Biology subjects

Qu, B.

Publications and source records attributed to Qu, B..

At least 19 recordsLinked to original sources

bioRxiv2026

Aberrant cortical subcortical somatosensory network organization is associated with impaired tactile-motion perception in akinetic-rigid Parkinson's disease

BackgroundParkinsons disease (PD) is associated with somatosensory dysfunction, yet higher-order tactile-motion processing and its neural basis remain poorly understood. Here, we combined psychophysical assessment of tactile-motion perception with resting-state functional MRI (rs-fMRI) to investigate how altered sensorimotor network organization relates to tactile perceptual deficits in akinetic-rigid dominant PD (PDAR). MethodsForty-six participants (25 PDAR and 21 healthy controls, HCs) underwent clinical evaluation and resting-state functional MRI scanning. A subset of participants (15 PDAR and 15 HCs) additionally completed a tactile-motion perception task assessing directional bias and speed sensitivity. ROI-to-ROI functional connectivity analyses were performed within a customized 26-node sensorimotor and cortico-basal ganglia-thalamo-cortical (CBGTC) network. ResultsCompared with HCs, PDAR patients exhibited significantly altered tactile-motion perception, including greater directional bias (p = 0.047) and reduced sensitivity to dynamic tactile speed (p < 0.001), reflecting diminished sensitivity to mid-to-high speeds. Resting-state functional connectivity analyses revealed widespread reductions in connectivity within cortical somatosensory regions (Areas 1, 2, 3a, 3b, 5), particularly between primary somatosensory and motor cortices. In contrast, increased connectivity was observed between basal ganglia-thalamic structures and cortical sensorimotor regions, including thalamus-M1 and GPi-sensorimotor connections (all p-FDR < 0.05). ConclusionsThese findings demonstrate a dual pattern of sensorimotor network reorganization in PDAR, characterized by disrupted cortical somatosensory integration alongside enhanced subcortical-cortical coupling. The present study provides evidence that higher-order tactile-motion dysfunction in PD is associated with large-scale abnormalities in distributed sensorimotor networks and highlights the somatosensory system as a potential target for future therapeutic intervention.

neuroscience↗

bioRxiv2026

Yellow fever vaccine propagation in primary human hepatocytes triggers antiviral and cytolytic responses

Yellow fever virus (YFV) infection can cause severe-to-fatal liver damage in humans, while immunization with the attenuated 17D vaccine strain has an excellent safety record, priming protective host immunity in the absence of pathology. To investigate virus-host correlates associated with these differential clinical outcomes, we combined YFV genome-level evolutionary analyses with investigations of vaccine and virulent strain hepatotropism. Evolutionary analyses confirmed purifying selection is the dominant force driving global YFV genome divergence, with functional constraints associated with the YFV transmission cycle selecting against vaccine attenuating mutations in virulent strains. In immune deficient hepatoma cells, 17D exhibited enhanced early propagation, spreading and apoptosis induction when compared to virulent strains. Ex vivo infections performed in primary human hepatocytes (PHH) from multiple donors confirmed robust propagation of both 17D and virulent YFV strains. RNA-sequencing revealed consistent and shared induction of IFNB and IFNL1-4, modulating overlapping gene programs associated with antiviral responses, immunity, chemotaxis and inflammation, cell-death, metabolic reprogramming and protein translation. Subtle differences in virion production kinetics and the magnitude and tempo of PHH transcriptional responses were observed. Antiviral responses to 17D were activated earlier while responses to virulent YFV were delayed but enhanced, mirroring virus propagation kinetics. More broadly, cellular responses to YFV infection are likely dominated by paracrine IFN signalling, with enriched LRP1 expression coupled with impaired IFN production in PHH contributing to YFVs robust hepatotropism. In summary, we demonstrate comparable propagation kinetics and PHH transcriptional responses to vaccine and virulent YFV strains, highlighting impaired hepatotropism is not a correlate of vaccine attenuation. These data imply that unknown barriers restrict liver access and associated organ pathology upon vaccination with 17D.

microbiology↗

bioRxiv2025

The mechanism how Pretubulysin-induced microtubule disassembly improves T cell search efficiency

