Biology subjects

Xu, T.

Publications and source records attributed to Xu, T..

At least 163 records · Page 9Linked to original sources

bioRxiv2023

Comparison between Canine and Porcine Models of Chronic Deep Venous Thrombosis

Venous thromboembolism(VTE) refers to deep venous thrombosis(DVT) and pulmonary embolism(PE), which is a worldwide problem and has very high morbidity and mortality. The research of venous thrombosis involves pathogenesis, pathophysiology, and therapeutic attempt. Alternative experimental animal models have changed dramatically over the past 20 years, from small murine models to large ones. Larger animal models offer more options and are more consistent with human physiology. This article aims to induce chronic deep venous thrombosis in the left iliac vein in canine and porcine models and compare these two models. We think that feasible large animal models can better translate the results of therapeutic research into clinical application.

animal behavior and cognition↗

bioRxiv2023

MiR-302-Induced anti-aging neural stem cells enhance cognitive function and extend lifespan

Neural stem cells play a vital role in maintaining tissue stability and extending lifespan. Transplanting these cells to treat neurodegenerative diseases faces challenges like cellular aging, low viability, and immune rejection. We have effectively reprogrammed human fibroblasts into induced neural stem cells (iNSCs) via a single-factor miR-302a strategy, which converted skin fibroblasts into human-induced neural stem cells (hiNSCs) within 2-3 days. These cells showed delayed aging and increased resistance to oxidative stress compared to wild-type cells. Implanting them into the hippocampus of senescence-accelerated mice improved cognitive performance in severe Alzheimers, prolonged lifespan by 34%, increased fatigue resistance, and improved hair regeneration and reproductive capacity. Our findings suggest that miR-302a-hiNSCs can improve functional recovery in Alzheimers and promote healthy aging.

animal behavior and cognition↗

bioRxiv2023

Phytochrome higher order mutants reveal a complex set of light responses in the moss Physcomitrium patens

O_LIPhytochromes are photoreceptors enabling plants to respond to various light conditions. Independent gene duplication events resulted in small phytochrome gene families in mosses, ferns, and seed plants. This phytochrome diversity is hypothesised to be critical for sensing and adapting to different light conditions, but experimental evidence for this idea is lacking for mosses and ferns. C_LIO_LIThe model moss species Physcomitrium patens contains seven phytochromes grouped into three clades, PHY1/3, PHY2/4, and PHY5. Here, we used CRISPR/Cas9 generated single and higher order mutants to investigate their role in light-regulation of protonema and gametophore growth, protonema branching, and induction of gametophores. C_LIO_LIWe found both specific and partially overlapping roles for the three clades of moss phytochromes in regulating these responses in different light conditions, and we identified a mechanism for sensing simulated canopy shade different from the mechanism in seed plants. PHY1/3 clade phytochromes act as primary far-red light receptors, while PHY5 clade phytochromes are the primary red light receptors. PHY2/4 clade phytochromes have functions in both red and far-red light. C_LIO_LISimilar to seed plants, gene duplication events in the phytochrome lineage in mosses were followed by functional diversification into red and far-red light sensing phytochromes. C_LI

plant biology↗

bioRxiv2023

Individual differences in time-varying and stationary brain connectivity during movie watching from childhood to early adulthood: Effects of age, sex, and behavioral associations

Spatially remote brain regions exhibit dynamic functional interactions across various task conditions. While time-varying functional connectivity during movie watching shows sensitivity to movie content, stationary functional connectivity remains relatively stable across videos. These findings suggest that dynamic and stationary functional interactions may represent different aspects of brain function. However, the relationship between individual differences in time-varying and stationary connectivity and behavioral phenotypes remains elusive. To address this gap, we analyzed an open-access functional MRI dataset comprising participants aged 5 to 22 years, who watched two cartoon movie clips. We calculated regional brain activity, time-varying connectivity, and stationary connectivity, examining associations with age, sex, and behavioral assessments. Model comparison revealed that time-varying connectivity was more sensitive to age and sex effects compared with stationary connectivity. The preferred age models exhibited quadratic log age or quadratic age effects, indicative of inverted-U shaped developmental patterns. In addition, females showed higher consistency in regional brain activity and time-varying connectivity than males. However, in terms of behavioral predictions, only stationary connectivity demonstrated the ability to predict full-scale intelligence quotient. These findings suggest that individual differences in time-varying and stationary connectivity may capture distinct aspects of behavioral phenotypes.

