Biology subjects

Tian, X.

Publications and source records attributed to Tian, X..

At least 163 records · Page 9Linked to original sources

bioRxiv2021

A magnetic field prevents alcoholic liver disease by reducing oxidative stress

The radical-pair recombination change will affect the generation of free radicals, which can be regulated by static magnetic fields (SMFs) in a SMF setting dependent way. It is well known that alcohol consumption leads to significantly increased free radical levels and health risks, which lacks effective treatment method besides alcohol abstinence. Here we compared different SMF settings and found that a downward SMF of [~]0.1 T with magnetic flux of [~]4.5x10-3 Wb could effectively alleviate alcohol-induced liver damage and lipid accumulation, and improve liver function. The inflammation, reactive oxygen species (ROS) level and oxidative stress were significantly reduced. EPR (electron paramagnetic resonance) experiments also confirmed the reduced amount of free radical by SMF treatment. Moreover, the lifespan of heavy alcohol drinking mice was also significantly changed due to the SMF effects on liver cell ROS level, DNA synthesis and liver cell regeneration. Our study shows that moderate SMFs with specific parameters have great promises to be developed into a physical method to reduce alcohol-induced liver damage in the future.

physiology↗

bioRxiv2021

A luciferase prosubstrate and a red bioluminescent calcium indicator to image neuronal activity

Genetically encoded fluorescent indicators have been broadly used to monitor neuronal activity in live animals, but invasive surgical procedures are required. This study presents a functional bioluminescence imaging (fBLI) method for recording the activity of neuronal ensembles in the brain in awake mice. We developed a luciferase prosubstrate activatable in vivo by nonspecific esterase to enhance the brain delivery of the luciferin. We further engineered a bright, bioluminescent indicator with robust responsiveness to calcium ions (Ca2+) and appreciable emission above 600 nm. Integration of these advantageous components enabled the imaging of Ca2+ dynamics in awake mice minimally invasively with excellent signal- to-background and subsecond temporal resolution. This study thus establishes a new paradigm for studying brain functions in health and disease.

neuroscience↗

bioRxiv2021

Integrated resource for functional and structural connectivity of the marmoset brain

Comprehensive integration of structural and functional connectivity data is required to model brain functions accurately. While resources for studying the structural connectivity of non-human primate brains already exist, their integration with functional connectivity data has remained unavailable. Here we present a comprehensive resource that integrates the most extensive awake marmoset resting-state fMRI data available to date (39 marmoset monkeys, 710 runs, 12117 mins) with previously published cellular-level neuronal tracing (52 marmoset monkeys, 143 injections) and multi-resolution diffusion MRI datasets. The combination of these data allowed us to (1) map the fine-detailed functional brain networks and cortical parcellations; (2) develop a deep-learning-based parcellation generator that preserves the topographical organization of functional connectivity and reflects individual variabilities, and (3) investigate the structural basis underlying functional connectivity by computational modeling. This resource will enable modeling structure-function relationships and facilitate future comparative and translational studies of primate brains.

neuroscience↗

bioRxiv2021

Transcriptome analysis of SARS-CoV-2 naive and recovered individuals vaccinated with inactivated vaccine

The urgent approval of the use of the inactivated COVID-19 vaccine is essential to reduce the threat and burden of the epidemic on global public health, however, our current understanding of the host immune response to inactivated vaccine remains limited. Herein, we performed serum IgG antibody detection and transcriptomics analysis on 20 SARS-CoV-2 naive individuals who received multiple doses of inactivated vaccine and 5 SARS-CoV-2 recovered individuals who received single dose of inactivated vaccine. Our research revealed the important role of many innate immune pathways after vaccination, identified a significant correlation with the third dose of booster vaccine and proteasome-related genes, and found that SARS-CoV-2 recovered individuals can produces a strong immune response to a single dose of inactivated vaccine. These results help us understand the reaction mechanism of the hosts molecular immune system to the inactivated vaccine, and provide a basis for the choice of vaccination strategy.

microbiology↗

bioRxiv2021

De novo assembly of 20 chickens reveals the undetectable phenomenon for thousands of core genes on sub-telomeric regions