To clean tissue from tumorigenic and infected cells, cytotoxic T lymphocytes (CTLs) must navigate confined environments in vivo, locate the infected cells and eliminate them. Impaired CTL migration towards the tumor can limit the efficacy of immunotherapy. Microtubules (MTs) have emerged as promising targets, because destabilizing MTs enhances T-cell migration and subsequent killing, yet the underlying mechanisms are poorly understood. Here, we use pretubulysin, a potent MT depolymerizer, to uncover how MT dynamics regulate CTL motility. Complete MT disassembly markedly increased CTL infiltration and migration in 3D matrices. To investigate how altered migration affects target elimination, we employed a persistent random-walk model parameterized solely with experimental motility data. The model shows that the increase in speed and persistence induced by pretubulysin explains enhanced search efficiency increasing the encounter rate of CTLs with target cells. The simulations also predict how these gains in search efficiency scale with tissue thickness and CTL density. Mechanistically, MT depolymerization in activated CTLs triggers localized actomyosin accumulation at the uropod. This enhances rear contraction forces and promotes faster, more persistent migration and efficient search. Our findings clarify how MT dynamics influence CTL ability to eliminate targets in 3D environments and highlights the potential of MT-targeting agents such as pretubulysin to optimize T cell-based immunotherapies.

cell biology↗

bioRxiv2024

T cell polarization and NFAT translocation are stiffness-dependent and are differentially regulated by Piezo1 and Orai1

Effective T cell responses against tumor cells require diverse effector functions including polarization towards tumor cells to form immunological synapses and nuclear factor of activated T-cells (NFAT)-dependent gene transcription. While the role of tumor cell softening has been associated with malignancy, stemness, and metastasis, potentially contributing to immune evasion, its impact on cellular processes in T cells is not well understood. Here, we show that both T cell polarization and NFAT nuclear translocation are modulated by target stiffness in a Ca2+ dependent manner. Using both anti-CD3 antibody-functionalized substrates with varying stiffness as surrogates for target cells or softened tumor cells, we found that both, reorientation of microtubule organizing center (MTOC) towards the tumor cells, a hallmark for T cell polarization, and NFAT translocation were impaired on softer hydrogels or following contact with softer cancer cells. The amplitudes of intracellular Ca2+ signals were dependent on stiffness, and removal of extracellular Ca2+ inhibited stiffness-dependent T cell responsiveness. While stiffness-dependent Ca2+ signaling was crucial for both, T cell polarization and NFAT translocation, Ca2+ influx through Piezo1, a mechanosensitive ion channel, mediated stiffness-dependent MTOC reorientation but not NFAT translocation. In contrast, Ca2+ influx through store-operated Orai channels mediated NFAT translocation but not MTOC reorientation. Our results demonstrate that tumor cell stiffness directly influences T cell functionality through distinct Ca2+ influx pathways, revealing cell softening as an essential mechanism employed by malignant cells to evade immune surveillance.

immunology↗

bioRxiv2023

Unveiling interactions of spatial-temporal information in tactile motion perception

The intricate interplay of spatial and temporal information in tactile-motion perception remains elusive. Despite strides in decoding neural signals for direction, speed and texture in tactile perception, nuanced interactions persist as challenges. Addressing this, we investigated direction and speed tactile perception, exploring the intricate spatial-temporal dynamics. Psychophysical experiments manipulated direction and speed parameters using a laboratory-designed fingerpad ball-stimulator. A pivotal discovery includes quadrant-dependent anisotropic distortion in perceived motion direction, expanding the well-known notion of a specific preferred orientation. Spatial features primarily influence inherent responses, while temporal features impact stimulus-specific responses, shedding light on dynamic directional perception. The introduction of a psychometric function improved the modeling of tactile-motion speed perception, incorporating both linear and nonlinear components for a more accurate representation. This study provides intriguing insights into the neural mechanisms in tactile-motion perception, with potential applications for somatosensation in brain-machine interfaces. TeaserThis study unveils the intricate interplay of perceiving tactile motion, shedding light on the mysteries of tactile sensations.

neuroscience↗

bioRxiv2023

High-throughput and in-depth analysis of plasma proteome by UV-assisted protein digestion, 5-plex labeling and MS-based high abundance protein removal method

