Biology subjects

Chen, L.

Publications and source records attributed to Chen, L..

At least 469 records · Page 26Linked to original sources

bioRxiv2024

Mannose Supplementation Curbs Liver Steatosis and Fibrosis in Murine MASH by Inhibiting Fructose Metabolism

Metabolic dysfunction-associated steatohepatitis (MASH) can progress to cirrhosis and liver cancer. There are no approved medical therapies to prevent or reverse disease progression. Fructose and its metabolism in the liver play integral roles in MASH pathogenesis and progression. Here we focus on mannose, a simple sugar, which dampens hepatic stellate cell activation and mitigates alcoholic liver disease in vitro and in vivo. In the well-validated FAT-MASH murine model, oral mannose supplementation improved both liver steatosis and fibrosis at low and high doses, whether administered either at the onset of the model ("Prevention") or at week 6 of the 12-week MASH regimen ("Reversal"). Thein vivo anti-fibrotic effects of mannose supplementation were validated in a second model of carbon tetrachloride-induced liver fibrosis. In vitro human and mouse primary hepatocytes revealed that the anti-steatotic effects of mannose are dependent on the presence of fructose, which attenuates expression of ketohexokinase (KHK), the main enzyme in fructolysis. KHK is decreased with mannose supplementation in vivo and in vitro, and overexpression of KHK abrogated the anti-steatotic effects of mannose. Our study identifies mannose as a simple, novel therapeutic candidate for MASH that mitigates metabolic dysregulation and exerts anti-fibrotic effects.

cell biology↗

bioRxiv2024

Inhibition of Alpha Interferon-Induced miR-873 Negatively Affects the Hepatitis B Virus Expression

BackgroundAlpha interferon (IFN-)-based therapy can effectively treat chronic hepatitis B virus (HBV) infection, which remains a serious public health problem. This study aims to identify the potential biomarker of IFN treatment and investigate the effects of miR-873 on chronic hepatitis B (CHB). MethodsWe utilized the random forest to screen core differentially expressed miRNAs (DEmiRNAs) based on the miRNA (GSE29911) dataset. DEmiRNAs expressions were determined in clinical samples from CHB patients and normal controls. HBV-transfected hepatoma cell lines were constructed for vitro study. Quantitative real-time reverse transcription PCR (RT-qPCR) was used to determine miRNA mRNA expressions. ELISA assays were used to detect the secretion levels of HBsAg and HBeAg. ResultsBoruta feature selection revealed miR-873 hinting at a predictive marker for IFN response. MiR-873 was significantly up-regulated in the CHB patients, as compared with normal controls (P<0.001). Increased expression of miR-873 was also found in HBV-infected cells (P<0.001). With IFN- treatment, miR-873 was significantly down-regulated in HBV-infected Huh-7 and HepG-NTCP cells (P<0.05). IFN- treatment and miR-873 inhibitor significantly reduced HBsAg and HBeAg level (P<0.05). The inhibitory effect was enhanced by blocking the IFN--induced miR-873 downregulation by inhibitor transfection (P<0.05). In miR-873 mimic-treated cells, the inhibitory effect was greatly supressed by blocking the IFN--induced miR-873 downregulation by mimic transfection (P< 0.01). ConclusionWe provide evidence that inhibition of miR-873 by IFN- enhances the antiviral effects of IFN-. Our study provides a potential strategy to enhance the anti-HBV effect of IFN- by inhibiting miR-873 expression.

molecular biology↗

bioRxiv2024

A Dimerization-dependent Allosteric Activation for Receptor-like Kinase in Plants

