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Wang, R.

Publications and source records attributed to Wang, R..

At least 343 records · Page 19Linked to original sources
bioRxiv2022

A Corollary Discharge Circuit in Human Speech

When we vocalize, our brain distinguishes self-generated sounds from external ones. A corollary discharge signal supports this function in animals, however, in humans its exact origin and temporal dynamics remain unknown. We report Electrocorticographic (ECoG) recordings in neurosurgical patients and a novel connectivity approach based on Granger-causality that reveals major neural communications. We find a reproducible source for corollary discharge across multiple speech production paradigms localized to ventral speech motor cortex before speech articulation. The uncovered discharge predicts the degree of auditory cortex suppression during speech, its well-documented consequence. These results reveal the human corollary discharge source and timing with far-reaching implication for speech motor-control as well as auditory hallucinations in human psychosis. Significance statementHow do organisms dissociate self-generated sounds from external ones? A fundamental brain circuit across animals addresses this question by transmitting a blueprint of the motor signal to sensory cortices, referred to as a corollary discharge. However, in humans and non-human primates auditory system, the evidence supporting this circuit has been limited to its direct consequence, auditory suppression. Furthermore, an impaired corollary discharge circuit in humans can lead to auditory hallucinations. While hypothesized to originate in the frontal cortex, direct evidence localizing the source and timing of an auditory corollary discharge is lacking in humans. Leveraging rare human neurosurgical recordings combined with connectivity techniques, we elucidate the exact source and dynamics of the corollary discharge signal in human speech. One-sentence summaryWe reveal the source and timing of a corollary discharge from speech motor cortex onto auditory cortex in human speech.

neuroscience↗
bioRxiv2022

A gene expression analysis and immune infiltration between lesioned and preserved subchondral bone in osteoarthritis

BackgroundOsteoarthritis (OA) is a degenerative disease which need more research. The purpose of this study was to performed gene expression analysis and immune infiltration between lesioned and preserved subchondral bone, and validation with datasets and experiment of multiple tissues. MethodsThe different expressed genes(DEGs) of GSE51588 datasets between lesioned and preserved tibial plateaus of OA patients were conducted. Moreover, functional annotation and protein-protein interaction (PPI) network were applied for exploring the potential therapeutic targets in OA subchondral bones between lesioned and preserved sides. In addition, multiple tissues were used to screen out co-expressed genes and the expression levels of identified candidate DEGs was detected by quantitative real-time polymerase chain reaction (qRT-PCR) in OA. Finally, immune infiltration analysis was conducted. ResultsA total of 1010 DEGs were identified, including upregulated 423 genes, 587 downregulated genes. Upregulated genes showed that BP terms were enriched in "skeletal system development", "sister chromatid cohesion","ossification" etc. Pathways were enriched in "Wnt signaling pathway," "Proteoglycans in cancer," Downregulated genes showed that BP terms were enriched in "inflammatory response," "xenobiotic metabolic process", "positive regulation of inflammatory response". Pathways were enriched in "Neuroactive ligand-receptor interaction", "AMPK signaling pathway" etc. JUN, TNF, IL1B,were the hub genes in the PPI network. Col1A1 and LRRC15 were screened out by multiple datasets and validated by experiments. Immune infiltration showed adipocytes and endothelial cells infiltrated less in lesioned samples. ConclusionOur research might provide valuable information for exploring the pathogenesis mechanism of OA and identifying the potential therapy targets for OA diagnosis.

molecular biology↗
bioRxiv2022

Mapping the adaptor protein complex interaction network in Arabidopsis identifies P34 as a common stability regulator