Human plasma contains various proteins, some of which reflect individuals physiological health state or predict diseases. Therefore, plasma analysis can provide a wealth of information on novel biomarkers for clinical diagnosis and prognosis. The use of mass spectrometry (MS) for high-throughput and in-depth quantitative proteomic analysis of plasma allows for highly specific and quantitative readout, but is challenging because of the high dynamic range of protein abundances. Here, we introduce a robust, high-throughput, and in-depth workflow for plasma proteome analysis based on UV-assisted rapid protein digestion, 5-plex dimethyl labeling, and MS-based high abundance protein removal. UV-assisted protein digestion could quantify the same protein numbers as traditional enzymatic hydrolysis and achieve a low miss-cleavage rate in only 20 minutes. And the MS-based high abundance protein removed 5-plex DIA method, which does not require extra protein depletion procedures, enables quantitative analysis of more than 600 proteins using an equivalent MS analysis time of 30 minutes per sample. The average relative error was 6.9%. We believe the method is beneficial for analyzing large numbers of trace-level clinical samples and broaden a vision for the discovery of low abundance protein markers.

biochemistry↗

bioRxiv2023

Human pluripotent stem cell-derived hepatocyte-like cells for hepatitis D virus studies

Current culture systems available for studying hepatitis D virus (HDV) are suboptimal. In this study, we demonstrate that hepatocyte-like cells (HLCs) derived from human pluripotent stem cells (hPSCs) are fully permissive to HDV infection across various tested genotypes. When co- infected with the helper hepatitis B virus (HBV) or transduced to express the HBV envelope protein HBsAg, HLCs effectively secrete infectious progeny virions. We also show that HLCs expressing HBsAg support extracellular spread of HDV, thus providing a valuable platform for testing available anti-HDV regimens. By challenging the cells along the differentiation with HDV infection, we have identified CD63 as a potential HDV/HBV co-entry factor, which was rate-limiting HDV infection in immature hepatocytes. Given their renewable source and the potential to derive hPSCs from individual patients, we propose HLCs as a promising model for investigating HDV biology. Our findings offer new insights into HDV infection and expand the repertoire of research tools available for the development of therapeutic interventions. TeaserA human stem cell-derived hepatocyte culture model for hepatitis D virus studies

microbiology↗

bioRxiv2023

A high-throughput 3D kinetic killing assay

In vivo, immune killer cells must infiltrate into tissues and search for their cognate target cells in 3D environments. To investigate the cytotoxic function of immune killer cells, there is currently a significant need for an in vitro kinetic assay that resembles 3D in vivo features. Our work presents a high-throughput kinetic killing assay in 3D that is a robust and powerful tool for evaluating the killing efficiency of immune killer cells, as well as the viability of tumor cells under in vivo-like conditions. This assay holds particular value for assessing primary human CTLs and NK cells and can also be applied to primary murine killer cells. By utilizing collagen concentrations to mimic healthy tissue, soft tumors, and stiff tumors, this assay enables the evaluation of cell function and behavior in physiologically and pathologically relevant scenarios, particularly in the context of solid tumors. Furthermore, this assay shows promise as a personalized strategy for selecting more effective drugs/treatments against tumors, using primary immune cells for individual patients to achieve improved clinical outcomes.

immunology↗

bioRxiv2023

PIEZO1-mediated mechanosensing governs NK cell killing efficiency in 3D

Natural killer (NK) cells play a vital role in eliminating tumorigenic cells. Efficient locating and killing of target cells in complex three-dimensional (3D) environments are critical for their functions under physiological conditions. However, the role of mechanosensing in regulating NK cell killing efficiency in physiologically relevant scenarios is poorly understood. Here, we report that the responsiveness of NK cells is regulated by tumor cell stiffness. NK cell killing efficiency in 3D is impaired against softened tumor cells, while it is enhanced against stiffened tumor cells. Notably, the durations required for NK cell killing and detachment are significantly shortened for stiffened tumor cells. Furthermore, we have identified PIEZO1 as the predominantly expressed mechanosensitive ion channel among the examined candidates in NK cells. Perturbation of PIEZO1 abolishes stiffness-dependent NK cell responsiveness, significantly impairs the killing efficiency of NK cells in 3D, and substantially reduces NK cell infiltration into 3D collagen matrices. Conversely, PIEZO1 activation enhances NK killing efficiency as well as infiltration. In conclusion, our findings demonstrate that PIEZO1-mediated mechanosensing is crucial for NK killing functions, highlighting the role of mechanosensing in NK cell killing efficiency under 3D physiological conditions and the influence of environmental physical cues on NK cell functions.