Receptor-like kinases (RLKs) are essential in plants and phosphorylation is a critical step for their function. Interestingly, RLKs have many non-catalytic kinases/ pseudokinases and the biochemical basis for these pseudokinases remains unclear. FERONIA (FER) is an RLK with kinase activity, but the necessity of its kinase activity for genetic functions has been debated. Here, we uncovered that the kinase-deficient variant FERK565R can activate kinase activity in FER and its homologous through homo/heterodimerization-dependent allosteric activation. We further showed that reactive oxygen species (ROS) significantly promote the dimerization of FER family members. Next, we revealed that mutating the FER P740 within the G-H loop reduces FER dimerization and disrupts its allosteric activation, thus attenuating FERs transphosphorylation for its substrate. This disruption in allosteric activation abolishes the genetic function of FERK565R, impacting ROS production and ABA-mediated stomatal movements. Additionally, we found that MEDOS1 (MDS1), a member of the FER family, is incapable of catalyzing phosphotransfer, but can boost the kinase activity of FER and HERK1 through allosteric activation. These findings settle the debate on FERs inactivated forms, and reveal a new mechanism for allosteric activation of RLKs via redox signaling, enhancing our understanding of pseudokinases in plants. One-sentence summaryFER activates kinase activity of homologous family members through allosteric activation.

plant biology↗

bioRxiv2024

The asymmetric transfers of visual perceptual learning determined by the stability of geometrical invariants

We quickly and accurately recognize the dynamic world by extracting invariances from highly variable scenes, a process can be continuously optimized through visual perceptual learning (VPL). While it is widely accepted that the visual system prioritizes the perception of more stable invariants, the influence of the structural stability of invariants on VPL remains largely unknown. In this study, we designed three geometrical invariants with varying levels of stability for VPL: projective (e.g., collinearity), affine (e.g., parallelism), and Euclidean (e.g., orientation) invariants, following the Kleins Erlangen program. We found that learning to discriminate low-stability invariant transferred asymmetrically to those with higher stability, and that training on high-stability invariants enabled location transfer. To explore learning-associated plasticity in the visual hierarchy, we trained deep neural networks (DNNs) to model this learning procedure. We reproduced the asymmetric transfer between different invariants in DNN simulations and found that the distribution and time course of plasticity in DNNs suggested a neural mechanism similar to the reverse hierarchical theory (RHT), yet distinct in that invariant stability--not task difficulty or precision--emerged as the key determinant of learning and generalization. We propose that VPL for different invariants follows the Klein hierarchy of geometries, beginning with the extraction of high-stability invariants in higher-level visual areas, then recruiting lower-level areas for the further optimization needed to discriminate less stable invariants.

neuroscience↗

bioRxiv2024

Polaris Neurosense: A General-Purpose Non-invasive Neurotechnology Research Platform

This article describes our initial work toward a general-purpose platform for non-invasive neurotechnology research. This platform consists of a multi-modal wireless recording device, an associated software API, and full integration into BCI2000 software. The device is placed on the forehead and features two electroencephalographic (EEG) sensors, an inertial movement sensor (IMU), a photoplethysmogram (PPG) sensor, a microphone, and vibration-based feedback. Herein, we demonstrate different technical characteristics of our platform and its use in the context of sleep monitoring/modulation, simultaneous and synchronized recordings from different hardware, and evoked potentials. With further development and widespread dissemination, our platform could become an important tool for research into new non-invasive neurotechnology protocols in humans.

bioengineering↗

bioRxiv2024

Integrated Analyses of Multi-omic Data Derived from Paired Primary Lung Cancer and Brain Metastasis Reveals the Metabolic Vulnerability as a Novel Therapeutic Target

Lung cancer brain metastases (LC-BrMs) are frequently associated with dismal mortality rates in patients with lung cancer; however, standard of care therapies for LC-BrMs are still limited in their efficacy. A deep understanding of molecular mechanisms and tumor microenvironment of LC-BrMs will provide us with new insights into developing novel therapeutics for treating patients with LC-BrMs. Here, we performed integrated analyses of genomic, transcriptomic, proteomic and metabolomic data which were derived from a total number of 174 patients with paired and unpaired primary lung cancer and LC-BrM, spanning four published and two newly generated patient cohorts on both bulk and single cell levels. We uncovered that LC-BrMs exhibited significantly higher intra-tumor heterogeneity. We also observed that mutations in a subset of genes were almost always shared by both primary lung cancers and LC-BrM lesions, including TTN, TP53, MUC16, LRP1B, RYR2, and EGFR. In addition, the genome-wide landscape of somatic copy number alterations was similar between primary lung cancers and LC-BrM lesions. Nevertheless, several regions of focal amplification were significantly enriched in LC-BrMs, including 5p15.33 and 20q13.33. Intriguingly, integrated analyses of transcriptomic, proteomic and metabolomic data revealed mitochondrial-specific metabolism was activated but tumor immune microenvironment was suppressed in LC-BrMs. Subsequently, we validated our results by conducting real-time quantitative reverse transcription PCR experiments, immunohistochemistry and multiplexed immunofluorescence staining of patients paired tumor specimens. Patients with a higher expression of mitochondrial metabolism genes but a lower expression of immune genes in their LC-BrM lesions tended to have a worse survival outcome. Therapeutically, targeting oxidative phosphorylation with gamitrinib in patient-derived organoids specific to LC-BrMs induced apoptosis and inhibited cell proliferation. The combination of gamitrinib plus anti-PD-1 immunotherapy significantly improved survival of mice bearing LC-BrMs. In conclusion, our findings not only provide comprehensive and integrated perspectives of molecular underpinnings of LC-BrMs but also contribute to the development of a potential, rationale-based combinatorial therapeutic strategy with the goal of translating it into clinical trials for patients with LC-BrMs.

