPAR with clinically relevant ligands could impact herpesvirus infection using the model strain murine gammaherpesvirus-68. We found that PPAR agonists WY14643 and fenofibrate increased herpesvirus replication in vitro. In vivo, WY14643 increased viral replication and caused lethality in mice. Unexpectedly, these effects proved independent of PPAR. Investigating the mechanism of action for WY14643, we found that it suppresses production of type I interferon by inhibiting stimulator of interferon (STING), which lies downstream of the cytoplasmic DNA sensor cGAS. Thus, WY14643 regulates interferon downstream of cytoplasmic DNA recognition and increases herpesvirus replication in a PPAR-independent manner. Taken together, our data indicate that caution should be employed when using PPAR agonists in immuno-metabolic studies, as they can have off-target effects on viral replication. ImportancePPAR agonists are used clinically to treat both metabolic and inflammatory disorders. Because viruses are known to rewire host metabolism to their own benefit, the intersection of immunity, metabolism, and virology is an important research area. Our article is an important contribution to this field because for two reasons. First, it shows a role for PPAR agonists in altering virus detection by cells. Second, it shows that PPAR agonists can affect virus replication in a manner unrelated to their expected genetic function. This knowledge is valuable for anyone seeking to use PPAR agonists as a research tool.

immunology↗

bioRxiv2021

C. elegans enteric motor neurons fire synchronized action potentials underlying the defecation motor program

The C. elegans nervous system was thought to be strictly analog, constituted solely by graded neurons. We recently discovered neuronal action potentials in the sensory neuron AWA; however, the extent to which the C. elegans nervous system relies on analog or digital neural signaling and coding is unclear. Here we report that the enteric motor neurons AVL and DVB fire all-or-none calcium-mediated action potentials that play essential roles in the rhythmic defecation behavior in C. elegans. Both AVL and DVB synchronously fire giant action potentials to faithfully execute all-or-none expulsion following the intestinal pacemaker. AVL fires unusual compound action potentials with each positive calcium-mediated spike followed by a potassium-mediated negative spike. The depolarizing calcium spikes in AVL are mediated by a CaV2 calcium channel UNC-2, while the negative potassium spikes are mediated by a repolarization-activated potassium channel EXP-2. Whole-body behavior tracking and simultaneous neural imaging in free-moving animals suggest that action potentials initiated in AVL in the head propagate along its axon to the tail and activate DVB through the INX-1 gap junction. Synchronized action potential spikes between AVL and DVB, as well as the negative spike and long-lasting afterhyperpolarization in AVL, play an important function in executing expulsion behavior. This work provides the first evidence that in addition to sensory coding, C. elegans motor neurons also use digital coding scheme to perform specific functions including long-distance communication and temporal synchronization, suggesting further, unforeseen electrophysiological diversity remains to be discovered in the C. elegans nervous system.

neuroscience↗

bioRxiv2021

Evidence for the Presence of Hyphae and Fruiting Body Calcium Oxalate Crystallites in Schizophyllum commune

Biomineralization is a phenomenon in which organisms form crystals. Studies have shown that many fungi have the ability to biomineralize, it can exhibit calcium oxalate crystals on their hyphae and fruiting body. Schizophyllum commune is a common saprophytic fungus distributed all over the world, but there is little research on its biomineralization. In this paper, S. commune fruiting body from three different provinces of China were collected, and isolation for hyphal cultured to obtain several samples. Utilizing light microscope, FE-SEM, and EDAX, the existence of crystals on the fruiting body and mycelium of each strain was found, and their morphological characteristics and ion content were analyzed. It was ultimately established that biomineralization occurs on S. commune.

biochemistry↗

bioRxiv2021

Genome-wide DNA methylation and multi-omics study of human chondrocyte ontogeny and an epigenetic clock analysis of adult chondrocytes