immunology↗

bioRxiv2023

Spatiotemporal analysis of SARS-CoV-2 infection reveals an expansive wave of monocyte-derived macrophages associated with vascular damage and virus clearance in hamster lungs

Factors of the innate immune response to SARS-CoV-2 in the lungs are pivotal for the ability of the host to deal with the infection. In humans, excessive macrophage infiltration is associated with disease severity. Using 3D spatiotemporal analysis of optically cleared hamster lung slices in combination with virological, immunohistochemical and RNA sequence analyses, we visualized the spread of SARS-CoV-2 through the lungs and the rapid anti-viral response in infected lung epithelial cells, followed by a wave of monocyte-derived macrophage (MDM) infiltration and virus elimination from the tissue. These SARS-CoV-2 induced innate immune processes are closely related to the onset of necrotizing inflammatory and consecutive remodelling responses in the lungs, which manifests as extensive cell death, vascular damage, thrombosis, and cell proliferation. Here we show that MDM are directly linked to virus clearance, and appear in connection with tissue injury and blood vessel damage. Rapid initiation of prothrombotic factor upregulation, tissue repair and alveolar cell proliferation results in tissue remodelling, which is followed by fibrosis development despite a decrease in inflammatory and anti-viral activities. Thus, although the hamsters are able to resolve the infection following the MDM influx and repair lung tissue integrity, longer-term alterations of the lung tissues arise as a result of concurrent tissue damage and regeneration processes.

immunology↗

bioRxiv2022

In vitro evaluation of immune responses to bacterial hydrogels for the development of living therapeutic materials

In living therapeutic materials, organisms genetically programmed to produce and deliver drugs are encapsulated in porous matrices or hydrogels acting as physical barriers between the therapeutic organisms and the host cells. The therapeutic potential of such constructs has been highlighted in in vitro studies, but the translation to in vivo scenarios requires evaluation of the immune response to the presence of the encapsulated, living organisms. In this study, we investigate the responses of human peripheral blood mononuclear cells (PBMCs) exposed to a living therapeutic material consisting of engineered E. coli encapsulated in Pluronic F127-based hydrogels. The release of inflammation-related cytokines (IL-2, IL-4, IL-6, IL-10, IL-17A, TNF and IFN{gamma}) and cytotoxic proteins (granzyme A, granzyme B, perforin, granulysin, sFas, and sFasL) in response to the bacterial hydrogels, as well as the subsets of natural killer cells and T cells after exposure to the bacterial hydrogel for up to three days were examined. In direct contact with PBMCs, both E. coli and its endotoxin-free variant, ClearColi, induce apoptosis of the immune cells and trigger IL-6 release from the surviving cells. However, we found that encapsulation of the bacteria in Pluronic F127 diacrylate hydrogels considerably lowers their immunogenicity and practically abolishes apoptosis triggered by ClearColi. In comparison with E. coli, free and hydrogel-encapsulated ClearColi induced significantly lower levels of NK cell differentiation into the more cytolytic CD16dim subset. Our results demonstrate that ClearColi-encapsulated hydrogels generate low immunogenic response and are suitable candidates for the development of living therapeutic materials for in vivo testing to assess a potential clinical use. Nevertheless, we also observed a stronger immune response in pro-inflammatory PBMCs, possibly from donors with underlying infections. This suggests that including anti-inflammatory measures in living therapeutic material designs could be beneficial for such recipients.

immunology↗

bioRxiv2022

SARS-CoV-2 entry route impacts a range of downstream viral and cellular processes