cancer biology↗

bioRxiv2023

Generating single-cell gene expression profiles for high-resolution spatial transcriptomics based on cell boundary images

Stereo-seq is a cutting-edge technique for spatially resolved transcriptomics that combines subcellular resolution with centimeter-level field-of-view, serving as a technical foundation for analyzing large tissues at the single-cell level. Our previous work presents the first one-stop software that utilizes cell nuclei staining images and statistical methods to generate high-confidence single-cell spatial gene expression profiles for Stereo-seq data. With recent advancements in Stereo-seq technology, it is possible to acquire cell boundary information, such as cell membrane/wall staining images. To take advantage of this progress, we update our software to a new version, named STCellbin, which utilizes the cell nuclei staining images as a bridge to align cell membrane/wall staining images with spatial gene expression maps. By employing an advanced cell segmentation technique, accurate cell boundaries can be obtained, leading to more reliable single-cell spatial gene expression profiles. Experimental results verify that STCellbin can be applied on the mouse liver (cell membranes) and Arabidopsis seed (cell walls) datasets and outperforms other competitive methods. The improved capability of capturing single cell gene expression profiles by this update results in a deeper understanding of the contribution of single cell phenotypes to tissue biology. Availability & ImplementationThe source code of STCellbin is available at https://github.com/STOmics/STCellbin.

bioinformatics↗

bioRxiv2023

Single cell sequencing as a general variant interpretation assay

The human genome contains [~]70 million possible protein-altering variants, the vast majority of which are of uncertain clinical significance. Closing this gap is essential for accurate diagnosis of disease-causing variants and understanding their mechanisms of action. Towards this goal, we developed a pooled perturbation approach combining saturation mutagenesis with single cell RNA sequencing to map the effects of every single nucleotide variant in a gene. We sequenced [~]440,000 cells expressing variants in CDKN2A (p16INK4a), TP53, and SOD1, observing almost all possible protein-coding variants, with a mean of 61 cells per variant. Using single cell gene expression signatures, we show that each gene may contain multiple types of pathogenic variants that affect distinct downstream pathways. We demonstrate that single cell expression signatures outperform existing bulk experimental assays and computational models for predicting pathogenicity, and summarize both the utility and potential limitations of single cell sequencing as a general variant interpretation assay.

genomics↗

bioRxiv2023

Trigeminal nerve direct current stimulation causes sustained increase in neural activity in the rat hippocampus