Articular chondrocytes undergo functional changes and their regenerative potential declines with age. Although the molecular mechanisms guiding articular cartilage aging is poorly understood, DNA methylation is known to play a mechanistic role in aging. However, our understanding of DNA methylation in chondrocyte development across human ontogeny is limited. To better understand DNA methylome changes, methylation profiling was performed in human chondrocytes. This study reveals association between methylation of specific CpG sites and chondrocyte age. We also determined the putative binding targets of STAT3, a key age-patterned transcription factor in fetal chondrocytes and genetic ablation of STAT3 induced a global genomic hypermethylation. Moreover, an epigenetic clock built for adult human chondrocytes revealed that exposure of aged adult human chondrocytes to STAT3 agonist, decreased epigenetic age. Taken together, this work will serve as a foundation to understand development and aging of chondrocytes with a new perspective for development of rejuvenation agents for synovial joints.

molecular biology↗

bioRxiv2021

Generation of SIV resistant T cells and Macrophages from Nonhuman Primate Induced Pluripotent Stem Cells with Edited CCR5 locus

Adoptive therapies with genetically modified somatic T cells rendered HIV resistant have shown promise for AIDS therapy. A renewable source of HIV resistant human T cells from induced pluripotent stem cells (iPSCs) would further facilitate and broaden the applicability of these therapies. Here, we report successful targeting of the CCR5 locus in iPSCs generated from peripheral blood T cells (T-iPSCs) or fibroblasts (fib-iPSCs) from Mauritian Cynomolgus macaques (MCM), using CRISPR/Cas9 technology. We found that CCR5 editing does not affect pluripotency or hematopoietic and T cell differentiation potentials of fib-iPSCs. However, deletion of CCR5 in T-iPSCs leads to selective loss of their T cell redifferentiation potential without affecting myeloid development. T cells and macrophages produced from CCR5-edited MCM- iPSCs did not support replication of the CCR5-tropic simian immunodeficiency viruses SIVmac239 (T-cell tropic) and SIVmac316 (macrophage-tropic). Overall, these studies provide a platform for further exploration of AIDS therapies based on gene-edited iPSCs in a nonhuman primate preclinical model.

cell biology↗

bioRxiv2021

PAM-interacting domain swapping is extensively utilized in nature to evolve CRISPR-Cas9 nucleases with altered PAM specificities

It has been anticipated that protospacer adjacent motif (PAM) specificity of the CRISPR-Cas9 nucleases protospacer appears to be modular. Here we present the finding that naturally occurring domain swapping has been extensively involved in altering its PAM specificities. Sequence analysis of streptococcal Cas9 sequences revealed conservation of three distinct PAM-interacting motifs, with phylogenetic analysis of full-length Cas9 and the PID demonstrating that PAM-interacting domain (PID) domain swapping was extensively utilized to diversify its PAM specificity. An extended analysis of 582 representative Cas9 sequences revealed that this PID swapping was broadly present in most of the investigated genera. Mimicking the natural PID domain swapping, a functional chimeric enzyme, based on the scaffold of compact Staphylococcus aureus Cas9, with novel NNAAAA PAM specificity was developed. In summary, our findings shed new light on a rich source of exchangeable PID domains in Cas9 genes, which can be mined for domain swapping aiming to an effective PAM refinement.

biochemistry↗

bioRxiv2021

Unbalanced dietary patterns contribute to the pathogenesis of precocious puberty by affecting gut microbiota and host metabolites

Precocious puberty (PP) mostly stems from endocrine disorders. However, its triggering factors, especially for the early onset of partial PP, and the associated pathogenic mechanisms remain ambiguous. In this study, a systematic analysis in the form of a questionnaire of lifestyles, gut microbiome, and serum metabolome data was carried out to examine the pathogenesis of PP in a cohort comprised of 200 girls, with or without PP. The analysis revealed substantial alterations in gut microbiota, serum metabolites, as well as lifestyle patterns in the PP group, which were characterized by an elevated abundance of {beta}-glucuronidase-producing and butyrate-producing bacteria, and excessive lipid concentration with decreased levels of organic nitrogen compounds in the serum of the participants. These differential microbes and metabolites tend to be reliable non-invasive diagnostic biomarkers aiding the early diagnosis of PP and exhibit a strong discriminative power (AUC = 0.93 and AUC = 0.97, respectively). Furthermore, the microbial biomarkers were confirmed in an independent validation cohort (n = 83, AUC = 0.85). Moreover, structural equation modeling revealed that unhealthy dietary habits were the primary contributors for the alteration of gut microbiota and serum metabolites, triggering the imbalance in the host hormones that leads to premature physical development. Our study determines a causal relationship among the gut microbiota, host metabolites, diet, and clinical characteristics of preadolescent girls who experienced early onset of PP, and formulates non-invasive diagnostic tools demonstrating excellent performance for the early detection of PP.