The gene numbers and evolutionary rates of birds were assumed to be much lower than that of mammals, which in sharp contrast to the huge species number and morphological diversity of birds. It is very necessary to construct a complete avian genome and analyze its evolution.We constructed a chicken pan-genome from 20 de novo genome assemblies with high sequencing depth, newly identified 1,335 protein-coding genes and 3,011 long noncoding RNAs. The majority of these novel genes were detected across most individuals of the examined transcriptomes but were accidentally measured in each of the DNA sequencing data regardless of Illumina or PacBio technology. Furthermore, different from previous pan-genome models, most of these novel genes were overrepresented on chromosomal sub-telomeric regions, surrounded with extremely high proportions of tandem repeats, and strongly blocked DNA sequencing. These hidden genes were proved to be shared by all chicken genomes, included many housekeeping genes, and enriched in immune pathways. Comparative genomics revealed the novel genes had three-fold elevated substitution rates than known ones, updating the evolutionary rates of birds. Our study provides a framework for constructing a better chicken genome, which will contribute towards the understanding of avian evolution and improvement of poultry breeding.

genomics↗

bioRxiv2021

SYMBIOSIS: Synthetic Manipulable Biobricks via Orthogonal Serine Integrase Systems

Serine integrases are emerging as one of the most powerful biological tools for synthetic biology. They have been widely used across genome engineering and genetic circuit design. However, developing serine integrase-based tools for directly/precisely manipulating synthetic biobricks is still missing. Here, we report SYMBIOSIS, a versatile method that can robustly manipulate DNA parts in vivo and in vitro. First, we proposed a "Keys match Locks" model to demonstrate that three orthogonal serine integrases are able to irreversibly and stably switch on seven synthetic biobricks with high accuracy in vivo. Then, we demonstrated that purified integrases can facilitate the assembly of "Donor" and "Acceptor" plasmids in vitro to construct composite plasmids. Finally, we used SYMBIOSIS to assemble different chromoprotein genes and create novel colored Escherichia coli. We anticipate that our SYMBIOSIS strategy will accelerate synthetic biobricks manipulation, genetic circuit design, and multiple plasmids assembly for synthetic biology with broad potential applications.

synthetic biology↗

bioRxiv2021

Double-edged role of resource competition in gene expression noise and control

Despite extensive investigation demonstrating that resource competition can significantly alter the circuits deterministic behaviors, a fundamental issue is how resource competition contributes to the gene expression noise and how the noise can be controlled. Utilizing a two-gene circuit as a prototypical system, we uncover a surprising double-edged role of resource competition in gene expression noise: the competition decreases noise through a resource constraint but generates its own type of noise which we name as "resource competitive noise." Utilization of orthogonal resources enables retaining the noise reduction conferred by resource constraint while removing the added resource competitive noise. The noise reduction effects are studied using three negative feedback controller types: negatively competitive regulation (NCR), local, and global controllers, each having four placement architectures in the protein biosynthesis pathway (mRNA or protein inhibition on transcription or translation). Our results show that both local and NCR controllers with mRNA-mediated inhibition are efficacious at reducing noise, with NCR controllers demonstrating a superior noise-reduction capability. We also find that combining negative feedback controllers with orthogonal resources can improve the local controllers. This work provides deep insights into the origin of stochasticity in gene circuits with resource competition and guidance for developing effective noise control strategies.

synthetic biology↗

bioRxiv2021

PHB3 Regulates Lateral Root Primordia Formation via NO-mediated Degradation of AUX/IAAs

We previously showed that PHB3 regulates auxin-stimulated lateral root (LR) formation; however, the underlying molecular mechanism is unknown. Here, we demonstrate that PHB3 regulates LR development mainly through influencing lateral root primordia (LRP) initiation via affecting nitric oxide (NO) accumulation. The reduced LRP in phb3 was largely rescued by exogenous NO donor SNAP treatment. The decreased NO accumulation in phb3 caused a lower expression of GATA23 and LBD16 through inhibiting the degradation of IAA14/28. Overexpression of either GATA23 or LBD16 in phb3 mutant background recovered the reduced LRP number phenotype. These results indicate that PHB3 regulates LRP initiation via NO-mediated auxin signaling through regulating the degradation of IAA14/28. HighlightPHB3 regulates IAA28 and IAA14 degradation by controlling NO accumulation, and thereby regulating LR founder cell identification and the transition to asymmetric division.

developmental biology↗

bioRxiv2021

Hyaluronidase-1-mediated glycocalyx impairment underlies endothelial abnormalities in polypoidal choroidal vasculopathy