Transcranial direct current stimulation (tDCS) is a noninvasive neuromodulation method that can modulate many brain functions including learning and memory. Recent evidence suggests that tDCS memory effects may be caused by co-stimulation of scalp nerves such as the trigeminal nerve (TN), and not the electric field in the brain. The TN gives input to brainstem nuclei, including the locus coeruleus that controls noradrenaline release across brain regions, including hippocampus. However, the effects of TN direct current stimulation (TN-DCS) are currently not well understood. In this study we hypothesized that TN-DCS manipulates hippocampal activity via an LC-noradrenergic bottom-up pathway. We recorded neural activity in rat hippocampus using multichannel silicon probes. We applied 3 minutes of 0.25 mA or 1 mA TN-DCS, monitored hippocampal activity for up to 1 hour and calculated spikes-rate and spike-field coherence metrics. Subcutaneous injections of xylocaine were used to block TN and intraperitoneal injection of clonidine to block the LC pathway. We found that 1 mA TN-DCS caused a significant increase in hippocampal spike-rate lasting 45 minutes in addition to significant changes in spike-field coherence, while 0.25 mA TN-DCS did not. TN blockage prevented spike-rate increases, confirming effects were not caused by the electric field in the brain. When 1 mA TN-DCS was delivered during clonidine blockage no increase in spike-rate was observed, suggesting an important role for the LC-noradrenergic pathway. These results provide a neural basis to support a tDCS TN co-stimulation mechanism. TN-DCS emerges as an important tool to potentially modulate learning and memory. HighlightsO_LITrigeminal nerve direct current stimulation (TN-DCS) boosts hippocampal spike rates C_LIO_LITN-DCS alters spike-field coherence in theta and gamma bands across the hippocampus. C_LIO_LIBlockade experiments indicate that TN-DCS modulated hippocampal activity via the LC-noradrenergic pathway. C_LIO_LITN-DCS emerges as a potential tool for memory manipulation. C_LI Figure Graphic Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=178 SRC="FIGDIR/small/571341v1_ufig1.gif" ALT="Figure 1"> View larger version (35K): org.highwire.dtl.DTLVardef@d60a69org.highwire.dtl.DTLVardef@4598daorg.highwire.dtl.DTLVardef@1363f89org.highwire.dtl.DTLVardef@856b2e_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2023

Lrp10 suppresses IL7R limiting CD8 T cell homeostatic expansion and anti-tumor immunity.

Signals emanating from the T cell receptor (TCR), co-stimulatory receptors, and cytokine receptors each influence CD8 T cell fate. Understanding how these signals respond to homeostatic and microenvironmental cues can reveal new ways to therapeutically direct T cell function. Through forward genetic screening in mice, we discovered that loss-of-function mutations in LDL receptor related protein 10 (Lrp10) caused naive and central memory CD8 T cells to accumulate in peripheral lymphoid organs. Lrp10 encodes a conserved cell surface protein of unknown immunological function. Lrp10 was induced with T cell activation and its expression post-translationally suppressed IL7 receptor (IL7R) levels. Accordingly, Lrp10 deletion enhanced T cell homeostatic expansion through IL7R signaling. Lrp10-deficient mice were also intrinsically resistant to syngeneic tumors. This phenotype depended on dense tumor infiltration of CD8 T cells that displayed increased memory cell characteristics, reduced terminal exhaustion, and augmented responses to immune checkpoint inhibition. Here, we present Lrp10 as a new negative regulator of CD8 T cell homeostasis and a host factor that controls tumor resistance with implications for immunotherapy.

immunology↗

bioRxiv2023

Molecular Determinants and Signaling Effects of PKA RIα Phase Separation

Spatiotemporal regulation of intracellular signaling molecules, such as the 3,5-cyclic adenosine monophosphate (cAMP)-dependent protein kinase (PKA), ensures the specific execution of various cellular functions. Liquid-liquid phase separation (LLPS) of the ubiquitously expressed PKA regulatory subunit RI was recently identified as a major driver of cAMP compartmentation and signaling specificity. However, the molecular determinants of RI LLPS remain unclear. Here, we reveal that two separate dimerization interfaces combined with the cAMP-induced release of the PKA catalytic subunit (PKA-C) from the pseudosubstrate inhibitory sequence are required to drive RI condensate formation in cytosol, which is antagonized by docking to A-kinase anchoring proteins. Strikingly, we find that the RI pseudosubstrate region is critically involved in the formation of a non-canonical R:C complex, which serves to maintain low basal PKA activity in the cytosol by enabling the recruitment of active PKA-C to RI condensates. Our results suggest that RI LLPS not only facilitates cAMP compartmentation but also spatially restrains active PKA-C, thus highlighting the functional versatility of biomolecular condensates in driving signaling specificity.

