Biology subjects

Wang, R.

Publications and source records attributed to Wang, R..

At least 307 records · Page 17Linked to original sources

bioRxiv2023

Unveiling consistency in flexibility: the role of reward and cognitive control in moral decisions

Moral decisions are multifaceted with two essential aspects, flexibility and consistency. However, the interaction between these two and the underlying mechanisms is rarely studied. Here, we combined mouse-tracking and functional magnetic resonance imaging (fMRI) together in a value-based moral decision task, which allows us to quantify accumulative history responses as self-consistency. Using a multi-attribute time-dependent drift-diffusion model (tDDM), we disentangled the role of consistency and self-interest, highlighting the dominant role of cognitive-control-related regions. The drift rate of self-consistency was directly associated with the brain activity responsible for cognitive control, while the relationship between the reward and the activity of the related brain regions was mediated by the mouse-tracking index area under the curve(AUC). Dorsolateral prefrontal cortex was revealed as a hub connecting prACC and ventral striatum, whose functional connectivity was correlated with consistency drift rate and reward drift rate respectively. Furthermore, decision flexibility was quantified by choice entropy, which links to mouse tracking indices and the activity of cognitive -control related regions. Together, our study uncovers the interplay between self-consistency and reward in behavior, and highlights the key role of cognitive control in modulating these two attributes, thereby deepening our understanding of consistency and flexibility in moral decisions.

neuroscience↗

bioRxiv2023

The tRNA Gm18 Methyltransferase TARBP1 Promotes Hepatocellular Carcinoma Progression via Metabolic Reprogramming of Glutamine

Cancer cells rely on metabolic reprogramming to sustain the prodigious energetic requirements for rapid growth and proliferation. Glutamine metabolism is frequently dysregulated in cancers and is being exploited as a potential therapeutic target. In current study, we identified TARBP1 (TAR (HIV-1) RNA Binding Protein 1) as a novel driver gene critical for glutamine metabolic reprogramming in tumor through the CRISPRi/Cas9 screening. Our in vivo and in vitro assays demonstrated that TARBP1 is the methyltransferase of Guanosine 2-O-methylation targeting position 18 (G18) of tRNAGln (TTG/CTG) and tRNASer (TGA/GCT), and loss of Gm18 modification diminishes the stability of tRNAs. Therefore, TARBP1 is critical for maintaining efficient translation of mRNA, in particular the glutamine transportor-ASCT2 (also known as SCL1A5). Importantly, TARBP1 is frequently amplified and overexpressed in HCC, consequentially promotes the protein synthesis of ASCT2 and glutamine import to fuel the growth of cancer cell, which is associated with poor patient survival. Taken together, this study reveals the critical role of TARBP1 in HCC progression through glutamine metabolic reprogramming and provides a potential target for tumor therapy.

cancer biology↗

bioRxiv2023

Alcohol inhibits sociability via serotonin inputs to the nucleus accumbens

Social interaction is a core component of motivational behavior that is perturbed across multiple neuropsychiatric disorders, including alcohol use disorder (AUD). Positive social bonds are neuroprotective and enhance recovery from stress, so reduced social interaction in AUD may delay recovery and lead to alcohol relapse. We report that chronic intermittent ethanol (CIE) induces social avoidance in a sex-dependent manner and is associated with hyperactivity of serotonin (5-HT) neurons in the dorsal raphe nucleus (DRN). While 5-HTDRN neurons are generally thought to enhance social behavior, recent evidence suggests that specific 5-HT pathways can be aversive. Using chemogenetic iDISCO, the nucleus accumbens (NAcc) was identified as one of 5 regions that were activated by 5-HTDRN stimulation. We then employed an array of molecular genetic tools in transgenic mice to show that 5-HTDRN inputs to NAcc dynorphin neurons drive social avoidance in male mice after CIE by activating 5-HT2C receptors. NAcc dynorphin neurons also inhibit dopamine release during social interaction, reducing the motivational drive to engage with social partners. This study reveals that excessive serotonergic drive after chronic alcohol can promote social aversion by inhibiting accumbal dopamine release. Drugs that boost brain serotonin levels may be contraindicated for individuals with AUD.