microbiology↗

bioRxiv2020

Metformin prevented high glucose-induced endothelial reactive oxygen species via OGG1 in an AMPKα-Lin-28 dependent pathway

Metformin improved vascular function in obese type 2 diabetic patients. 8-oxoguanine glycosylase (OGG1), a main DNA glycosylase, was involved in vascular complications in diverse diseases. However, whether metformin suppressed endothelial ROS via OGG1 pathway was unclear. Human umbilical vein endothelial cells (HUVECs) were exposed to HG (high glucose) or HG with metformin. OGG1 and AMPf levels were measured after metformin treatment while HG-caused ROS was measured by DHE prober. Diabetic mice were induced by daily intraperitoneal injections of streptozotocin (STZ). Metformin reduced Endothelial ROS caused by HG via upregulating OGG1. Additionally, OGG1 protein expression was dependent on its mRNA stability, which was reversed by genetic inhibition of AMPK and Lin-28. The role of OGG1 on ROS stimulated by HG was partially dependent on NFKB/NOX4 pathway in HUVECs. These results suggested that metformin contacted HG-induced endothelial ROS via AMPK/Lin-28/OGG1 pathway.

cell biology↗

bioRxiv2020

Th2 Cytokine Modulates Herpesvirus Reactivation in a Cell Type Specific Manner

Gammaherpesviruses, such as Epstein-Barr virus (EBV), Kaposis sarcoma associated virus (KSHV), and murine {gamma}-herpesvirus 68 (MHV68), establish latent infection in B cells, macrophages, and non-lymphoid cells, and can induce both lymphoid and non-lymphoid cancers. Research on these viruses has relied heavily on immortalized B cell and endothelial cell lines. Therefore, we know very little about the cell type specific regulation of virus infection. We have previously shown that treatment of MHV68-infected macrophages with the cytokine interleukin-4 (IL-4) or challenge of MHV68-infected mice with an IL-4-inducing parasite leads to virus reactivation. However, we do not know if all latent reservoirs of the virus, including B cells, reactivate the virus in response to IL-4. Here we used an in vivo approach to address the question of whether all latently infected cell types reactivate MHV68 in response to a particular stimulus. We found that IL-4 receptor expression on macrophages was required for IL-4 to induce virus reactivation, but that it was dispensable on B cells. We further demonstrated that the transcription factor, STAT6, which is downstream of the IL-4 receptor and binds a viral promoter in macrophages, did not bind to the viral promoter in B cells. These data suggest that stimuli that promote herpesvirus reactivation may only affect latent virus in particular cell types, but not in others. ImportanceHerpesviruses establish life-long quiescent infections in specific cells in the body, and only reactivate to produce infectious virus when precise signals induce them to do so. The signals that induce herpesvirus reactivation are often studied only in one particular cell type infected with the virus. However, herpesviruses establish latency in multiple cell types in their hosts. Using murine gammaherpesvirus-68 (MHV68) and conditional knockout mice, we examined the cell type specificity of a particular reactivation signal, interleukin-4 (IL-4). We found that IL-4 only induced herpesvirus reactivation from macrophages, but not from B cells. This work indicates that regulation of virus latency and reactivation is cell type specific. This has important implications for therapies aimed at either promoting or inhibiting reactivation for the control or elimination of chronic viral infections.

microbiology↗

bioRxiv2020

Stress Assessment of Vestibular Endurance Training for Civil Aviation Flight Students Based on EEG