cell biology↗

bioRxiv2023

Virological characteristics of the SARS-CoV-2 JN.1 variant

The SARS-CoV-2 BA.2.86 lineage, first identified in August 2023, is phylogenetically distinct from the currently circulating SARS-CoV-2 Omicron XBB lineages, including EG.5.1 and HK.3. Comparing to XBB and BA.2, BA.2.86 carries more than 30 mutations in the spike (S) protein, indicating a high potential for immune evasion. BA.2.86 has evolved and its descendant, JN.1 (BA.2.86.1.1), emerged in late 2023. JN.1 harbors S:L455S and three mutations in non-S proteins. S:L455S is a hallmark mutation of JN.1: we have recently shown that HK.3 and other "FLip" variants carry S:L455F, which contributes to increased transmissibility and immune escape ability compared to the parental EG.5.1 variant. Here, we investigated the virological properties of JN.1.

microbiology↗

bioRxiv2023

SAN: mitigating spatial covariance heterogeneity in cortical thickness data collected from multiple scanners or sites

In neuroimaging studies, combining data collected from multiple study sites or scanners is becoming common to increase the reproducibility of scientific discoveries. At the same time, unwanted variations arise by using different scanners (inter-scanner biases), which need to be corrected before downstream analyses to facilitate replicable research and prevent spurious findings. While statistical harmonization methods such as ComBat have become popular in mitigating inter-scanner biases in neuroimaging, recent methodological advances have shown that harmonizing heterogeneous covariances results in higher data quality. In vertex-level cortical thickness data, heterogeneity in spatial autocorrelation is a critical factor that affects covariance heterogeneity. Our work proposes a new statistical harmonization method called SAN (Spatial Autocorrelation Normalization) that preserves homogeneous covariance vertex-level cortical thickness data across different scanners. We use an explicit Gaussian process to characterize scanner-invariant and scanner-specific variations to reconstruct spatially homogeneous data across scanners. SAN is computationally feasible, and it easily allows the integration of existing harmonization methods. We demonstrate the utility of the proposed method using cortical thickness data from the Social Processes Initiative in the Neurobiology of the Schizophrenia(s) (SPINS) study. SAN is publicly available as an R package.

neuroscience↗

bioRxiv2023

Effects of greening-induced warming and cooling on tree phenology in temperate and boreal forests

Tree phenology, periodic biological events in trees, is highly sensitive to climate change. It has been reported that forest greening can influence the local climate by altering the seasonal surface energy budget. However, tree phenological responses to forest greening remains poorly understood at large spatial scales. Combining remote-sensing derived phenological and leaf area indices since 2001, herein we show that forest greening led to earlier spring (-1.05 {+/-} 0.17 d) and autumn phenology (-1.95 {+/-} 0.14 d) in temperate and boreal forests. Our results show that forest greening in winter and spring decreased surface albedo and thus resulted in biophysical warming that caused earlier spring leaf phenology. In contrast, forest greening in summer and autumn triggered biophysical cooling by enhancing evapotranspiration, which led to earlier autumn leaf phenology. These findings suggest that forest greening could significantly alter tree phenology through seasonal biophysical impacts. Therefore, it is essential to incorporate these complicated biophysical impacts of greening into tree phenology models to accurately predict future shifts in tree phenology under future climate change.

ecology↗

bioRxiv2023

Aftereffects of Delay Adaptation in Visual and Tactile Duration Reproduction

Brief actions involve multiple temporal cues that may not always synchronize, and in basic action-effect relationships, the effect is often delayed. How the brain incorporates delays across modalities in a sensorimotor duration reproduction remains unclear. To investigate this, we conducted two experiments on duration reproduction with delayed sensory feedback. Participants reproduced durations in either visual (Experiment 1) or tactile (Experiment 2) modalities. In the adaptation phase, a contingent sensory feedback, either visual or tactile, was delayed by 150 ms in one session and synchronized in the control session, with accuracy feedback provided after each trial. In the testing phase, random action-effect delays (0-150 ms) were introduced and accuracy feedback was removed. The findings revealed that accuracy feedback effectively recalibrated motor time but did not eliminate the delay. Without accuracy feedback, tactile reproduction relied more on the tactile feedback than on motor time, resulting in greater lengthening of motor reproduction compared to the visual feedback. These findings suggest that temporal delay adaptation is influenced by accuracy feedback and sensorimotor integration, with sensorimotor reliability assigning a higher weight to the tactile than the visual modality.