neuroscience↗

bioRxiv2023

Acoustically-Targeted Measurement of Transgene Expression in the Brain

Gene expression is a critical component of brain physiology and activity, but monitoring this expression in the living brain represents a significant challenge. Here, we introduce a new paradigm called Recovery of Markers through InSonation (REMIS) for noninvasive measurement of gene expression in the brain with cell-type, spatial, and temporal specificity. Our approach relies on engineered protein markers that are designed to be expressed in neurons and exit into the interstitium. By applying ultrasound to targeted brain regions, these markers are released into the bloodstream, where they can be readily detected using biochemical techniques. REMIS can noninvasively confirm gene delivery and measure endogenous signaling in specific brain sites through a simple insonation and a subsequent blood test. Using REMIS, we successfully measured chemogenetic induction of neuronal activity in ultrasound-tar-geted brain regions. REMIS recovery of markers is reliable and demonstrated improved recovery of markers from the brain into the blood in every tested animal. Overall, our work establishes a noninvasive, spatially-specific means of monitoring gene delivery outcomes and endogenous signaling in mammalian brains, opening up possibilities for brain research and noninvasive monitoring of gene therapies in the brain.

bioengineering↗

bioRxiv2023

Aird-ComboComp: A combinable compressor framework with a dynamic-decider for lossy mass spectrometry data compression

Mass spectrum (MS) data volumes increase with an improved ion acquisition ratio and a highly accurate mass spectrometer. However, the most widely used data format, mzML, does not take advantage of compression methods and improved read performances. Several compression algorithms have been proposed in recent years, and they consider a number of factors, including, numerical precision, metadata read strategies and the compression performance. Due to limited compression ratio, the high-throughput MS data format is still quite large. High bandwidth and memory requirements severely limit the applicability of MS data analysis in cloud and mobile computing. ComboComp is a comprehensive improvement to the Aird data format. Instead of using the general-purpose compressor directly, ComboComp uses two integer-purpose compressors and four general-purpose compressors, and obtains the best compression combination with a dynamic decider, achieving the most balanced compression ratio among all the numerous varieties of compressors. ComboComp supports a seamless extension of the new integer and generic compressors, making it an evolving compression framework. The improvement of compression rate and decoding speed greatly reduces the cost of data exchange and real-time decompression, and effectively reduces the hardware requirements of MS data analysis. Analyzing mass spectrum data on IoT devices can be useful in real-time quality control, decentralized analysis, collaborative auditing, and other scenarios. We tested ComboComp on 11 datasets generated by commonly used MS instruments. Compared with Aird-ZDPD, the compression size can be reduced by an average of 12.9%. The decompression speed is increased by an average of 27.1%. The average compression time is almost the same as that of ZDPD. The high compression rate and decoding speed make the Aird format effective for data analysis on small memory devices. This will enable MS data to be processed normally even on IoT devices in the future. We provide SDKs in three languages, Java, C# and Python, which offer optimized interfaces for the various acquisition modes. All the SDKs can be found on Github: https://github.com/CSi-Studio/Aird-SDK.

bioinformatics↗

bioRxiv2023

Spatially-resolved single-cell atlas of ascidian endostyle provides insights into the origin of vertebrate pharyngeal organs

The pharynx is an endoderm innovation in deuterostome ancestors, the vertebrate descendent structure of which is a pharyngeal developmental organizer involving multi-germ layer and organ derivatives. However, the evolutionary origination of complicated pharynx organs in vertebrates is still largely unknown. Endostyle, a transitional pharyngeal organ exclusively in basal chordates provides an opportunity to reveal the origin of pharyngeal organs. Here, utilizing cutting-edged Stereo-seq and single-cell RNA-seq, we constructed the first spatially-resolved single-cell atlas in the endostyle of urochordate ascidian Styela clava, where the spatial location of Stereo-seq and high capture efficiency of single-cell RNA-seq complement each other and identified 23 highly differentiated cell types. We identified a previously overlooked hemolymphoid region (HLR), which harbors immune and blood cell clusters with enriched stemness capacities, illuminating a mixed rudiment and stem-cell niches for the blood and lymphoid system. More excitingly, we discovered a mechanical-sensitive hair cell candidate in zone 3 homologous to vertebrate acoustico-lateralis system, which was supported by the expression of in situ hybridization-verified inner ear-specific markers, including PTPRQ, USH2A, WHRN, and ADGRV1, ultracellular structure evidence and cross-species comparison. These results thoroughly renewed the comprehension of the basal-chordate pharynx and provides expressional evidence for multiplexed pharyngeal organ evolution.