neuroscience↗

bioRxiv2023

Variation in spatial dependencies across the cortical mantle discriminates the functional behaviour of primary and association cortex

Recent theories of cortical organisation maintain that important features of brain function emerge through the spatial arrangement of regions of cortex. For example, areas of association cortex are located in regions of cortex furthest from sensory and motor cortex. Association cortex is also interdigitated since adjacent regions can have relatively different patterns of functional connectivity. It is assumed that topographic properties such as distance between cortical regions constrain their functions. For example, large distances between association and sensory and motor systems may enable these areas of cortex to maintain differentiable neural patterns, while an interdigitated organisation may enable association cortex to contain many functional systems in a relatively compact space. We currently lack a formal understanding of how spatial organisation impacts brain function, limiting the ability to leverage cortical topography to facilitate better interpretations of a regions function. Here we use variograms, a quantification of spatial autocorrelation, to develop a cortex-wide profile of how functional similarity changes as a function of the distance between regions. We establish that function changes gradually within sensory and motor cortex as the distance between regions increases, while in association cortex function changes rapidly over shorter distances. Subsequent analysis suggests these differential classes of spatial dependency are related to variation in intracortical myelin between sensory motor and association cortex. Our study suggests primary and association cortex are differentiated by the degree to which function varies over space, emphasising the need to formally account for spatial properties when estimating a systems contribution to cognition and behaviour. Significance statementThe spatial arrangements of regions in the human brain are hypothesised to underpin important features of a brain regions function. Currently, however, we lack a formal understanding of how topography shapes brain function, limiting our ability to leverage topographical perspectives to inform better theories of brain function. Here we use a formal mathematical approach to establish that in regions of association cortex function varies across the cortex more rapidly than in sensory and motor cortex, a phenomenon linked to levels of intracortical myelin. This result highlights how topographical features distinguish between cortical regions with different functional profiles and provides a formal account of how spatial differences support different features of brain function.

neuroscience↗

bioRxiv2022

Microbiome features differentiating unsupervised-stratification based clusters of patients with abnormal glycometabolism

The alteration of gut microbiota structure plays a pivotal role in the pathogenesis of abnormal glycometabolism. However, the microbiome features identified in patient groups stratified solely based on glucose levels remain controversial among different studies.. In this study, we stratified 258 participants (discovery cohort) into three clusters according to an unsupervised method based on 16 clinical parameters involving the levels of blood glucose, insulin, and lipid. We found 67 cluster-specific microbiome features (i.e., amplicon sequence variants, ASVs) based on 16S rRNA gene V3-V4 region sequencing. Specifically, ASVs belonging to Barnesville and Alistipes were enriched in Cluster 1, in which participants had the lowest blood glucose levels, high insulin sensitivity, and high-fecal short-chain fatty acid concentration. ASVs belonging to Prevotella copri and Ruminococcus gnavus were enriched in Cluster 2, which was characterized by a moderate level of blood glucose, serious insulin resistance, and high levels of cholesterol and triglyceride. Cluster 3 was characterized by a high level of blood glucose and insulin deficiency, enriched with ASVs in P. copri and Bacteroides vulgatus. In addition, machine learning classifiers using the 67 cluster-specific ASVs were used to distinguish individuals in one cluster from those in the other two clusters both in discovery and testing cohorts (N = 83). Therefore, microbiome features identified based on the unsupervised stratification of patients with more inclusive clinical parameters may better reflect microbiota alterations associated with the progression of abnormal glycometabolism. IMPORTANCEThe gut microbiota is altered in patients with type 2 diabetes (T2D) and prediabetes. The association of particular bacteria with T2D, however, varied among studies, which has made it challenging to develop precision medicine approaches for the prevention and alleviation of T2D. Blood glucose level is the only parameter in clustering patients when identifying the T2D-related bacteria in previous studies. This stratification ignores the fact that patients within the same blood glucose range differ in their insulin resistance and dyslipidemia, which also may be related to disordered gut microbiota. In addition to parameters of blood glucose levels, we also used additional parameters involving insulin and lipid levels to stratify participants into three clusters and further identified cluster-specific microbiome features. We further validated the association between these microbiome features and glycometabolism with an independent cohort. This work highlights the importance of stratification of patients with blood glucose, insulin, and lipid levels when identifying the microbiome features associated with the progression of abnormal glycometabolism.