BackgroundPolypoidal choroidal vasculopathy (PCV), a subtype of age-related macular degeneration (AMD), is characterized by polyp-like dilatation of blood vessels and turbulent blood flow in the choroid of the eye. Gold standard anti-vascular endothelial growth factor (anti-VEGF) therapy often fails to regress polypoidal lesions in patients. Current animal models have also been hampered by their inability to recapitulate such vascular lesions. These underscore the need to identify VEGF-independent pathways in PCV pathogenesis. ResultsWe cultivated blood outgrowth endothelial cells (BOECs) from PCV patients and normal controls to serve as our experimental disease models. When BOECs were exposed to heterogeneous flow, single-cell transcriptomic analysis revealed that PCV BOECs preferentially adopted migratory-angiogenic cell state, while normal BOECs undertook proinflammatory cell state. PCV BOECs also had a repressed protective response to flow stress by demonstrating lower mitochondrial functions. We uncovered that elevated hyaluronidase-1 in PCV BOECs led to increased degradation of hyaluronan, a major component of glycocalyx that interfaces between flow stress and vascular endothelium. Notably, knockdown of hyaluronidase-1 in PCV BOEC improved mechanosensitivity through activation of Kruppel-like factor 2, a flow-responsive transcription factor, which in turn modulated PCV BOEC migration. Barrier permeability due to glycocalyx impairment in PCV BOECs was also reversed by hyaluronidase-1 knockdown. Correspondingly, hyaluronidase-1 was detected in PCV patient vitreous humor and plasma samples. ConclusionsHyaluronidase-1 inhibition could be a potential therapeutic modality in preserving glycocalyx integrity and endothelial stability in ocular diseases with vascular origin.

cell biology↗

bioRxiv2021

Selective Src-Family B Kinases Inhibition Promotes Pulmonary Artery Endothelial Cell Dysfunction.

Protein tyrosine kinase (PTK) inhibition is efficacious in treating conditions ranging from cancer to fibrosis but can be limited by endothelial cell dysfunction. In trials of protein tyrosine kinase inhibitors (TKIs) a broad range of vascular effects is observed, inducing clinically detrimental endothelial cell apoptosis, impaired barrier function, or improved pulmonary vascular resistance in pulmonary arterial hypertension (PAH). We hypothesize this range of effects is due to subsets of PTKs either impairing or promoting endothelial homeostasis by modulating Bone Morphogenetic Protein receptor 2 (BMPR2) signaling, a pathway essential for vascular development and dysfunctional in PAH. In a high-throughput siRNA screen we find SRC-Family B PTKs activate whereas SRC-Family A PTKs suppress BMPR2 signaling, measured by the transcription factor inhibitor of differentiation 1 (Id1). Induced loss of function of the strongest ID1 activating PTK LCK (a Src-B kinase) in human pulmonary artery endothelial cells suppresses BMPR2 signaling and induces multiple measures of endothelial dysfunction. However, loss of function of the strongest ID1 inhibitor PTK FYN (a Src- A kinase) does the opposite. Whole-genome transcriptional analysis identifies two multi-gene signatures inversely regulated by LCK and FYN we term "endothelial" and "inflammatory". To find TKIs mimicking selective Src-A and Src-B inhibition, we use Connectivity map to identify drugs connecting to the endothelial and inflammatory signatures. We find several TKIs: a pro-inflammatory (Regorafanib), a BMPR2 potentiating (Brivanib), and a BMPR2 suppressing (Quizartinib). Here we show a dichotomy in pathway regulation by Src- A and -B kinases that may have utility in transcriptionally based drug discovery.

molecular biology↗

bioRxiv2021

Connectome-based model predicts individual psychopathic traits in college students

BackgroundPsychopathic traits have been suggested to increase the risk of violations of socio-moral norms. Previous studies revealed that abnormal neural signatures are associated with elevated psychopathic traits; however, whether the intrinsic network architecture can predict psychopathic traits at the individual level remains unclear. MethodsThe present study utilized connectome-based predictive modeling (CPM) to investigate whether whole-brain resting-state functional connectivity (RSFC) can predict psychopathic traits in the general population. RS functional magnetic resonance imaging data were collected from 84 college students with varying psychopathic traits measured by the Levenson Self-Report Psychopathy Scale (LSRP). ResultsWe found that RSFC of the negative networks predicted individual differences in total LSRP and secondary psychopathy scores but not primary psychopathy score. Particularly, nodes with the most connections in the predictive connectome anchored in the prefrontal cortex (e.g., anterior prefrontal cortex and orbitofrontal cortex) and limbic system (e.g., anterior cingulate cortex and insula). In addition, the connections between the occipital network (OCCN) and cingulo-opercular network (CON) served as a significant predictive connectome for total LSRP and secondary psychopathy score. ConclusionCPM constituted by whole-brain RSFC significantly predicted psychopathic traits individually in the general population. The prefrontal cortex and limbic system at the anatomic level and the CON and OCCN at the functional network level plays a special role in the predictive model--reflecting atypical executive control and affective processing for individuals with elevated psychopathic traits. These findings may provide some implications for early detection and potential intervention of psychopathic tendency.