ObjectiveThe main goal of our study is to clarify the EEG characteristics of the stress response caused by vestibular endurance training under the real conditions. MethodsTen pilot trainees received a series of acute anti-vertigo training stimulations on the rotary ladder while recording electroencephalographic data (64 electrodes). Afterwards, the subjects anti-vertigo ability was tested for the best performance after 1 month of training, and verifying whether it is relating to the EEG signals we collected before. Results(1) The absolute power of waves in the C3 and C4 regions is same as the difference between 1 min before and 2 min after stimulation, and their activity is enhanced by stimulation. Otherwise, the activation of the C3 region after 5min of stimulation is still significant changed. (2) Discover a spearman rank correlation, the waves in the C3 and C4 the greater the power change, the better the performance of the subject in the proficient stage. ConclusionsC3 and C4 areas are specific brain regions of the stress response of anti-vertigo endurance training, and the absolute power of the wave can be used as a parameter for identifying the degree of motion sickness (MS). The absolute power changes of waves in the C3 and C4 areas are positively correlated with their anti-vertigo potential. SignificanceThe increasing of the absolute power of wave in the C3 and C4 is a manifestation of MS stress adaptability.

neuroscience↗

bioRxiv2020

Identification of microbial markers across populations in early detection of colorectal cancer

Several studies have investigated the association between microbial and colorectal cancer (CRC). However, the replicable markers for early stage adenoma diagnosis across multiple populations remain elusive. Here, a meta-analysis of six studies, comprising a total of 1057 fecal samples, was performed to identify candidate markers. By adjusting the potential confounders, 11 and 26 markers (P<0.05) were identified and separately applied into constructing Random Forest classifier models to discriminate adenoma from control, and adenoma from CRC, achieving robust diagnostic accuracy with AUC = 0.80 and 0.89, respectively. Moreover, these markers demonstrated high diagnostic accuracy in independent validation cohorts. Pooled functional analysis and targeted qRT-PCR based genetic profiles reveal that the altered microbiome triggers different pathways of ADP-heptose and menaquinone biosynthesis (P<0.05) in adenoma vs. control and adenoma vs. CRC sequences respectively. The combined analysis of heterogeneous studies confirm adenoma-specific but universal markers across multi-populations, which improves early diagnosis and prompt treatment of CRC.

pathology↗

bioRxiv2020

Diversity and biogeography of Woesearchaeota: A comprehensive analysis of multi-environment data

Woesearchaeota is a newly proposed archaeal phylum frequently detected in various environments. Due to the limited systematical study, little is known about their distribution, taxonomy, and metabolism. Here, we conducted a comprehensive study for Woesearchaeota with 16S ribosomal RNA (rRNA) gene sequencing data of 27,709 samples and metagenomic whole genome sequencing (WGS) data of 1,266 samples. We find that apart from free-living environments, Woesearchaeota also widely distribute in host-associated environments. And host-associated environmental parameters greatly affect their distribution. 81 Woesearchaeota genomes, including 33 genomes firstly reconstructed in this project, were assigned to 59 Woesearchaeota species, suggesting their high taxonomic diversity. Comparative analysis indicated that Woesearchaeota have an open pan-genome with small core genome. Metabolic reconstruction showed that particular metabolic pathway absence in specific environments, demonstrated the metabolic diversity of Woesearchaeota varies in differences environments. These results have placed host-associated environments into the global biogeography of Woesearchaeota and have demonstrated their genomic diversity for future investigation of adaptive evolution.

ecology↗

bioRxiv2020

Divergent ion selectivity and sensitivity to anti-hypertensive and non-steroidal anti-inflammatory drugs of DEG/ENaC/ASIC channels in C. elegans