microbiology↗

bioRxiv2022

Systematic evaluation of anatomical details on transcranial electric stimulation and transcranial magnetic stimulation induced electric fields in a non-human primate model

Non-human primates (NHPs) have become key for translational research in noninvasive brain stimulation (NIBS). However, in order to create comparable stimulation conditions to humans it is vital to evaluate and match electric fields across species. Numerical models to simulate electric fields are an important tool for experimental planning in NHPs and translation to human studies. It is thus essential to evaluate how anatomical details in NHP models affect NIBS electric fields. Here, we create a highly accurate head model of a non-human primate (NHP) from 10.5 T MR data. We systematically evaluate how muscle tissue and head size (due to different MRI fields of view) affect simulation results in transcranial electric and magnetic stimulation (TES and TMS). Our findings indicate that the inclusion of muscle can affect TES electric field strength up to 29.5% while TMS is largely unaffected. Additionally, comparing a full head model to a cropped head model illustrates the impact of head size on electric fields for both TES and TMS. We find opposing effects between TES and TMS with an increase up to 13.5% for TES and a decrease up to 21.5% for TMS for the cropped head model compared to the full head model. Our results provide important insights into the level of anatomical detail needed for NHP head models and can inform future translational efforts for NIBS studies. HighlightsO_LIWe created a high resolution non-human primate FEM head model from 10.5 T MR data. C_LIO_LIWe ran transcranial electric and magnetic stimulation (TES and TMS) simulations to evaluate the effects of muscle and head size on the induced electric field in the brain. C_LIO_LIWe simulated both isotropic and anisotropic muscle conductivities. C_LIO_LIMuscle tissue can greatly affect simulation results for TES (increase electric field strength by up to 29.5%), but not for TMS. C_LIO_LIThere are opposing, but large effects of using a full head model versus a cropped head model for both TES (increase up to 13.5%) and TMS (decrease of up to 21.5%) C_LI

neuroscience↗

bioRxiv2022

Cell surface auxin signalling directly targets PIN-mediated auxin fluxes for adaptiveplant development

Phytohormone auxin and its directional transport mediate much of the remarkably plastic development of higher plants. Positive feedback between auxin signaling and transport is a key prerequisite for (i) self-organizing processes including vascular tissue formation and (ii) directional growth responses such as gravitropism. Here we identify a mechanism, by which auxin signaling directly targets PIN auxin transporters. Via the cell-surface ABP1-TMK1 receptor module, auxin rapidly induces phosphorylation and thus stabilization of PIN2. Following gravistimulation, initial auxin asymmetry activates autophosphorylation of the TMK1 kinase. This induces TMK1 interaction with and phosphorylation of PIN2, stabilizing PIN2 at the lower root side, thus reinforcing asymmetric auxin flow for root bending. Upstream of TMK1 in this regulation, ABP1 acts redundantly with the root-expressed ABP1-LIKE auxin receptor ABL3. Such positive feedback between cell-surface auxin signaling and PIN-mediated polar auxin transport is fundamental for robust root gravitropism and presumably also for other self-organizing developmental phenomena.

plant biology↗

bioRxiv2022

Self-regulation of PIN1-driven auxin transport by cell surface-based auxin signaling in Arabidopsis

PIN-FORMED (PIN)-driven auxin transport contributes to establishing and maintaining a dynamic auxin concentration gradient alongside plant tissues, which drives the majority of developmental processes in plants. To maintain developmental plasticity in ever-changing environments, plants have evolved self-organizing feedback machinery between auxin signaling and its transport, which has been shown to play essential roles in many fundamental plant processes. However, the molecular mechanism behind this mutual regulation has not yet been clarified. Here, we identified a cell surface-triggered auxin signaling that regulates the PIN1-mediated auxin efflux and further developmental patterning in Arabidopsis. Auxin was able to stimulate PIN1 phosphorylation in plants through transmembrane kinases (TMKs), key components in auxin signaling, at the plasma membrane. TMK1 and TMK4 directly interacted with and phosphorylated PIN1 and functioned redundantly in the regulation of PIN1 polarity in plant cells. The phosphorylation sites in PIN1 proteins, targeted by both auxin and TMKs, were required for PIN1 trafficking and polarity, which further controlled auxin responses and downstream developmental patterning in Arabidopsis. Therefore, our findings provide a direct mechanism for the self-regulation between auxin signaling and transport that drives the auxin flows and proper development in plants.

