Biology subjects

Zuo, Y.

Publications and source records attributed to Zuo, Y..

36 records · Page 2Linked to original sources

bioRxiv2022

Vitamin C is an efficient natural product for prevention of SARS-CoV-2 infection by targeting ACE2 in both cell and in vivo mouse models

ACE2 is a major receptor for cell entry of SARS-CoV-2. Despite advances in targeting ACE2 to inhibit SARS-CoV-2s binding, how to efficiently and flexibly control ACE2 levels for prevention of SARS-CoV-2 infection has not been explored. Here, we revealed Vitamin C (VitC) administration as an effective strategy to prevent SARS-CoV-2 infection. VitC reduced ACE2 protein levels in a dose-dependent manner, while partial reduction of ACE2 can greatly restrict SARS-CoV-2 infection. Further studies uncovered that USP50 is a crucial regulator of ACE2 protein levels, and VitC blocks the USP50-ACE2 interaction, thus promoting K48-linked polyubiquitination at Lys788 and degradation of ACE2, without disrupting ACE2 transcriptional expression. Importantly, VitC administration reduced host ACE2 and largely blocked SARS-CoV-2 infection in mice. This study identified an in vivo ACE2 balance controlled by both USP50 and an essential nutrient VitC, and revealed a critical role and application of VitC in daily protection from SARS-CoV-2 infection. HighlightsO_LIVitC reduces ACE2 protein levels in a dose-dependent manner C_LIO_LIVitC and USP50 regulate K48-linked ubiquitination at Lys788 of ACE2 C_LIO_LIVitC blocks the interaction between USP50 and ACE2 C_LIO_LIVitC administration lowers host ACE2 and prevents SARS-CoV-2 infection in vivo C_LI O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=151 SRC="FIGDIR/small/499651v1_ufig1.gif" ALT="Figure 1"> View larger version (60K): org.highwire.dtl.DTLVardef@196682borg.highwire.dtl.DTLVardef@190f14dorg.highwire.dtl.DTLVardef@d22b59org.highwire.dtl.DTLVardef@1c0faa_HPS_FORMAT_FIGEXP M_FIG C_FIG The deubiquitinase USP50 controls ACE2 protein stability and levels, while Vitamin C blocks the USP50-ACE2 interaction and therefore results in ACE2 degradation, offering a flexible and efficient approach to protection of the host from SARS-CoV-2 infection.

microbiology↗

bioRxiv2022

Injectable hydrogel embedded with mesenchymal stem cells repairs severe spinal cord injury

Mesenchymal stem cell (MSC) transplantation was suggested as a promising approach to treat spinal cord injury (SCI). However, the heterogeneity of MSC and the lack of appropriate delivery methods impede its clinical application. To tackle these challenges, we first generated human MSCs derived from a single cell with a great homogeneity of batch quality and then developed a biocompatible injectable hydrogel to embed these cells to treat severe SCI. In a clinically relevant rat severe SCI model, we showed that the injection of MSCs with injectable hydrogel into the lesion site promoted robust functional recovery, while the intrathecal delivery of MSCs only resulted in limited therapeutic effects. Mechanistically, the hydrogel protected MSCs from the damage of harmful neuroinflammatory microenvironment in the spinal cord lesion. The hydrogel with the survived MSCs ameliorates the neuroinflammatory microenvironment of spinal cord lesion, preventing cavity formation and leads to the remnant of spared axons/tissues, which results in a better prognosis in the end.

bioengineering↗

bioRxiv2022

Protein 3D structure-based neural networks highly improve the accuracy in compound-protein binding affinity prediction

Due to the lack of a method to efficiently represent the multimodal information of a protein, including its structure and sequence information, predicting compound-protein binding affinity (CPA) still suffers from low accuracy when applying machine learning methods. To overcome this limitation, in a novel end-to-end architecture (named FeatNN), we develop a coevolutionary strategy to jointly represent the structure and sequence features of proteins and ultimately optimize the mathematical models for predicting CPA. Furthermore, from the perspective of data-driven approach, we proposed a rational method that can utilize both high- and low-quality databases to optimize the accuracy and generalization ability of FeatNN in CPA prediction tasks. Notably, we visually interpret the feature interaction process between sequence and structure in the rationally designed architecture. As a result, FeatNN considerably outperforms the state-of-the-art (SOTA) baseline in virtual drug screening tasks, indicating the feasibility of this approach for practical use. FeatNN provides an outstanding method for higher CPA prediction accuracy and better generalization ability by efficiently representing multimodal information of proteins via a coevolutionary strategy.