neuroscience↗

bioRxiv2021

A subset of CB002 xanthine analogues bypass p53-signaling to restore a p53 transcriptome and target an S-phase cell cycle checkpoint in tumors with mutated-p53

Mutations in TP53 occur commonly in the majority of human tumors and confer aggressive tumor phenotypes including metastasis and therapy resistance. CB002 and structural-analogues restore p53 signaling in tumors with mutant-p53 but we find that unlike other xanthines such as caffeine, pentoxifylline, and theophylline, they do not deregulate the G2-checkpoint. Novel CB002-analogues induce pro-apoptotic Noxa protein in an ATF3/4-dependent manner, whereas caffeine, pentoxifylline, and theophylline do not. By contrast to caffeine, CB002-analogues target an S-phase checkpoint associated with increased p-RPA/RPA2, p-ATR, decreased Cyclin A, p-histone H3 expression and downregulation of essential proteins in DNA-synthesis and -repair. CB002-analogue #4 enhances cell death, and decreases Ki-67 in patient-derived tumor-organoids without toxicity to normal human cells. Preliminary in vivo studies demonstrate anti-tumor efficacy in mice. Thus, a novel class of anti-cancer drugs show activation of p53 pathway signaling in tumors with mutated p53, and target an S-phase checkpoint.

cancer biology↗

bioRxiv2021

Extracellular vesicles from neuronal cells promote neural induction of mESCs through cyclinD1

Extracellular vesicles (EVs) that are thought to mediate the transport of proteins and RNAs involved in intercellular communication. Here, we show dynamic changes in the buoyant density and abundance of extracellular vesicles that are secreted by PC12 cells stimulated with nerve growth factor (NGF), N2A cells treated with retinoic acid to induce neural differentiation and mESCs differentiated into neuronal cells. EVs secreted from in vitro differentiated cells promote neural induction of mouse embryonic stem cells (mESCs). Cyclin D1 enriched within the EVs derived from differentiated neuronal cells contributes to this induction. EVs purified from cells overexpressing cyclin D1 are more potent in neural induction of mESC cells. Depletion of cyclin D1 from the EVs reduced the neural induction effect. Our results suggest that extracellular vesicles regulate neural development through sorting of cyclin D1. SummaryExtracellular vesicles (EVs) may mediate intercellular communication through the transfer of cargo molecules. Here, we report that cyclinD1 is sorted into EVs during neuronal differentiation and that these EVs help to promote the neural induction of mouse embryonic stem cells.

cell biology↗

bioRxiv2021

A recombinant receptor-binding domain in trimeric form generates completely protective immunity against SARS-CoV-2 infection in nonhuman primates

Safe and effective vaccination is critical to combatting the COVID-19 pandemic. Here, we developed a trimeric SARS-CoV-2 receptor-binding domain (RBD) subunit vaccine candidate that simulates the natural structure of the spike (S) trimer glycoprotein. Immunization with RBD-trimer induced robust humoral and cellular immune responses and a high level of neutralizing antibodies that were maintained for at least 4 months. Moreover, the antibodies that were produced in response to the vaccine effectively neutralized the SARS-CoV-2 501Y.V2 variant. Of note, when the titers of the antibodies dropped to a sufficiently low level, only one boost quickly activated the anamnestic immune response, resulting in complete protection against the SARS-CoV-2 challenge in rhesus macaques without typical histopathological changes or viral replication in the lungs and other respiratory tissues. Our results indicated that immunization with SARS-CoV-2 RBD-trimer could raise long-term and broad immunity protection in nonhuman primates, thereby offering an optimal vaccination strategy against COVID-19.

immunology↗

bioRxiv2021

Neptune: An environment for the delivery of genomic medicine

PurposeGenomic medicine holds great promise for improving healthcare, but integrating searchable and actionable genetic data into electronic health records remains a challenge. Here, we describe Neptune, a system for managing the interaction between a clinical laboratory and an electronic health record system. MethodsWe developed Neptune and applied it to two clinical sequencing projects that required report customization, variant reanalysis and EHR integration. ResultsNeptune enabled the analysis of data for generation of and delivery to EHR systems of over 15,000 clinical genomic reports. These projects demanded customizable clinical reports that contained a variety of genetic data types including SNVs, CNVs, pharmacogenomics and polygenic risk scores. Two variant reanalysis activities were also supported, highlighting this important workflow. ConclusionsMethods are needed for delivering structured genetic data to EHRs. This need extends beyond developing data formats to providing infrastructure that manages the reporting process itself. Neptune was successfully applied on two high-throughput clinical sequencing projects to build and deliver clinical reports to EHR systems. The software is open and available at https://gitlab.com/bcm-hgsc/neptune.