evolutionary biology↗

bioRxiv2023

Time, Space and Single-Cell Resolved Molecular Trajectory of Cell Populations and the Laterality of the Body Plan at Gastrulation

Understanding of the molecular drivers of lineage diversification and tissue patterning during primary germ layer development requires in-depth knowledge of the dynamic molecular trajectories of cell lineages across a series of developmental stages of gastrulation1-7. Through computational modeling, we constructed at single-cell resolution a spatio-temporal compendium of the molecular trajectories of germ-layer derivatives in gastrula-stage mouse embryos. This molecular atlas infers the developmental trajectories of single-cell populations and the molecular network activity underpinning the specification and differentiation of the germ-layer lineages. Analysis of the heterogeneity of cellular composition of cell populations at defined positions in the epiblast revealed progressive diversification of cell types, mirroring the process of lineage allocation during gastrulation. A novel observation is the difference in the contribution of cells on contralateral sides of the epiblast to mesoderm derivatives of the early organogenesis embryo, and the enhanced BMP signaling activity in right-side mesoderm of E7.5 embryo. Perturbation of BMP signaling activity at late gastrulation led to randomization of left-right (L-R) molecular asymmetry in the lateral mesoderm of early-somite-stage embryo. Our findings indicate the asymmetric BMP activity during gastrulation may be critical for the symmetry breaking process associated with specification of L-R body asymmetry ahead of the acquisition of functionality of the L-R organizer.

developmental biology↗

bioRxiv2023

DCBLD1 modulates angiogenesis by regulating of the VEGFR-2 endocytosis in endothelial cells

ObjectiveUnwanted angiogenesis is involved in the progression of various malignant tumors and cardiovascular diseases, and the factors that regulate angiogenesis are potential therapeutic targets. We tested the hypothesis that DCBLD1 (Discoidin, CUB, and LCCL domain-containing protein 1) is a co-receptor of VEGFR-2 and modulates angiogenesis in endothelial cells(ECs). Approach and ResultsA carotid artery ligation model and retinal angiogenesis assay were used to study angiogenesis using globe knockout or EC-specific conditional DCBLD1 knockout mice in vivo. Immunoblotting, immunofluorescence staining, plasma-membrane subfraction isolation, Co-immunoprecipitation and mass-spectrum assay were performed to clarify the molecular mechanisms.Loss of DCBLD1 impaired VEGF response and inhibited VEGF-induced EC proliferation and migration. DCBLD1 deletion interfered with adult and developmental angiogenesis. Mechanistically, DCBLD1 bound to VEGFR-2 and regulated the formation of VEGFR-2 complex with negative regulators: protein tyrosine phosphatases, E3 ubiquitin ligases(Nedd4 and c-Cbl), and also DCBLD1 knockdown promoted lysosome-mediated VEGFR-2 degradation in ECs. ConclusionsThese findings demonstrated the essential role of endothelial DCBLD1 in regulating VEGF signaling and provided evidence that DCBLD1 promotes VEGF-induced angiogenesis by limiting the dephosphorylation, ubiquitination, and lysosome degradation after VEGFR-2 endocytosis. We proposed that endothelial DCBLD1 is a potential therapeutic target for ischemic cardiovascular diseases by the modulation of angiogenesis through regulating of the VEGFR-2 endocytosis.

molecular biology↗

bioRxiv2023

Somatic Calcium Signals from Layer II/III Motor Cortex for Continuous Neural Decoding