The degenerin channels, epithelial sodium channels, and acid-sensing ion channels (DEG/ENaC/ASICs) play important roles in sensing mechanical stimuli, regulating salt homeostasis, and responding to acidification in the nervous system. They have two transmembrane domains separated by a large extracellular domain and are believed to assemble as homomeric or heteromeric trimers. Based on studies of selected family members, these channels are assumed to form non-voltage gated and sodium-selective channels sensitive to the anti-hypertensive drug, amiloride. They are also emerging as a target of nonsteroidal anti-inflammatory drugs (NSAIDs). C. elegans has more than two dozen genes encoding DEG/ENaC/ASIC subunits, providing an excellent opportunity to examine variations in drug sensitivity. Here, we analyze a subset of the C. elegans DEG/ENaC/ASIC proteins to test the hypothesis that individual family members vary not only in their ability to form homomeric channels, but also in their drug sensitivity. We selected five C. elegans DEG/ENaC/ASICs (DEGT-1, DEL-1, UNC-8, MEC-10 and MEC-4) that are co-expressed in mechanosensory neurons and expressed gain-of-function d mutant isoforms in Xenopus laevis oocytes. We found that only DEGT-1d, UNC-8d, and MEC-4d formed homomeric channels and that, unlike MEC-4d and UNC-8d, DEGT-1d channels were insensitive to amiloride and its analogs. As reported for rat ASIC1a, NSAIDs inhibit DEGT-1d and UNC-8d channels. Unexpectedly, MEC-4d was strongly potentiated by NSAIDs, an effect that was decreased by mutations in the putative NSAID binding site in the extracellular domain. Collectively, these findings reveal that not all DEG/ENaC/ASIC channels are amiloride-sensitive and that NSAIDs can both inhibit and potentiate these channels. SummaryAnimal physiology depends on degenerin, epithelial sodium, and acid-sensing ion channels (DEG/ENaC/ASICs). By measuring the sensitivity of three C. elegans DEG/ENaC/ASICs to five amiloride analogs and five NSAIDs, we show that individual channels have distinct pharmacological footprints.

biophysics↗

bioRxiv2020

RIP1 kinase activity promotes steatohepatitis through mediating cell death and inflammation in macrophages

Hepatocyte cell death and liver inflammation have been well recognized as central characteristics of nonalcoholic steatohepatitis (NASH), however, the underlying molecular basis remains elusive. The kinase receptor-interacting protein 1 (RIP1) is a key regulator of apoptosis, necroptosis and inflammation, we thus hypothesized that the kinase activity of RIP1 may be involved in the pathogenesis of NASH. Wild-type and RIP1 kinase-dead (Rip1K45A/K45A) mice were fed with methionine-and choline-deficient diet (MCD) or high-fat diet (HFD) to establish distinct NASH models. In both models, compared to WT mice, Rip1K45A/K45A mice exhibited significantly less liver injury, less steatosis, decreased inflammation, and less cell death in liver tissue. Moreover, hepatic fibrosis as characterized by Sirius Red staining, expression of -SMA and other fibrosis markers, were significantly alleviated in Rip1K45A/K45A mice than WT controls. Furthermore, using bone marrow transplantation to create chimeric mice, we found that it is the RIP1 kinase in hematopoietic-derived macrophages contributing mostly to the disease progression in NASH. Results from in vitro studies were in agreement with the in vivo data, demonstrating that RIP1 kinase was required for inflammasome activation and cell death induced by saturated fatty acid (palmitic acid) in bone marrow-derived macrophages (BMDMs). At last, we also found that the phosphorylation and expression of RIP1 was obviously increased in patients with NAFLD or NASH, but not in healthy controls. In summary, our results indicate that RIP1 kinase is activated during the pathogenesis of steatohepatitis, and consequently induces inflammation and cell death in macrophages, contributing to the disease progression. Our study suggests that macrophage RIP1 kinase represents a specific and potential target for the treatment of NASH.

immunology↗

bioRxiv2019

Metabolic Control of Viral Infection through PPAR-α Regulation of STING Signaling