plant biology↗

bioRxiv2022

ABLs and TMKs are co-receptors for extracellular auxin

Extracellular perception of auxin, an essential phytohormone in plants, has been debated for decades. Auxin binding protein 1 (ABP1) physically interacts with quintessential transmembrane kinases (TMKs) and was proposed to act as an extracellular auxin receptor, but its role was disputed because abp1 knockout mutants lack obvious morphological phenotypes. Here we identified two new auxin-binding proteins, ABL1 and ABL2, that are localized to the apoplast and directly interact with the extracellular domain of TMKs in an auxin-dependent manner. Furthermore, functionally redundant ABL1 and ABL2 genetically interact with TMKs and exhibit functions that are overlapping with those of ABP1 as well as independent of ABP1. Importantly, the extracellular domain of TMK1 itself binds auxin and synergizes with either ABP1 or ABL1 in auxin binding. Thus, our findings discovered new auxin receptors ABL1 and ABL2 having functions overlapping with but distinct from ABP1 and acting together with TMKs as co-receptors for extracellular auxin.

plant biology↗

bioRxiv2022

Naturalistic viewing: An open-access dataset using simultaneous EEG-fMRI

In this work, we present a dataset that combines functional magnetic imaging (fMRI) and electroencephalography (EEG) to use as a resource for understanding human brain function in these two imaging modalities. The dataset can also be used for optimizing preprocessing methods for simultaneously collected imaging data. The dataset includes simultaneously collected recordings from 22 individuals (ages: 23-51) across various visual and naturalistic stimuli. In addition, physiological, eye tracking, electrocardiography, and cognitive and behavioral data were collected along with this neuroimaging data. Visual tasks include a flickering checkerboard collected outside and inside the MRI scanner (EEG-only) and simultaneous EEG-fMRI recordings. Simultaneous recordings include rest, the visual paradigm Inscapes, and several short video movies representing naturalistic stimuli. Raw and preprocessed data are openly available to download. We present this dataset as part of an effort to provide open-access data to increase the opportunity for discoveries and understanding of the human brain and evaluate the correlation between electrical brain activity and blood oxygen level-dependent (BOLD) signals.

neuroscience↗

bioRxiv2022

Normalized Semi-Covariance Co-Efficiency Analysis of Spike Proteins from SARS-CoV-2 variant Omicron and Other Coronaviruses for their Infectivity and Virulence

Spectrum-based Mass-Charge modeling is increasingly used in biological analysis. To explain statistical phenomenon with positive and negative fluctuations of amino acid charges in spike protein sequences from Omicron and other coronaviruses, we propose calculation-based Mass-Charge modeling, a normalized derivation algorithm with exact Excel and MATLAB tool involving separate quadrant extension to normalized covariance, which is still compatible with Pearson covariance co-efficiency. The number of amino acids, molecular weight, isoelectric point, amino acid composition, charged residues, mass-charge ratio, hydropathicity of the proteins were taken into consideration in the analyses, and the relative peak and dip of the average with spike protein sequences based on hydrophobic mass to isoelectric charges of amino acids were also examined. The analyses with the algorithm provide more clear insights leading to revealing underline evolving trends of the viral proteins. Spike proteins from SARS-CoV-2 variants, seasonal and murine coronaviruses were taken as representative examples in this study. The analyses demonstrate that the Mass-Charge covariance co-efficiency can distinguish subtle differences between biological properties of spike proteins and correlate well with viral infectivity and virulence.

bioinformatics↗

bioRxiv2022

Fear of missing out (FOMO) associates with reduced cortical thickness in core regions of the posterior default mode network and higher levels of problematic smartphone and social media use