The latest research shows that calcium signals can provide a new signal source for brain-machine interfaces (BMI). However, it remains a question whether the calcium signals from layer 2/3 motor cortex can be used for continuous neural decoding. And how they are involved in movement coding is also worth investigating. Here we collect the somatic signals in M1 layer 2/3 while mice performed a lever-press task under the one-photon imaging. We first present the potential of somatic calcium signals from layer 2/3 in continuous neural decoding through an improved recurrent neural network. Layer 2/3 neurons exhibit three types of calcium dynamics with distinct spatiotemporal coding patterns involved in the movement. Pre-pressing and pressing neurons enable sparse coding of movement through complementary spatiotemporal information. While post-pressing neurons predict the lever movement most accurately through the calcium dynamics with higher fidelity. These results demonstrate the capability of calcium signals from layer 2/3 neurons as a motor BMI driver and underscore their diversity in motor coding, opening a new avenue for studying the motor cortex and designing optical BMIs.

neuroscience↗

bioRxiv2023

Single-cell transcriptome analysis reveals the cellular atlas of human intracranial aneurysm and highlights inflammation features associated with aneurysm rupture

Intracranial aneurysm (IA) is pouch-like pathological dilations of cerebral arteries, which often affects middle-aged people and culminates in life-threatening hemorrhagic stroke. A deeper knowledge of the cellular and gene expression perturbations in human IA tissue deepens our understanding of disease mechanisms and facilitates developing pharmacological targets for unruptured IA. In this study, 21,332 qualified cells were obtained from cell-sparse ruptured and unruptured human IA tissues and a detailed cellular profile was determined, including conventional endothelial cells, smooth muscle cells (SMC), fibroblasts and the newly identified pericytes. Notably, striking proportion of immune cells were identified in IA tissue, with the number of monocyte/macrophages and neutrophils being remarkably higher in ruptured IA. By leveraging external datasets and machine learning algorithms, a subset of macrophages characterized by high expression of CCL3 and CXCL3, and transcriptional activation of NF-{kappa}B and HIVEP2 was identified as the cell most associated with IA rupture. Further, the interactome of CCL3/CXCL3 macrophages disclosed their role in regulating vascular cell survival and orchestrating inflammation. In summary, this study illustrated the profile and interactions of vascular and immune cells in human IA tissue and the opportunities for targeting local chronic inflammation.

cell biology↗

bioRxiv2023

Degenerated CRISPRs widely regulate Cas expression to balance immunity and cost

CRISPR RNAs (crRNAs) and Cas proteins together provide prokaryotes with adaptive immunity against genetic invaders. How Cas expression is fine-tuned to avoid energy burden while satisfying the dynamic need of crRNAs remains poorly understood. Here we experimentally demonstrated widespread degenerated mini-CRISPRs encode CreR (Cas-regulating) RNAs to mediate autorepression of type I-B, I-E and V-A Cas proteins, based on their partial complementarity to cas promoters. This autorepression decreases energy burden and autoimmune risks, thus mitigating the fitness cost on host cell, and remarkably, senses and responds to alterations in the volume of canonical crRNAs, which compete with CreR for Cas proteins. Moreover, CreR-guided Cas autorepression can be subverted by diverse anti-CRISPR (Acr) proteins that destruct Cas proteins, which in turn replenishes the weapon depot. Our data unveil a general degenerated crRNA-guided autorepression paradigm for diverse Cas effectors, which highlights the intricate (self-)regulation of CRISPR-Cas and its transcriptional counterstrategy against Acr attack.

microbiology↗

bioRxiv2023

Unfolded Protein Response Factor ATF6 Augments T Helper Cell Responses and Promotes Mixed Granulocytic Airway Inflammation

The unfolded protein response (UPR) is associated with the risk of asthma, including treatment- refractory severe asthma. Several recent studies demonstrated a pathogenic role of activating transcription factor 6 (ATF6 or ATF6), one of the essential arms of UPR, in airway structural cells. However, its role in T helper (TH) cells has not been well examined. In this study, we found that ATF6 was selectively induced by STAT6 and STAT3 in TH2 and TH17 cells, respectively. ATF6 upregulated UPR genes and promoted the differentiation and cytokine secretion of TH2 and TH17 cells. T cell-specific Atf6-deficiency impaired TH2 and TH17 responses in vitro and in vivo and attenuated mixed granulocytic experimental asthma. ATF6 inhibitor Ceapin A7 suppressed ATF6 downstream gene expression and TH cell cytokine expression in both murine and human memory CD4+ T cells. At the chronic stage of asthma, administration of Ceapin A7 lessened TH2 and TH17 responses in vivo, leading to alleviation of both airway neutrophilia and eosinophilia. Thus, our results demonstrate a critical role of ATF6 in TH2 and TH17 cell-driven mixed granulocytic airway disease, suggesting a novel option to combat steroid-resistant mixed and even T2-low endotypes of asthma by targeting ATF6.