bioinformatics↗

bioRxiv2022

Improving functional recovery after severe spinal cord injury by a noninvasive dual functional approach of neuroprotection and neuromodulation

Despite tremendous unmet medical needs, there is no effective pharmacological treatment to promote functional recovery after spinal cord injury (SCI). Although multiple pathological events have been implicated in SCI, the development of a noninvasive pharmacological approach to simultaneously target the different mechanisms involved in SCI remains a formidable challenge. In this study, we report the development of a noninvasive nanodrug delivery system that consists of ROS-responsive amphiphilic copolymers and an encapsulated neurotransmitter-conjugated KCC2 agonist. We show that upon intravenous administration, the nanodrugs were able to enter the injured spinal cord due to blood spinal cord barrier disruption and ROS-responsive disassembly. Remarkably, once in the injured spinal cord, these nanodrugs exhibited dual functions: scavenging ROS accumulated in the lesion to protect spared connections and increasing neuronal excitability in the injured spinal cord through targeted delivery of the KCC2 agonist to inhibitory neurons. Thus, the noninvasive treatment led to significant functional recovery in the rats with contusive SCI. Together, these findings provide a much-needed translational pharmacological approach for treating severe SCI.

neuroscience↗

bioRxiv2021

Chronic adolescent exposure to cannabis in mice leads to long-term sex-biased changes in gene expression networks across brain regions

During adolescence, frequent and heavy cannabis use can lead to serious adverse health effects and cannabis use disorders (CUD). Rodent models of adolescent exposure to the main psychoactive component of cannabis, delta-9-tetrahydrocannabinol (THC), mimic the behavioral alterations observed in adolescent users. However, the underlying molecular mechanisms remain largely unknown. Here, we treated female and male mice with high doses of THC during early adolescence and assessed their memory and social behaviors in late adolescence. We then profiled the transcriptome of five brain regions involved in cognitive and addiction-related processes. We applied gene coexpression network analysis and identified gene coexpression modules, termed cognitive modules, that simultaneously correlated with THC treatment and memory traits reduced by THC. The cognitive modules were related to endocannabinoid signaling in the female dorsal medial striatum, inflammation in the female ventral tegmental area, and synaptic transmission in the male nucleus accumbens. Moreover, cross-brain region module-module interaction networks uncovered intra- and inter-region molecular circuitries influenced by THC. Lastly, we identified key driver genes of gene networks associated with THC in mice and genetic susceptibility to CUD in humans. This analysis revealed a common regulatory mechanism linked to CUD vulnerability in the nucleus accumbens of females and males, which shared four key drivers (Hapln4, Kcnc1, Elav12, Zcchc12). These genes regulate transcriptional subnetworks implicated in addiction processes, synaptic transmission, brain development, and lipid metabolism. Our study provides novel insights into disease mechanisms regulated by adolescent exposure to THC in a sex- and brain region-specific manner.

neuroscience↗

bioRxiv2021

Lasting effects of low-calorie sweeteners on glucose regulation, sugar intake, and memory

Low-calorie sweetener (LCS) consumption in children has increased due to widespread LCS presence in the food environment and efforts to mitigate obesity through sugar replacement. However, mechanistic studies on the impact of early-life LCS consumption are lacking. Therefore, we developed a rodent model to evaluate the effects of daily LCS consumption (acesulfame potassium, saccharin, or stevia) during adolescence on adult metabolic, gut microbiome, neural, and behavioral outcomes. Results reveal that habitual early-life LCS consumption disrupts post-oral glucose tolerance and impairs hippocampal-dependent memory in the absence of weight gain. Furthermore, LCS consumption reduces lingual sweet taste receptor expression and alters sugar-motivated appetitive and consummatory responses. RNA sequencing analyses reveal that LCS also impacts collagen- and synaptic signaling-related gene pathways in the hippocampus and nucleus accumbens, respectively, in a sex-dependent manner. Collectively, these results suggest that regular early-life LCS consumption yields long-lasting impairments in metabolism, sugar-motivated behavior, and hippocampal-dependent memory.

neuroscience↗

bioRxiv2021

Co-aggregation with Apolipoprotein E modulates the function of Amyloid-β in Alzheimer's disease

Which isoforms of apolipoprotein E (apoE) we inherit determine our risk of developing late-onset Alzheimers Disease (AD), but the mechanism underlying this link is poorly understood. In particular, the relevance of direct interactions between apoE and amyloid-{beta} (A{beta}) remains controversial. Here, single-molecule imaging shows that all isoforms of apoE associate with A{beta} in the early stages of aggregation and then fall away as fibrillation happens. ApoE-A{beta} co-aggregates account for [~]50% of the mass of soluble A{beta} aggregates detected in the frontal cortices of homozygotes with the higher-risk APOE4 gene. Our results connect inherited APOE genotype with the risk of developing AD by demonstrating how, in an isoform- and lipidation-specific way, apoE modulates the aggregation, clearance and toxicity of A{beta}. Selectively removing non-lipidated apoE4-A{beta} co-aggregates enhances clearance of toxic A{beta} by glial cells, and reduces inflammation and membrane damage, demonstrating a clear path to AD therapeutics.