Fear of missing out (FOMO) promotes the desire or urge to stay continuously connected with a social reference group and updated on their activities, which may result in escalating and potentially addictive smartphone and social media use. The present study aimed to determine whether the neurobiological basis of FOMO encompasses core regions of the reward or social brain, and the associations with the level of problematic smartphone or social media use. We capitalized on a dimensional neuroimaging approach to examine cortical thickness and subcortical volume associations in a comparably large sample of healthy young individuals (n = 167). Meta-analytic network and behavioral decoding were employed to further characterize the identified regions. Higher levels of FOMO associated with lower cortical thickness in the precuneus. In contrast, no associations between FOMO and variations in striatal morphology were observed. Meta-analysis decoding revealed that the identified precuneus region exhibited a strong functional interaction with the default mode network (DMN) engaged in social cognitive and self-referential domains. Together the present findings suggest that individual variations in FOMO are associated with the brain structural architecture of the right precuneus, a core hub within a large-scale functional network resembling the DMN involved in social and self-referential processes. FOMO may promote escalating social media and smartphone use via social and self-referential processes rather than reward-related processes per se.

neuroscience↗

bioRxiv2022

A ZTF-7/RPS-2 complex mediates the cold-warm response in C. elegans

Temperature greatly affects numerous biological processes in all organisms. How multicellular organisms respond to and are impacted by hypothermic stress remains elusive. Here, we found that cold-warm stimuli induced depletion of the RNA exosome complex in the nucleoli but enriched it in the nucleoplasm. To further understand the function and mechanism of cold-warm stimuli, we conducted forward genetic screening and identified ZTF-7, which is required for RNA exosome depletion from nucleoli upon transient cold-warm exposure in C. elegans. ZTF-7 is a putative ortholog of human ZNF277 that may contribute to language impairments. Immunoprecipitation followed by mass spectrometry (IP-MS) found that ZTF-7 interacted with RPS-2, which is a ribosomal protein of the small subunit and participates in pre-rRNA processing. A partial depletion of RPS-2 and other proteins of the small ribosomal subunit blocked the cold-warm stimuli-induced reduction of exosome subunits from the nucleoli. These results established a novel mechanism by which C. elegans responds to environmental cold-warm exposure.

genetics↗

bioRxiv2022

Cortical gradients during naturalistic processing are hierarchical and modality-specific

Understanding cortical topographic organization and how it supports complex perceptual and cognitive processes is a fundamental question in neuroscience. Previous work has characterized functional gradients that demonstrate large-scale principles of cortical organization. How these gradients are modulated by rich ecological stimuli remains unknown. Here, we utilize naturalistic stimuli via movie-fMRI to assess macroscale functional organization. We identify principal movie gradients that delineate separate hierarchies anchored in sensorimotor, visual, and auditory/language areas. At the opposite/heteromodal end of these perception-to-cognition axes, we find a more central role for the frontoparietal network along with the default network. Even across different movie stimuli, movie gradients demonstrated good reliability, suggesting that these hierarchies reflect a brain state common across different naturalistic conditions. The relative position of brain areas within movie gradients showed stronger and more numerous correlations with cognitive behavioral scores compared to resting state gradients. Together, these findings provide an ecologically valid representation of the principles underlying cortical organization while the brain is active and engaged in multimodal, dynamic perceptual and cognitive processing. HighlightsO_LIMovie-fMRI reveals novel, more granular principles of hierarchical cortical organization C_LIO_LITop movie gradients delineate three separate perception-to-cognition hierarchies C_LIO_LIA distinctive third gradient in movie-watching is anchored by auditory/language regions C_LIO_LIGradient scores demonstrate good reliability even across different movie stimuli C_LIO_LIMovie gradients yield stronger correlations with behavior relative to resting state gradients C_LI

neuroscience↗

bioRxiv2022

Macro-scale patterns in functional connectivity associated with ongoing thought patterns and dispositional traits