immunology↗

bioRxiv2023

Microsnoop: a generalist tool for the unbiased representation of heterogeneous microscopy images

Microscopy image profiling is becoming increasingly important in biological research. Microsnoop is a new deep learning-based representation tool that has been trained on large-scale microscopy images using masked self-supervised learning, eliminating the need for manual annotation. Microsnoop can unbiasedly profile a wide range of complex and heterogeneous images, including single-cell, fully imaged, and batch-experiment data. Its performance was evaluated on seven high-quality datasets, containing over 358,000 images and 1,270,000 single cells with varying resolutions and channels from cellular organelles to tissues. The results show that Microsnoop outperforms previous generalist and even custom algorithms, demonstrating its robustness and state-of-the-art performance in all biological applications. Furthermore, Microsnoop can contribute to multi-modal studies and is highly inclusive of GPU and CPU capabilities. It can be easily and freely deployed on local or cloud computing platforms.

bioinformatics↗

bioRxiv2023

InjectionDesign: Plate Design with Optimized Stratified Block Randomization for Modern LC/GC-MS-Based Sample Preparation

Plate Design is a necessary and time-consuming operation for GC/LC-MS based sample preparation. The implementation of the inter-batch balancing algorithm and the intra-batch randomization algorithm can have a significant impact on the final analysis results. For researchers without programming skills, a stable and efficient online service for plate design is necessary. However, most exist products do not currently have online services, and are not optimized for GC/LC-MS instruments with custom injection capabilities. Here we describe InjectionDesign, a free online plate design service focus on GC/LC-MS-based multi-omics experiment design. It offers the ability to separate the position design from the sequence design, making the output more compatible with the requirements of a modern mass spectrometer-based laboratory. In addition, it has implemented an optimized block randomization algorithm, which can be better applied to sample stratification with block randomization for unbalanced distribution. It is easy to use, with built-in support for common instrument models and quick export to worksheet. InjectionDesign is an open-source project based on Java. Researchers can get the source code of the project from Github: https://github.com/CSi-Studio/InjectionDesign. A free web service is also provided: http://www.injection.design. Demo Projecthttp://www.injection.design/#/project/detail?projectId=Test

bioinformatics↗

bioRxiv2023

Myomatrix arrays for high-definition muscle recording

Neurons coordinate their activity to produce an astonishing variety of motor behaviors. Our present understanding of motor control has grown rapidly thanks to new methods for recording and analyzing populations of many individual neurons over time. In contrast, current methods for recording the nervous systems actual motor output - the activation of muscle fibers by motor neurons - typically cannot detect the individual electrical events produced by muscle fibers during natural behaviors and scale poorly across species and muscle groups. Here we present a novel class of electrode devices ("Myomatrix arrays") that record muscle activity at unprecedented resolution across muscles and behaviors. High-density, flexible electrode arrays allow for stable recordings from the muscle fibers activated by a single motor neuron, called a "motor unit", during natural behaviors in many species, including mice, rats, primates, songbirds, frogs, and insects. This technology therefore allows the nervous systems motor output to be monitored in unprecedented detail during complex behaviors across species and muscle morphologies. We anticipate that this technology will allow rapid advances in understanding the neural control of behavior and in identifying pathologies of the motor system.

neuroscience↗

bioRxiv2023

MYC-driven increases in mitochondrial DNA copy number occur early and persist throughout prostatic cancer progression