neuroscience↗

bioRxiv2021

De novo genome assembly and functional annotation for Fusarium langsethiae

MotivationFusarium langsethiae is a T-2 and HT-2 mycotoxins producing Fusarium species firstly characterised in 2004. It is commonly isolated from oats in Northern Europe. T-2 and HT-2 mycotoxins exhibit immunological and haemotological effects in animal health mainly through inhibition of protein, RNA and DNA synthesis. The development of a high-quality and comprehensively annotated assembly for this species is therefore essential in providing the molecular understanding and the mechanism of T-2 and HT-2 biosynthesis in F. langsethiae to help develop effective control strategies. ResultsThe F. langsethiae assembly was produced using PacBio long reads, which were then assembled independently using Canu, SMARTdenovo and Flye; producing a genome assembly total length of 59Mb and N50 of 3.51Mb. A total of 19,336 coding genes were identified using RNA-Seq informed ab-initio gene prediction. Finally, predicting genes were annotated using the basic local alignment search tool (BLAST) against the NCBI non-redundant (NR) genome database and protein hits were annotated using InterProScan. Genes with blast hits were functionally annotated with Gene Ontology. Contactf.mohareb@cranfield.ac.uk Data availabilityRaw sequence reads and assembled genome can be downloaded from: GenBank under the accession JAFFKB000000000

genomics↗

bioRxiv2020

Somatic Cell Nuclear Transfer Embryos Show Massive Dysregulation of Genes Involved in Transcription Pathway

Transcription is the most fundamental molecular event that occurs with zygotic genome activation (ZGA) during embryo development. However, the potential association between transcription pathways and low cloning efficiency of nuclear transfer (NT) embryos remains elusive. Here, we integrated a series of RNA-seq data on NT embryos to deciphering the molecular barriers of NT embryo development. Comparative transcriptome analysis indicated that incomplete activation of transcription pathways functions as a barrier for NT embryos. Then, the gene regulatory network (GRN) identified that crucial factors responsible for transcription play a coordinated role in epigenome erasure and pluripotency regulation during normal embryo development. But in NT embryos, massive genes involved in transcription pathways were varying degrees of inhibition. Our study therefore provides new insights into understanding the barriers to NT embryo reprogramming.

bioinformatics↗

bioRxiv2020

Amplification, not spreading limits rate of tau aggregate accumulation in Alzheimer's disease

Both the replication of protein aggregates and their spreading throughout the brain are implicated in the progression of Alzheimers disease (AD). However, the rates of these processes are unknown and the identity of the rate-determining process in humans has therefore remained elusive. By bringing together chemical kinetics with measurements of tau seeds and aggregates across brain regions, we are able to quantify their replication rate in human brains. Remarkably, we obtain comparable rates in several different datasets, with 5 different methods of tau quantification, from seed amplification assays in vitro to tau PET studies in living patients. Our results suggest that the overall rate of accumulation of tau in neocortical regions is limited not by spreading between brain regions but by local replication, which doubles the number of seeds every ~5 years. Thus, we propose that limiting local replication constitutes the most promising strategy to control tau accumulation during AD.

biophysics↗

bioRxiv2020

Dppa2/4 promotes zygotic genome activation by binding to GC-rich region of proximal promoter in signaling pathways

Developmental pluripotency associated 2 (Dppa2) and Dppa4 as positive drivers were helpful for transcriptional regulation of ZGA. Here, we systematically assessed the cooperative interplay between Dppa2 and Dppa4 in regulating cell pluripotency of three cell types and found that simultaneous overexpression of Dppa2/4 can make induced pluripotent stem cells closer to embryonic stem cells. Compared with other pluripotency transcription factors (TFs), Dppa2/4 tends to bind on GC-rich region of proximal promoter (0-500bp). Moreover, there was more potent effect of Dppa2/4 regulation on signaling pathways than other TFs, in which 75% and 85% signaling pathways were significantly activated by Dppa2 and Dppa4, respectively. Notably, Dppa2/4 also can dramatically trigger the decisive signaling pathways for facilitating ZGA, including Hippo, MAPK and TGF-beta signaling pathways and so on. At last, we found that Alkaline phosphatase placental-like 2 (Alppl2) was significantly activated at the 2-cell stage in mouse embryos and 4-8 cell stage in human embryos, further predicted that Alppl2 was directly regulated by Dppa2/4 as a candidate driver of ZGA to regulate pre-embryonic development.