SARS-CoV-2 entry is promoted by both cell-surface TMPRSS2 and endolysosomal cathepsins. To investigate the impact of differentially routed virions on host and viral processes, lung epithelial cells expressing distinct combinations of entry factors were infected with authentic viruses. Entry route determined early rates of viral replication and transcription, egress and inhibitor sensitivity, with differences observed between virus strains. Transcriptional profiling revealed that induction of innate immunity was correlated to viral genome and transcript abundance in infected cells. Surface entry triggered early activation of antiviral responses, reducing cumulative virion production, while endolysosomal entry delayed antiviral responses and prolonged virus shedding due to extended cell viability. The likely molecular footprints of escape from antiviral effector targeting were also recorded in viral genomes and correlated with entry route-dependent immune status of cells. TMPRSS2 orthologues from diverse mammals, but not zebra fish, facilitated infection enhancement, which was more pronounced for ancestral strains. Leveraging RNA-seq and scRNA-seq datasets from SARS-CoV-2 infected hamsters, we validate aspects of our model in vivo. In summary, we demonstrate that distinct cellular and viral processes are linked to viral entry route, collectively modulating virus shedding, cell-death rates and viral genome evolution.

microbiology↗

bioRxiv2022

The response mechanism of oreorchis patens (Lindl.) Lindl. to cold stress

Cold stress, a major environmental factor, has an important impact on the production of landscape plants and crop yield, and its stress and resistance mechanisms have always been hot research issues. Oreorchis patens (Lindl.) Lindl., an important germplasm resource, has strong frost resistance and can resist low temperatures of -40 {degrees}C. However, the mechanism by which O. patens responds to cold stress remains poorly understood. Here, we examined the adaptation to the low-temperature environment of O. patens by changing the leaf tissue structure, while the synergistic effect of osmotic regulation, reactive oxygen scavenging and protein improved the resistance to cold stress. In addition, analysis of the photosynthetic system showed that cold stress changes the photosynthetic capacity of O. patens leaves to affect cold resistance. Analysis by nonparametric transcriptome sequencing revealed 2402 genes that were differentially expressed, most of which were related to resistance. Simultaneously, quantitative real-time polymerase chain reaction (qRT-PCR) analysis obtained results consistent with the transcriptome. These results indicated that O. patens could alter leaf structure and physiological and biochemical metabolic processes by initiating resistance-related molecular regulatory networks to improve the ability to resist cold stress. This study was the first to discuss the physiological, biochemical and molecular regulatory mechanisms of O. patens resistance to cold stress, which laid a foundation for revealing the biological and molecular mechanisms of overwintering of O. patens and breeding cold-resistant horticultural crops in northern China.

plant biology↗

bioRxiv2021

Verbena officinalis L. regulates killing efficiency of natural killer cells

Natural killer (NK) cells play a key role in eliminating pathogen-infected cells. Verbena officinalis (V. officinalis) has been used as a medical plant in traditional and modern medicine, exhibiting anti-tumor and anti-inflammation activities, but its roles in immune responses still remains largely elusive. In this work, investigated the regulation of inflammation and NK functions by V. officinalis extract (VO-extract). In an influenza virus infection mouse model, oral administration of VO-extract alleviated lung injury, promoted maturation and activation of NK cells residing in the lung, and decreased the levels of inflammatory cytokines (IL-6, TNF- and IL-1{beta}) in the serum. We further analyzed the impact of five bioactive components of VO-extract on NK killing functions. Among them, Verbenalin enhanced NK killing efficiency significantly as determined by real-time killing assays based on plate-reader or high-throughput live-cell imaging in 3D using primary human NK cells. Further investigation showed that treatment of Verbenalin accelerated killing processes by reducing the contact time of NK cells with their target cells without affecting NK proliferation, expression of cytotoxic proteins, or lytic granule degranulation. Together, our findings reveal that low doses of V. officinalis can achieve a satisfactory anti-inflammation effect against viral infection in vivo, and V. officinalis regulates activation, maturation and killing functions of NK cells. NK killing efficiency is enhanced by Verbenalin from V. officinalis, suggesting a promising potential of verbenalin to fight viral infection.

immunology↗

bioRxiv2021

A noval lightsheet scattering microscopy for long-term visualization of cell-ECM interaction