Complex macro-scale patterns of brain activity that emerge during periods of wakeful rest provide insight into the organisation of neural function, how these differentiate individuals based on their traits, and the neural basis of different types of self-generated thoughts. Although brain activity during wakeful rest is valuable for understanding important features of human cognition, its unconstrained nature makes it difficult to disentangle neural features related to personality traits from those related to the thoughts occurring at rest. Our study builds on recent perspectives from work on ongoing conscious thought that highlight the interactions between three brain networks - ventral and dorsal attention networks, as well as the default mode network. We combined measures of personality with state-of-the-art indices of ongoing thoughts at rest and brain imaging analysis and explored whether this tri-partite view can provide a framework within which to understand the contribution of states and traits to observed patterns of neural activity at rest. To capture macro-scale relationships between different brain systems, we calculated cortical gradients to describe brain organisation in a low dimensional space. Our analysis established that for more introverted individuals, regions of the ventral attention network were functionally more aligned to regions of the somatomotor system and the default mode network. At the same time, a pattern of detailed self-generated thought was associated with a decoupling of regions of dorsal attention from regions in the default mode network. Our study, therefore, establishes that interactions between attention systems and the default mode network are important influences on ongoing thought at rest and highlights the value of integrating contemporary perspectives on conscious experience when understanding patterns of brain activity at rest.

neuroscience↗

bioRxiv2022

Polycomb Repressive Complex 1 subunit Cbx4 positively regulates effector responses in CD8 T cells

CD8 T cell differentiation is controlled by the crosstalk of various transcription factors and epigenetic modulators. Uncovering the different players in regulating this process is fundamental to improving immunotherapy and designing novel therapeutic approaches. Here, we show that Polycomb Repressive Complex (PRC)1 subunit Chromobox (Cbx)4 favors differentiation to effector CD8 T cells. Cbx4 deficiency in CD8 T cells induced transcriptional signature and phenotype of memory cells, increasing the formation of memory population during acute viral infection. It has been previously shown that besides chromodomain-mediated binding to H3K27me3, Cbx4 function as a SUMO E3 ligase in a SUMO interacting motifs (SIM)-dependent way. The overexpression of Cbx4 mutants in distinct domains showed that this protein regulates CTL differentiation primarily in a SIM-dependent way and partially through its chromodomain. Our data revealed a novel role of a Polycomb group protein Cbx4 controlling CD8 T lymphocyte differentiation and indicates the SUMOylation process as a key molecular mechanism connected to chromatin modification in this process. SummaryUnderstanding the epigenetic control of CTL differentiation is critical for the manipulation of these cells in immunotherapy protocols. This article demonstrates a novel role for Cbx4, a Polycomb-group protein, in supporting CD8 T cell commitment to an effector cell phenotype.

immunology↗

bioRxiv2022

Discovery of a novel monoclonal PD-L1 antibody H1A that promotes T-cell mediated tumor killing activity in renal cell carcinoma

In the last decade, the therapeutic landscape of renal cell carcinoma has rapidly evolved with the addition of PD-1/PD-L1 immune checkpoint inhibitors in the armamentarium of oncologists. Despite clinical evidence of improved oncological outcomes, only a minority of patients experience long-lasting antitumor immune response and complete response. The intrinsic and acquired resistance to PD-1/PD-L1 immune checkpoint blockade is an important challenge for patients and clinicians as no reliable tool has been developed to predict individualized response to immunotherapy. In this study, we demonstrate the translational relevance of an ex-vivo functional assay that measure the tumor cell killing ability of patient-derived CD8 T cells isolated from peripheral blood. Cytotoxic activity of CD8 T cells was improved at 3-month post-radical nephrectomy compared to baseline and it was associated with higher circulating levels of tumor-reactive effector CD8 T cells (CD11ahighCX3CR1+GZMB+). Pretreatment of peripheral immune cells with FDA-approved PD-1/PD-L1 inhibitors enhanced tumor cell killing activity of CD8 T cells but differential response was observed at the individual patient level. Finally, we found a newly developed monoclonal antibody (H1A), which induces PD-L1 degradation, demonstrated superior efficacy in promoting T-cell mediated tumor killing activity compared to FDA-approved PD-1/PD-L1 inhibitors. PBMC immunophenotyping by mass cytometry revealed enrichment of effector CD8 T cells in H1A-treated PBMC. To conclude, our study lays the ground for future investigation of the therapeutic value of H1A as a next-generation immune checkpoint inhibitor. Furthermore, further work is needed to evaluate the potential of measuring T-cell cytotoxicity activity as a tool to predict individual response to immune checkpoint inhibitors in patients with advanced renal cell carcinoma.

immunology↗