bioinformatics↗

bioRxiv2021

Imagined speech can be decoded from low- and cross-frequency features in perceptual space

Reconstructing intended speech from neural activity using brain-computer interfaces (BCIs) holds great promises for people with severe speech production deficits. While decoding overt speech has progressed, decoding imagined speech have met limited success, mainly because the associated neural signals are weak and variable hence difficult to decode by learning algorithms. Using three electrocorticography datasets totalizing 1444 electrodes from 13 patients who performed overt and imagined speech production tasks, and based on recent theories of speech neural processing, we extracted consistent and specific neural features usable for future BCIs, and assessed their performance to discriminate speech items in articulatory, phonetic, vocalic, and semantic representation spaces. While high-frequency activity provided the best signal for overt speech, both low- and higher-frequency power and local cross-frequency contributed to successful imagined speech decoding, in particular in phonetic and vocalic, i.e. perceptual, spaces. These findings demonstrate that low-frequency power and cross-frequency dynamics contain key information for imagined speech decoding, and that exploring perceptual spaces offers a promising avenue for future imagined speech BCIs.

neuroscience↗

bioRxiv2020

Canopy micrometeorology monitoring in diverse climates innovatively improves the evaluation heat-induced sterility of rice under climate change

This study is the first and unique of open-field studies to assess the determination process of heat-induced spikelet sterility (HISS) of rice by using the same variety and the same monitoring system, MINCER (Micrometeorological Instrument for Near Canopy Environment of Rice), covering the major-rice growing regions from Sub-Saharan Africa, South, Southeast, and East Asia, and USA. Applying the observation data from the monitoring network, MINCERnet, to the canopy heat balance model, IM2PACT, it was quantitatively corroborated in open-field conditions worldwide that the canopy and panicle transpiration and their evaporative cooling effect played a great role on the micrometeorological gap between the ambient air temperature and the panicle temperature, and that the sterility rate due to HISS in open-fields can be evaluated accurately in diverse climates by the mean panicle temperature at flowering hours in the flowering period. The heat balance structure suggested that the risk of HISS should be higher in high humidity climates rather than in dry climates also in the future, which lead to the importance of the humidity accuracy as well as of the air temperature in climate scenarios and their spatial downscaling for future prediction of rice heat stress and production. Applying the heat-tolerant variety was suggested to be able to keep the sterility due to HISS low in all climates. It is needed of the approach using the panicle temperature as indicator of HISS by intervening sub-model and/or monitoring of micrometeorology inside the canopy to reduce uncertainties in future rice yield prediction under various adaptation measures.

plant biology↗

bioRxiv2020

P53-independent restoration of p53 pathway in tumors with mutated p53 through ATF4 transcriptional modulation by ERK1/2 and CDK9

A long-term goal in the cancer-field has been to develop strategies for treating p53-mutated tumors. A novel small-molecule, PG3-Oc, restores p53 pathway-signaling in tumor cells with mutant-p53, independently of p53/p73. PG3-Oc partially upregulates the p53-transcriptome (13.7% of public p53 target-gene dataset; 15.2% of in-house dataset) and p53-proteome (18%, HT29; 16%, HCT116-p53-/-). Bioinformatic analysis indicates critical p53-effectors of growth-arrest (p21), apoptosis (PUMA, DR5, Noxa), autophagy (DRAM1), and metastasis-suppression (NDRG1) are induced by PG3-Oc. ERK1/2- and CDK9-kinases are required to upregulate ATF4 by PG3-Oc which restores p53 transcriptomic-targets in cells without functional-p53. PG3-Oc represses MYC (ATF4-independent), and upregulates PUMA (ATF4-dependent) in mediating cell death. With largely nonoverlapping transcriptomes, induced-ATF4 restores p53 transcriptomic targets in drug-treated cells including functionally important mediators such as PUMA and DR5. Our results demonstrate novel p53-independent drug-induced molecular reprogramming involving ERK1/2, CDK9, and ATF4 to restore upregulation of p53 effector genes required for cell death and tumor suppression.

cancer biology↗