Visualizing interactions between cells and the extracellular matrix (ECM) mesh is important to understand cell behavior and regulatory mechanisms by the extracellular environment. However, long term visualization of three-dimensional (3D) matrix structures remains challenging mainly due to photobleaching or blind spots perpendicular to the imaging plane. Here, we combine label-free light-sheet scattering microcopy (LSSM) and fluorescence microscopy to solve these problems. We verified that LSSM can reliably visualize structures of collagen matrices from different origin including bovine, human and rat tail. The quality and intensity of collagen structure images acquired by LSSM did not decline with time. LSSM offers abundant wavelength choice to visualize matrix structures, maximizing combination possibilities with fluorescently-labelled cells, allowing visualizing of long-term ECM-cell interactions in 3D. Interestingly, we observed ultrathin thread-like structures between cells and matrix using LSSM, which were not observed by normal fluorescence microscopy. Transient local alignment of matrix by cell-applied forces can be observed. In summary, LSSM provides a powerful and robust approach to investigate the complex interplay between cells and ECM.

biophysics↗

bioRxiv2021

Metabolic reprogramming of cytotoxic T lymphocytes by high glucose enhances pancreatic beta cell apoptosis via TRAIL

Cytotoxic T lymphocytes (CTLs) are involved in development of diabetes. However, the impact of excessive glucose on CTL-mediated antigen-independent killing remains elusive. Here, we report that TNF-related apoptosis inducing ligand (TRAIL) is substantially up- regulated in CTLs in environments with high glucose (HG) both in vitro and in vivo. The PI3K- Akt-NF{kappa}B axis and non-mitochondrial reactive oxygen species are essential in HG-induced TRAIL upregulation in CTLs. TRAILhigh CTLs induce apoptosis of pancreatic beta cell line 1.4E7. Metformin and Vitamin D synergistically reduce HG-enhanced expression of TRAIL in CTLs and coherently protect 1.4E7 cells from TRAIL-mediated apoptosis. Notably, in patients with diabetes, correlation between Vitamin D concentrations in plasma and glucose levels is linked to HG-enhanced TRAIL expression on CTLs. Microarray data reveal that OXCT2, an important enzyme in ketone body catabolism, is a promising target in response to vitamin D. Our work not only reveals a novel mechanism of CTL involvement in progression of diabetes, but also establishes CTLs as a target for combined metformin and vitamin D therapy to protect pancreatic beta cells of diabetic patients.

immunology↗

bioRxiv2021

The transcription factor Zeb2 drives differentiation of age-associated B cells

Age-associated B-cells (ABCs) accumulate during infection, aging and autoimmunity, contributing to lupus pathogenesis. Here, we screen for transcription factors driving ABC formation and find Zeb2 is required for human and mouse ABC differentiation in-vitro. ABCs are reduced in ZEB2 haploinsufficient individuals and in mice lacking Zeb2 in B-cells. In mice with TLR7-driven lupus, Zeb2 is essential for ABC formation and autoimmune pathology. Zeb2 binds to the +20kb intronic enhancer of Mef2b, repressing Mef2b-mediated germinal center B-cell differentiation and promoting ABC formation. Zeb2 also targets genes important for ABC specification and function including Itgax. Zeb2-driven ABC differentiation requires Jak-Stat signaling, and treatment with the Jak1/3 inhibitor tofacitinib reduces ABC accumulation in autoimmune mice and patients. Zeb2 thus emerges as a driver of B-cell autoimmunity. One-Sentence SummaryZeb2 is essential for Age-associated B cells differentiation and function.

immunology↗

bioRxiv2021

Collagen density defines 3D migration of CTLs and their consequent cytotoxicity against tumor cells

Solid tumors are often characterized by condensed extracellular matrix (ECM). The impact of dense ECM on cytotoxic T lymphocytes (CTL) function is not fully understood. Here, we report that CTL-mediated cytotoxicity is substantially impaired in dense collagen matrices. Although the intrinsic killing machinery including expression of cytotoxic proteins and degranulation was intact, CTL motility was substantially compromised in dense collagen. We found that for 3D CTL migration, persistence and velocity was regulated by collagen stiffness and the porosity, respectively. Interestingly, 3D CTL velocity is strongly correlated with their nuclear deformability/flexibility during migration, which is regulated by the microtubule network. Moreover, CTL migration was completely abolished by inhibition of actin polymerization and or myosin IIA. Remarkably, disruption of the microtubule-networks significantly improves the impaired migration, search efficiency, and cytotoxicity of CTLs in dense collagen. Our work suggests the microtubule network as a promising target to rescue impaired CTL killing capacity in solid tumor related scenarios.

immunology↗