bioinformatics↗

bioRxiv2020

Escherichia coli σ38 promoters use two UP elements instead of a -35 element: resolution of a paradoxand discovery that σ38 transcribes ribosomal promoters

1In E. coli, one RNA polymerase (RNAP) transcribes all RNA species, and different regulons are transcribed by employing different sigma ({sigma}) factors. RNAP containing{sigma} 38 ({sigma}S) activates genes responding to stress conditions such as stationary phase. The structure of{sigma} 38 promoters has been controversial for more than two decades. To construct a model of{sigma} 38 promoters using information theory, we aligned proven transcriptional start sites to maximize the sequence information, in bits, and identified a -10 element similar to{sigma} 70 promoters. We could not align any -35 sequence logo; instead we found two patterns upstream of the -35 region. These patterns have dyad symmetry sequences and correspond to the location of UP elements in ribosomal RNA (rRNA) promoters. Additionally the UP element dyad symmetry suggests that the two polymerase subunits, which bind to the UPs, should have two-fold dyad axis of symmetry on the polymerase and this is indeed observed in an X-ray crystal structure. Curiously the CTDs should compete for overlapping UP elements. In vitro experiments confirm that{sigma} 38 recognizes the rrnB P1 promoter, requires a -10, UP elements and no -35. This clarifies the long-standing paradox of how{sigma} 38 promoters differ from those of{sigma} 70.

molecular biology↗

bioRxiv2019

A general in vitro assay to study enzymatic activities of the ubiquitin system

The ubiquitin (Ub) system regulates a wide range of cellular signaling pathways. Several hundred E1, E2 and E3 enzymes are together responsible for protein ubiquitination, thereby controlling cellular activities. Due to the numerous enzymes and processes involved, studies on ubiquitination activities have been challenging. We here report a novel FRET-based assay to study the in vitro kinetics of ubiquitination. FRET is established between binding of fluorophore-labeled Ub to eGFP-tagged ZnUBP, a domain that exclusively binds unconjugated Ub. We name this assay the Free Ub Sensor System (FUSS). Using Uba1, UbcH5 and CHIP as model E1, E2 and E3 enzymes, respectively, we demonstrate that ubiquitination results in decreasing FRET efficiency, from which reaction rates can be determined. Further treatment with USP21, a deubiquitinase, leads to increased FRET efficiency, confirming the reversibility of the assay. We subsequently use this assay to show that increasing the concentration of CHIP or UbcH5 but not Uba1 enhances ubiquitination rates, and develop a novel machine learning approach to model ubiquitination. The overall ubiquitination activity is also increased upon incubation with tau, a substrate of CHIP. Our data together demonstrate the versatile applications of a novel ubiquitination assay that does not require labeling of E1, E2, E3 or substrates, and is thus likely compatible with any E1-E2-E3 combinations.

biochemistry↗

bioRxiv2019

Multifaceted Changes in Synaptic Composition and Astrocytic Involvement in a Mouse Model of Fragile X Syndrome

Fragile X Syndrome (FXS), a common inheritable form of intellectual disability, is known to alter neocortical circuits. However, its impact on the diverse synapse types comprising these circuits, or on the involvement of astrocytes, is not well known. We used immunofluorescent array tomography to quantify different synaptic populations and their association with astrocytes in layers 1 through 4 of the adult somatosensory cortex of a FXS mouse model, the FMR1 knockout mouse. The collected multi-channel data contained approximately 1.6 million synapses which were analyzed using a probabilistic synapse detector. Our study reveals complex, synapse-type and layer specific changes in the neocortical circuitry of FMR1 knockout mice. In layers 1 and 2/3, there is a significant decrease in the density of excitatory glutamatergic synapses, both VGluT1 and VGluT2 type, and their association with astrocytes, while the changes in inhibitory GABAergic synapses are less pronounced. Meanwhile in layer 4, there is a significant increase in the density of small VGluT1 synapses, with no changes in the astrocytic association of synapses. The ability to dissect the circuit deficits by synapse type and astrocytic involvement, will be crucial for understanding how these changes affect circuit function, and ultimately define targets for therapeutic intervention.

neuroscience↗

bioRxiv2018

Astroglial dysfunctions drive aberrant synaptogenesis in developing brain with lengthy general anesthesia