Adaptor protein (AP) complexes are evolutionarily conserved vesicle transport regulators that recruit coat proteins, membrane cargos and coated vesicle accessory proteins. Since in plants endocytic and post-Golgi trafficking intersect at the trans-Golgi network, unique mechanisms for sorting cargos of overlapping vesicular routes are anticipated. The plant AP complexes are part of the sorting machinery, but despite some functional information, their cargoes, accessory proteins, and regulation remain largely unknown. Here, by means of various proteomics approaches, we generated the overall interactome of the five AP and the TPLATE complexes in Arabidopsis thaliana. The interactome converged on a number of hub proteins, including the thus far unknown adaptin binding-like protein, designated P34. P34 interacted with the clathrin-associated AP complexes, controlled their stability and, subsequently, influenced clathrin-mediated endocytosis and various post-Golgi trafficking routes. Altogether, the AP interactome network offers substantial resources for further discoveries of unknown endomembrane trafficking regulators in plant cells.

plant biology↗
bioRxiv2022

Intestinal stem cell aging at single-cell resolution: functional perturbations alter cell developmental trajectory reversed by gerotherapeutics

The intestinal epithelium is consists of cells derived from continuously cycling Lgr5hi intestinal stem cells (Lgr5hi ISCs) that mature developmentally in an order fashion as the cells progress along the crypt-luminal axis. Perturbed function of Lgr5hi ISCs with aging is well documented but the consequent impact on overall mucosal homeostasis has not been defined. Using single-cell RNA sequencing, the progressive maturation of progeny was dissected in mouse intestine, which revealed that transcriptional reprogramming with aging in Lgr5hi ISCs retarded cell maturation in their progression along the crypt-luminal axis. Importantly, treatment with metformin or rapamycin at a late stage of mouse lifespan reversed the effects of aging on function of Lgr5hi ISCs and subsequent maturation of progenitors. The effects of metformin and rapamycin overlapped in reversing changes of transcriptional profiles, but were also complementary, with metformin more efficient than rapamycin in correcting the developmental trajectory. Therefore, our data identify novel effects of aging on stem cells and the maturation of their daughter cells contributing to the decline of functional Lgr5hi ISCs and the correction by geroprotectors.

cell biology↗
bioRxiv2022

A 4-bp natural deletion of maize Na+/H+ exchanger gene alters maize salt stress tolerance

Soil salinity is a major environmental constraint severely reducing plant growth and crop productivity worldwide. Knowledge of salt tolerance-related genes can facilitate improving crop salt tolerance and alleviating the threat of increasing saline area to world food security. Here, we identified a major locus SALT TOLERANCE 1 (qST1) conferring maize salt tolerance via bulked segregant RNA-Seq (BSR-Seq). qST1 encodes a plasma membrane Na+/H+ exchanger ZmSOS1 which is the ortholog of Arabidopsis thaliana SOS1 gene. In salt-sensitive variety D9H, the natural variation of 4-bp deletion in the coding sequence of ZmSOS1 gene was the causal allele for salt sensitivity. We identified two ethyl methanesulfonate-induced mutants, zmsos1-1 and zmsos1-2, which were sensitive to salt stress and cant complement salt-sensitive variety under salt stress within an allelism test. Overexpression of ZmSOS1 enhanced maize seedling salt tolerance. ZmSOS1 can increase the salt tolerance of Arabidopsis sos1-1 mutant and can be activated by AtSOS2 and AtSOS3 in yeast cells, suggesting that ZmSOS1 confers salt tolerance through the conserved SOS signaling pathway in maize. The detrimental allele harboring the 4-bp deletion was rarely found in the natural population but appeared in an important heterotic group composed of x1132x-derived inbred lines which have been used widely for breeding dozens of hybrid varieties in China. The 4-bp deletion-based molecular marker has been successfully used to improve salt-sensitive varieties in a backcross and marker-assisted breeding program by screening and purging this deleterious allele.

plant biology↗
bioRxiv2022

High-precision neural stimulation by a highly efficient candle soot fiber optoacoustic emitter