neuroscience↗

bioRxiv2023

Coherent categorical information triggers integration-related alpha dynamics

To create coherent visual experiences, the brain spatially integrates the complex and dynamic information it receives from the environment. We previously demonstrated that feedback-related alpha activity carries stimulus-specific information when two spatially and temporally coherent naturalistic inputs can be integrated into a unified percept. In this study, we sought to determine whether such integration-related alpha dynamics are triggered by categorical coherence in visual inputs. In an EEG experiment, we manipulated the degree of coherence by presenting pairs of videos from the same or different categories through two apertures in the left and right visual hemifields. Critically, video pairs could be video-level coherent (i.e., stem from the same video), coherent in their basic-level category, coherent in their superordinate category, or incoherent (i.e., stem from videos from two entirely different categories). We conducted multivariate classification analyses on rhythmic EEG responses to decode between the video stimuli in each condition. As the key result, we significantly decoded the video-level coherent and basic-level coherent stimuli, but not the superordinate coherent and incoherent stimuli, from cortical alpha rhythms. This suggests that alpha dynamics play a critical role in integrating information across space, and that cortical integration processes are flexible enough to accommodate information from different exemplars of the same basic-level category.

neuroscience↗

bioRxiv2023

MetaVision3D: Automated framework for the Generation of Spatial Metabolome Atlas in 3D

High-resolution spatial imaging is transforming our understanding of foundational biology. Spatial metabolomics is an emerging field that enables the dissection of the complex metabolic landscape and heterogeneity from a thin tissue section. Currently, spatial metabolism highlights the remarkable complexity in two-dimensional space and is poised to be extended into the three-dimensional world of biology. Here, we introduce MetaVision3D, a novel pipeline driven by computer vision techniques for the transformation of serial 2D MALDI mass spectrometry imaging sections into a high-resolution 3D spatial metabolome. Our framework employs advanced algorithms for image registration, normalization, and interpolation to enable the integration of serial 2D tissue sections, thereby generating a comprehensive 3D model of unique diverse metabolites across host tissues at mesoscale. As a proof of principle, MetaVision3D was utilized to generate the mouse brain 3D metabolome atlas (available at https://metavision3d.rc.ufl.edu/) as an interactive online database and web server to further advance brain metabolism and related research.

neuroscience↗

bioRxiv2023

A novel antagonist of the CCL5/CCR5 axis suppresses the tumor growth and metastasis of triple-negative breast cancer by CCR5-YAP1 regulation.

Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer (BC) with a high mortality rate, and few effective therapeutic strategies are available. CCL5/CCR5 is an appealing immunotherapeutic target for TNBC. However, its signaling mechanism is poorly understood and its direct antagonists have not been reported. Here, we developed a high-throughput screening (HTS) assay for discovering its antagonists. Verteporfin was identified as a more selective and potent antagonist than the known CCR5 antagonist maraviroc. Without photodynamic therapy, verteporfin demonstrated significant inhibition on TNBC tumor growth through immune regulation, remarkable suppression of lung metastasis by cell-intrinsic mechanism, and a significant extension of overall survival in vivo. Mechanistically, CCR5 was found to be essential for expression of the key hippo effector YAP1. It promoted YAP1 transcription via HIF-1 and exerted further control over the migration of CD8+ T, NK, and MDSC immune cells through chemokines CXCL16 and CXCL8 which were identified from RNA-seq. Moreover, the CCR5-YAP1 axis played a vital role in promoting metastasis by modulating {beta}-catenin and core epithelial-mesenchymal transition transcription factors ZEB1 and ZEB2. It is noteworthy that the regulatory relationship between CCR5 and YAP1 was observed across various BC subtypes, TNBC patients, and showed potential relevance in fifteen additional cancer types. Overall, this study introduced an easy-to-use HTS assay that streamlines the discovery of CCL5/CCR5 axis antagonists. Verteporfin was identified as a specific molecular probe of this axis with great potentials as a therapeutic agent for treating sixteen malignant diseases characterized by heightened CCR5 and YAP1 levels.

cancer biology↗