Lengthy use of general anesthetics (GAs) causes cognitive deficits in developing brain, which has raised significant clinical concerns such that FDA is warning on the use of GAs in children younger than 3 years. However, the molecular and cellular mechanisms for GAs-induced neurotoxicity remain largely unknown. Here we report that sevoflurane, a commonly used GA in pediatrics, causes compromised astrocyte morphogenesis, spatiotemporally correlated to the synaptic overgrowth with reduced synaptic function in developing cortex in a regional-, exposure-length- and age-specific manner. Sevoflurane disrupts astrocyte Ca2+ homeostasis both acutely and chronically, which leads to the down regulation of Ezrin, an actin-binding membrane protein, which we found is critically involved in astrocyte morphogenesis in vivo. Importantly, in normal developing brain, the genetic intervention of astrocyte morphogenesis is sufficient to produce the aberrant synaptic structure and function virtually identical to the ones induced by lengthy sevoflurane exposure. Our data uncover that astrocytes are unexpectedly central targets for GAs to exert toxic effects, and that astrocyte morphological integrity is crucial for synaptogenesis in the developing brain.

neuroscience↗

bioRxiv2018

Structural and Practical Identifiability of Dual-input Kinetic Modeling in Dynamic PET of Liver Inflammation

Dynamic 18F-FDG PET with tracer kinetic modeling has the potential to noninvasively evaluate human liver inflammation using the FDG blood-to-tissue transport rate K1. Accurate kinetic modeling of dynamic liver PET data and K1 quantification requires the knowledge of dual-blood input function from the hepatic artery and portal vein. While the arterial input function can be derived from the aortic region on dynamic PET images, it is difficult to extract the portal vein input function accurately from PET. The optimization-derived dual-input kinetic modeling approach has been proposed to overcome this problem by jointly estimating the portal vein input function and FDG tracer kinetics from time activity curve fitting. In this paper, we further characterize the model properties by analyzing the structural identifiability of the model parameters using the Laplace transform and practical identifiability using Monte Carlo simulation based on fourteen patient datasets. The theoretical analysis has indicated that all the kinetic parameters of the dual-input kinetic model are structurally identifiable, though subject to local solutions. The Monte Carlo simulation results have shown that FDG K1 can be estimated reliably in the whole-liver region of interest with reasonable bias, standard deviation, and high correlation between estimated and original values, indicating of practical identifiability of K1. The result has also demonstrated the correlation between K1 and histological liver inflammation scores is reliable. FDG K1 quantification by the optimization-derived dual-input kinetic model is promising for assessing liver inflammation.

bioengineering↗

bioRxiv2018

A genetically-encoded fluorescent acetylcholine indicator

Acetylcholine (ACh) regulates a diverse array of physiological processes throughout the body, yet cholinergic transmission in the majority of tissues/organs remains poorly understood due primarily to the limitations of available ACh-monitoring techniques. We developed a family of G-protein-coupled receptor activation-based ACh sensors (GACh) with sensitivity, specificity, signal-to-noise ratio, kinetics and photostability suitable for monitoring ACh signals in vitro and in vivo. GACh sensors were validated with transfection, viral and/or transgenic expression in a dozen types of neuronal and non-neuronal cells prepared from several animal species. In all preparations, GACh sensors selectively responded to exogenous and/or endogenous ACh with robust fluorescence signals that were captured by epifluorescent, confocal and/or two-photon microscopy. Moreover, analysis of endogenous ACh release revealed firing pattern-dependent release and restricted volume transmission, resolving two long-standing questions about central cholinergic transmission. Thus, GACh sensors provide a user-friendly, broadly applicable toolbox for monitoring cholinergic transmission underlying diverse biological processes.

neuroscience↗

bioRxiv2018

Relative Patlak Plot for Dynamic PET Parametric Imaging Without the Need for Early-time Input Function

The Patlak graphical method is widely used in parametric imaging for modeling irreversible radiotracer kinetics in dynamic PET. The net influx rate of radiotracer can be determined from the slope of the Patlak plot. The implementation of the standard Patlak method requires the knowledge of full-time input function from the injection time until the scan end time, which presents a challenge for use in the clinic. This paper proposes a new relative Patlak plot method that does not require early-time input function and therefore can be more efficient for parametric imaging. Theoretical analysis proves that the effect of early-time input function is a constant scaling factor on the Patlak slope estimation. Thus, the parametric image of the slope of the relative Patlak plot is related to the parametric image of standard Patlak slope by a global scaling factor. This theoretical finding has been further demonstrated by computer simulation and real patient data. The study indicates that parametric imaging of the relative Patlak slope can be used as a substitute of parametric imaging of standard Patlak slope for certain clinical tasks such as lesion detection and tumor volume segmentation.

bioengineering↗