Highly precise neuromodulation with a high efficacy poses great importance in neuroscience. Here, we developed a candle soot fiber optoacoustic emitter (CSFOE), capable of generating a high pressure of over 10 MPa, enabling highly efficient neuromodulation in vitro. The design of the fiber optoacoustic emitter, including the choice of the material and the thickness of the layered structure, was optimized in both simulations and experiments. The optoacoustic conversion efficiency of the optimized CSFOE was found to be ten times higher than the other carbon-based fiber optoacoustic emitters. Driven by a single laser, the CSFOE can perform dual-site optoacoustic activation of neurons, confirmed by calcium (Ca) imaging. Our work opens potential avenues for more complex and programmed control in neural circuits using a simple design for multisite neuromodulation in vivo.

neuroscience↗
bioRxiv2022

High-resolution de novo structure prediction from primary sequence

Recent breakthroughs have used deep learning to exploit evolutionary information in multiple sequence alignments (MSAs) to accurately predict protein structures. However, MSAs of homologous proteins are not always available, such as with orphan proteins or fast-evolving proteins like antibodies, and a protein typically folds in a natural setting from its primary amino acid sequence into its three-dimensional structure, suggesting that evolutionary information and MSAs should not be necessary to predict a proteins folded form. Here, we introduce OmegaFold, the first computational method to successfully predict high-resolution protein structure from a single primary sequence alone. Using a new combination of a protein language model that allows us to make predictions from single sequences and a geometry-inspired transformer model trained on protein structures, OmegaFold outperforms RoseTTAFold and achieves similar prediction accuracy to AlphaFold2 on recently released structures. OmegaFold enables accurate predictions on orphan proteins that do not belong to any functionally characterized protein family and antibodies that tend to have noisy MSAs due to fast evolution. Our study fills a much-encountered gap in structure prediction and brings us a step closer to understanding protein folding in nature.

bioinformatics↗
bioRxiv2022

Biphasic response of CD8 T cell to asparagine restriction maximizes its metabolic fitness and antitumoral functionality

Robust and effective T cell immune surveillance and cancer immunotherapy require properly allocating metabolic resources to sustain energetically costly processes, including growth and cytokine production. Amino acids are major cellular constituents that serve as protein building blocks, energy sources, and signaling molecules. Although T cells can synthesize all nonessential amino acids, including asparagine (Asn), activated CD8 T cells still consume considerable quantities of exogenous Asn. Unexpectedly, Asn restriction on CD8 T cells induced a biphasic response, consisting of sequential actions with opposing effects at two conceptually separated phases after activation. Asn restriction suppressed activation and cell cycle entry in the early phase by depleting the intracellular Asn pool while rapidly engaging an ATF4/NRF2-dependent stress response, conferring robust proliferation and effector function of CD8 T cells in the late phase. Mechanistically, ATF4 and NRF2 activation rendered CD8 T cells to utilize de novo biosynthesis of Asn, consuming less glucose and glutamine but producing more intracellular nucleotides for proliferation. Moreover, NRF2 activation promoted the expression of inflammatory and effector genes to enhance effector functions in CD8 T cells. Accordingly, Asn restriction or overexpression of ATF4 or NRF2 potentiated T cell-mediated antitumoral response in the metabolically restricted tumor microenvironment. Our studies revealed Asn as a critical metabolic node in directing the stress signaling to shape T cell metabolic fitness and effector functions. Asn restriction is a promising and clinically relevant strategy to enhance cancer immunotherapy.

immunology↗
bioRxiv2022

Early life stress exposure increases susceptibility to high fat/high sucrose diet in female mice