Increased mitochondrial function may render some cancers vulnerable to mitochondrial inhibitors. Since mitochondrial function is regulated partly by mitochondrial DNA copy number (mtDNAcn), accurate measurements of mtDNAcn could help reveal which cancers are driven by increased mitochondrial function and may be candidates for mitochondrial inhibition. However, prior studies have employed bulk macrodissections that fail to account for cell type-specific or tumor cell heterogeneity in mtDNAcn. These studies have often produced unclear results, particularly in prostate cancer. Herein, we developed a multiplex in situ method to spatially quantify cell type specific mtDNAcn. We show that mtDNAcn is increased in luminal cells of high-grade prostatic intraepithelial neoplasia (HGPIN), is increased in prostatic adenocarcinomas (PCa), and is further elevated in metastatic castration-resistant prostate cancer. Increased PCa mtDNAcn was validated by two orthogonal methods and is accompanied by increases in mtRNAs and enzymatic activity. Mechanistically, MYC inhibition in prostate cancer cells decreases mtDNA replication and expression of several mtDNA replication genes, and MYC activation in the mouse prostate leads to increased mtDNA levels in the neoplastic prostate cells. Our in situ approach also revealed elevated mtDNAcn in precancerous lesions of the pancreas and colon/rectum, demonstrating generalization across cancer types using clinical tissue samples.

cancer biology↗

bioRxiv2023

LRG1 is a novel ligand of HER3 and promotes metastatic colorectal cancer growth

Therapy failure for patients with metastatic colorectal cancer (mCRC) remains an overarching challenge in the clinic. We find that liver endothelial cells secrete soluble factor(s) to promote mCRC growth in vitro and in vivo. We identify LRG1 in ECs secretome, which promotes growth in tumor cells through binding and activation of HER3. Pharmacological blocking of the LRG1/HER3 axis using LRG1 antibody 15C4 completely attenuated LRG1-induced HER3 activation and in vitro and in vivo growth of the tumor. Moreover, LRG1-/- mice with CRC allografts in the liver had 2 times longer overall survival than tumor-bearing LRG1+/+ mice. Lastly, unbiased -omics analysis and target-specific inhibitors identified eIF4-protein synthesis is significantly activated by the LRG1/HER3/RSK1/2 axis. This work reveals a paracrine mechanism of mCRC growth in liver microenvironment and highlighted the potential of blocking LRG1-HER3 and involved downstream pathways for treating patients with mCRC. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=171 SRC="FIGDIR/small/529070v2_ufig1.gif" ALT="Figure 1"> View larger version (26K): org.highwire.dtl.DTLVardef@1a84299org.highwire.dtl.DTLVardef@1ac6654org.highwire.dtl.DTLVardef@1723260org.highwire.dtl.DTLVardef@4970a8_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2023

CRB3 navigates Rab11 trafficking vesicles to promote γTuRC assembly during ciliogenesis

The primary cilium plays important roles in regulating cell differentiation, signal transduction, and tissue organization. Dysfunction of the primary cilium can lead to ciliopathies and cancer. The formation and organization of the primary cilium are highly associated with cell polarity proteins, such as the apical polarity protein CRB3. However, the molecular mechanisms by which CRB3 regulates ciliogenesis and the location of CRB3 remain unknown. Here, we show that CRB3, as a navigator, regulates vesicle trafficking in {gamma}-TuRC assembly during ciliogenesis and cilium-related Hh and Wnt signaling pathways in tumorigenesis. Crb3 knockout mice display severe defects of the primary cilium in the mammary ductal lumen and renal tubule, while mammary epithelial-specific Crb3 knockout mice exhibit the promotion of ductal epithelial hyperplasia and tumorigenesis. CRB3 is essential for lumen formation and ciliary assembly in the mammary epithelium. We demonstrate that CRB3 localizes to the basal body and that CRB3 trafficking is mediated by Rab11-positive endosomes. Significantly, CRB3 interacts with Rab11 to navigate GCP6/Rab11 trafficking vesicles to CEP290, resulting in intact {gamma}-TuRC assembly. In addition, CRB3-depleted cells are unresponsive to the activation of the Hh signaling pathway, while CRB3 regulates the Wnt signaling pathway. Therefore, our studies reveal the molecular mechanisms by which CRB3 recognizes Rab11-positive endosomes to facilitate ciliogenesis, and regulates cilium-related signaling pathways in tumorigenesis.

cell biology↗