Peroxisomal proliferator activated receptors (PPARs) are sensors of dietary lipids and pharmacological targets in the treatment of metabolic disorders. PPAR ligands are also immunosuppressive. However, their function during infection is debated and the mechanisms that underlie their immunoregulatory properties are unclear. We investigated the consequences of PPAR activation during herpesvirus infection. We found that activation of PPAR- increased herpesvirus replication, suppressed type I interferon production and induced reactive oxygen species (ROS). We discovered that ROS induced by PPAR- stimulation suppressed the cytoplasmic DNA sensing pathway after direct activation of stimulator of interferon (STING), the ER adapter downstream of cytoplasmic DNA recognition. Although high ROS induces inflammasome activation and cytokine production, we found that ROS inhibited interferon production after cytoplasmic DNA recognition. Treatment of mice with a clinically relevant agonist of PPAR- increased herpesvirus replication and pathogenesis, comparable to levels observed previously in type I interferon receptor knockout mice. These findings reveal that activation of PPAR- regulates immunity to cytoplasmic DNA and DNA virus infection through inhibition of interferon. Moreover, these results demonstrate that STING signaling and interferon production is regulated by ROS.

immunology↗

bioRxiv2019

Dimensional Reduction of Emergent Spatiotemporal Cortical Dynamics via a Maximum Entropy Moment Closure

Modern electrophysiological recordings and optical imaging techniques have revealed a diverse spectrum of spatiotemporal neural activities underlying fundamental cognitive processing. Oscillations, traveling waves and other complex population dynamical patterns are often concomitant with sensory processing, information transfer, decision making and memory consolidation. While neural population models such as neural mass, population density and kinetic theoretical models have been used to capture a wide range of the experimentally observed dynamics, a full account of how the multi-scale dynamics emerges from the detailed biophysical properties of individual neurons and the network architecture remains elusive. Here we apply a recently developed coarse-graining framework for reduced-dimensional descriptions of neuronal networks to model visual cortical dynamics. We show that, without introducing any new parameters, how a sequence of models culminating in an augmented system of spatially-coupled ODEs can effectively model a wide range of the observed cortical dynamics, ranging from visual stimulus orientation dynamics to traveling waves induced by visual illusory stimuli. In addition to an efficient simulation method, this framework also offers an analytic approach to studying large-scale network dynamics. As such, the dimensional reduction naturally leads to mesoscopic variables that capture the interplay between neuronal population stochasticity and network architecture that we believe to underlie many emergent cortical phenomena.

neuroscience↗

bioRxiv2018

Statistical structure of locomotion and its modulation by odors

Most behaviors such as making tea are not stereotypical but have an obvious structure. However, analytical methods to objectively extract structure from non-stereotyped behaviors are immature. In this study, we analyze the locomotion of fruit flies and show that this non-stereotyped behavior is well-described by a Hierarchical Hidden Markov Model (HHMM). HHMM shows that a flys locomotion can be decomposed into a small number of locomotor features, and odors modulate locomotion by altering the time a fly spends performing different locomotor features. Importantly, although all flies in our dataset use the same set of locomotor features, individual flies vary considerably in how often they employ a given locomotor feature, and how this usage is modulated by odor. This variation is so large that the behavior of individual flies is best understood as being grouped into at least 3-5 distinct clusters, rather than variations around an average fly.

neuroscience↗

bioRxiv2018

A Mechanism for Synaptic Copy between Neural Circuits

The brain has a central, short-term learning module, the hippocampus, which transfers what it has learned to long-term memory in cortex during non-REM sleep. The putative mechanism responsible for this type of memory consolidation invokes hierarchically nested hippocampal ripples (100-250 Hz), thalamo-cortical spindles (7-15 Hz), and cortical slow oscillations (< 1 Hz) to enable transfer. Suppression of, for instance, thalamic spindles has been shown to impair hippocampus-dependent memory consolidation. Cortical oscillations are central to information transfer in neural systems. Significant evidence supports the idea that coincident spike input can allow the neural threshold to be overcome, and spikes to be propagated downstream in a circuit. Thus, an observation of oscillations in neural circuits would be an indication that repeated synchronous spiking is enabling information transfer. However, for memory transfer, in which synaptic weights must be being transferred from one neural circuit (region) to another, what is the mechanism? Here, we present a synaptic transfer mechanism whose structure provides some understanding of the phenomena that have been implicated in memory transfer, including the nested oscillations at various frequencies. The circuit is based on the principle of pulse-gated, graded information transfer between neural populations.\n\nPACS numbers: 87.18.Sn,87.19.lj,87.19.lm,87.19.lq

neuroscience↗