Exposure to stress early in life has been associated with adult-onset co-morbidities such as chronic pain, metabolic dysregulation, obesity, and inactivity. We have established an early life stress model using neonatal maternal separation (NMS) in mice, which displays evidence of increased body weight and adiposity, widespread mechanical allodynia, and hypothalamic-pituitary-adrenal axis dysregulation in male mice. Early life stress and consumption of a western style diet contribute to the development of obesity, however, relatively few pre-clinical studies have been performed in female rodents, which are known to be protected against diet induced obesity and metabolic dysfunction. In this study we gave naive and NMS female mice access to a high-fat/high-sucrose (HFS) diet beginning at 4 weeks of age. Robust increases in body weight and fat were observed in HFS-fed NMS mice during the first 10 weeks on the diet, driven partly by increased food intake. Female NMS mice on a HFS diet showed widespread mechanical hypersensitivity compared to either naive mice on a HFS diet or NMS mice on a control diet. HFS diet-fed NMS mice also had impaired glucose tolerance and fasting hyperinsulinemia. Strikingly, female NMS mice on a HFS diet showed evidence of hepatic steatosis with increased triglyceride levels and altered glucocorticoid receptor levels and phosphorylation state. They also exhibited increased energy expenditure as observed via indirect calorimetry and expression of pro-inflammatory markers in perigonadal adipose. Altogether, our data suggest that early life stress exposure increased the susceptibility of female mice to develop diet-induced metabolic dysfunction and pain-like behaviors.

physiology↗
bioRxiv2022

Bioorthogonal in-cell Labeling and Profiling of N6-isopentenyladenosine (i6A) Modified RNA

Chemical modifications in RNAs play critical roles in structural diversification and functional regulation of many vital biochemical processes. Several hydrophobic prenyl-modifications have been discovered in a variety of RNA species since the 1990s. Prenyl groups are the feedstocks of terpene and many other biological molecules and the processes of prenylation in different macromolecules have been widely studied. We present here a new chemical biology technique to identify and label i6A, a prenyl-modified RNA residue, based on the unique reactivity of the prenyl group. We also found that iodine-mediated cycloaddition reactions of the prenyl group occurs in a superfast manner, and converts i6A from a hydrogen-bond acceptor into a donor. Based on this reactivity, we developed an iodine-mediated oxidation and reverse transcription (IMORT) method to profile cellular i6A residues with a single-base resolution, allowing for the transcriptome-wide detection and analysis of various i6A-containing RNA species.

biochemistry↗
bioRxiv2022

Post-vaccination Omicron infections induce broader immunity across antigenic space than prototype mRNA COVID-19 booster vaccination or primary infection

The rapid emergence of new SARS-CoV-2 variants challenges vaccination strategies. Here, we measured antigenic diversity among variants and interpreted neutralizing antibody responses following single and multiple exposures in longitudinal infection and vaccine cohorts. Antigenic cartography using primary infection antisera showed that BA.2, BA.4/BA.5, and BA.2.12.1 are distinct from BA.1 and closer to the Beta cluster. Three doses of an mRNA COVID-19 vaccine increased breadth to BA.1 more than to BA.4/BA.5 or BA.2.12.1. Omicron BA.1 post-vaccination infection elicited antibody landscapes characterized by broader immunity across antigenic space than three doses alone, although with less breadth than expected to BA.2.12.1 and BA.4/BA.5. Those with Omicron BA.1 infection after two or three vaccinations had similar neutralizing titer magnitude and antigenic breadth. Accounting for antigenic differences among variants of concern when interpreting neutralizing antibody titers aids understanding of complex patterns in humoral immunity and informs selection of future COVID-19 vaccine strains.

microbiology↗
bioRxiv2022

Rapid Regulation of Local Temperature and TRPV1 Ion Channels with Wide-Field Plasmonic Thermal Microscopy

Plasmonic absorption of light can create significant local heat and has become a promising tool for rapid temperature regulation in diverse fields, from biomedical technology to optoelectronics. Current plasmonic heating usually relies on specially designed nanomaterials randomly distributed in the space and hardly provides uniform temperature regulation in a wide field. Herein we report a rapid temperature regulation strategy on a plain gold-coated glass slip using the plasmonic scattering microscopy, which can be referred to as wide-field plasmonic thermal microscopy (W-PTM). We calibrated the W-PTM by monitoring the phase transition of the temperature-sensitive polymer solutions, showing that it can provide a temperature regulation range of 33-80 {degrees}C. Moreover, the W-PTM provides imaging capability, thus allowing the statistical analysis of the phase-transitioned polymeric nanoparticles. Finally, we demonstrated that W-PTM can be used for noninvasive and local regulation of the transient receptor potential vanilloid 1 (TRPV1) ion channels in the living cells, which can be monitored by simultaneous fluorescence imaging of calcium influx. With the nondestructive local temperature-regulating and concurrent fluorescence imaging capability, we anticipate that W-PTM can be a powerful tool to study cellular activities associated with cellular membrane temperature changes.

bioengineering↗
bioRxiv2022

A Long-Circulating Vector for Aptamers Based upon Polyphosphodiester-Backboned Molecular Brushes

Aptamers face challenges for use outside the ideal conditions in which they are developed. These difficulties are most palpable in vivo due to nuclease activities, rapid clearance, and off-target binding. Herein, we demonstrate that a polyphosphodiester-backboned molecular brush can suppress enzymatic digestion, reduce non-specific cell uptake, enable long blood circulation, and rescue the bioactivity of a conjugated aptamer in vivo. The backbone along with the aptamer is assembled via solid-phase synthesis, followed by installation of poly(ethylene glycol) (PEG) side chains using a two-step process with near-quantitative efficiency. The synthesis allows for precise control over polymer size and architecture. Consisting entirely of building blocks that are generally recognized as safe for therapeutics, this novel molecular brush is expected to provide a highly translatable route for aptamer-based therapeutics.

pharmacology and toxicology↗
bioRxiv2022

Liver Endothelium Microenvironment Promotes HER3-mediated Cell Growth in Pancreatic ductal adenocarcinoma

[~]90% metastatic pancreatic ductal adenocarcinoma (mPDAC) occurs in the liver, and the 5-year survival rate for patients with mPDAC is only at 3%. We previously reported that liver endothelial cells (ECs) secreted soluble factors to promote colorectal cancer cell survival in a paracrine fashion. However, the effects of liver ECs on mPDAC have not been elucidated. In this study, we used primary ECs from non-neoplastic liver tissues. We treated PDAC cells with conditioned medium (CM) from liver ECs, with CM from PDAC as controls, and determined that liver EC-secreted factors increased PDAC cell growth. Using an unbiased receptor tyrosine kinase array, we identified human epidermal growth factor receptor 3 (HER3, also known as ErbB3) as a key mediator in EC-induced growth in PDAC cells that have HER3 expression (HER3 +ve). We found that EC-secreted neuregulins activated the HER3-AKT signaling axis, and that depleting neuregulins from EC CM or blocking HER3 with an antibody, seribantumab, attenuated EC-induced proliferation in HER3 +ve PDAC cells, but not in cells without HER3 expression. Furthermore, we determined that EC CM increased PDAC xenograft growth in vivo, and that seribantumab blocked EC-induced growth in xenografts with HER3 expression. These findings elucidated a paracrine role of liver ECs in promoting PDAC cell growth, and identified the HER3-AKT axis as a key mediator in EC-induced functions in PDAC cells with HER3 expression. Implicationsover 70% mPDAC express HER3. This study suggests the potential of using HER3-targeted therapies for treating patients with HER3 +ve mPDAC.

cancer biology↗
bioRxiv2022

Oxysterols drive inflammation via GPR183 during influenza virus and SARS-CoV-2 infection

RationaleSevere viral respiratory infections are often characterized by extensive myeloid cell infiltration and activation and persistent lung tissue injury. However, the immunological mechanisms driving excessive inflammation in the lung remain elusive. ObjectivesTo identify the mechanisms that drive immune cell recruitment in the lung during viral respiratory infections and identify novel drug targets to reduce inflammation and disease severity. MethodsPreclinical murine models of influenza virus and SARS-CoV-2 infection. ResultsOxidized cholesterols and the oxysterol-sensing receptor GPR183 were identified as drivers of monocyte-macrophage infiltration to the lung during influenza virus (IAV) and SARS-CoV-2 infections. Both IAV and SARS-CoV-2 infections upregulated the enzymes cholesterol 25-hydroxylase (CH25H) and cytochrome P450 family 7 subfamily member B1 (CYP7B1) in the lung, resulting in local production of the oxidized cholesterols 25-hydroxycholesterol and 7,25-dihydroxycholesterol (7,25-OHC). Loss-of-function mutation of GPR183, or treatment with a GPR183 antagonist, reduced macrophage infiltration and inflammatory cytokine production in the lungs of IAV- or SARS-CoV-2-infected mice. The GPR183 antagonist also significantly attenuated the severity of SARS-CoV-2 infection by reducing weight loss and viral loads. ConclusionThis study demonstrates that oxysterols drive inflammation in the lung and provides the first preclinical evidence for therapeutic benefit of targeting GPR183 during severe viral respiratory infections. Author SummaryViral infections trigger oxysterol production in the lung, attracting macrophages via GPR183. Blocking GPR183 reduced inflammation and disease severity in SARS-CoV-2 infection, making GPR183 a putative target for therapeutic intervention.

immunology↗
bioRxiv2022

An atlas of spider development at single-cell resolution provides new insights into arthropod embryogenesis

Spiders are a diverse order of chelicerates that diverged from other arthropods over 500 million years ago. Research on spider embryogenesis, particular studies using the common house spider Parasteatoda tepidariorum, has made important contributions to understanding the evolution of animal development, including axis formation, segmentation, and patterning. However, we lack knowledge about the cells that build spider embryos, their gene expression profiles and fate. Single-cell transcriptomic analyses have been revolutionary in describing these complex landscapes of cellular genetics in a range of animals. Therefore, we carried out single-cell RNA sequencing of P. tepidariorum embryos at stages 7, 8 and 9, which encompass the establishment and patterning of the body plan, and initial differentiation of many tissues and organs. We identified 20 cell clusters, from 18.5k cells, which were marked by many developmental toolkit genes, as well as a plethora of genes not previously investigated. There were differences in the cell cycle transcriptional signatures, suggestive of different proliferation dynamics, which related to distinctions between endodermal and some mesodermal clusters, compared with ectodermal clusters. We found many Hox genes were markers of cell clusters, and Hox gene ohnologs often were present in different clusters. This provided additional evidence of sub- and/or neo-functionalisation of these important developmental genes after the whole genome duplication in the arachnopulmonate ancestor (spiders, scorpions, and allies). We also examined the spatial expression of marker genes for each cluster to generate a comprehensive cell atlas of these embryonic stages. This revealed new insights into the cellular basis and genetic regulation of head patterning, hematopoiesis, limb development, gut development, and posterior segmentation. This atlas will serve as a platform for future analysis of spider cell specification and fate, and studying the evolution of these processes among animals at cellular resolution.

developmental biology↗
bioRxiv2022

Triangulation fails when neither linguistic, genetic, nor archaeological data support the Transeurasian narrative

Robbeets et al.1 argue that the dispersal of the so-called "Transeurasian" languages, a highly disputed language superfamily comprising the Turkic, Mongolian, Tungusic, Koreanic, and Japonic language families, was driven by Neolithic farmers in the West Liao River region of China. They adduce evidence from linguistics, archaeology, and genetics to support their claim. An admirable feature of the Robbeets et al.s paper is that all their datasets can be accessed. However, a closer investigation of all three types of evidence reveals fundamental problems with each of them. Robbeets et al.s analysis of the linguistic data does not conform to the minimal standards required by traditional scholarship in historical linguistics and contradicts their own stated sound correspondence principles. A reanalysis of the genetic data finds that they do not conclusively support the farming-driven dispersal of Turkic, Mongolian, and Tungusic, nor the two-wave spread of farming to Korea. Their archaeological data contain little phylogenetic signal, and we failed to reproduce the results supporting their core hypotheses about migrations. Given the severe problems we identify in all three parts of the "triangulation" process, we conclude that there is neither conclusive evidence for a Transeurasian language family nor for associating the five different language families with the spread of Neolithic farmers from the West Liao River region.

genetics↗