Biology subjects

Pan, Y.

Publications and source records attributed to Pan, Y..

At least 199 records · Page 11Linked to original sources

bioRxiv2022

In vivo transomic analyses of glucose-responsive metabolism in skeletal muscle reveal core differences between the healthy and obese states

Metabolic regulation in skeletal muscle is essential for blood glucose homeostasis. Obesity causes insulin resistance in skeletal muscle, leading to hyperglycemia and type 2 diabetes. In this study, we performed multiomic analysis of the skeletal muscle of wild-type (WT) and genetically obese (ob/ob) mice, and constructed regulatory transomic networks for metabolism after oral glucose administration. Our network revealed that metabolic regulation by glucose-responsive metabolites had a major effect on WT mice, especially carbohydrate metabolic pathways. By contrast, in ob/ob mice, much of the metabolic regulation by glucose-responsive metabolites was lost and metabolic regulation by glucose-responsive genes was largely increased, especially in carbohydrate and lipid metabolic pathways. We present some characteristic metabolic regulatory pathways found in central carbon, branched amino acids, and ketone body metabolism. Our transomic analysis will provide insights into how skeletal muscle responds to changes in blood glucose and how it fails to respond in obesity.

systems biology↗

bioRxiv2022

A novel PLS1 c.981+1G>A variant causes autosomal-dominant hereditary hearing loss in a family via up-regulation of the PI3K-Akt signaling pathway

BackgroundThe fimbrin protein family contains a variety of proteins, of which Plastin1 (PLS1) is an important member. The latest researches show that variations in the coding region of PLS1 gene is related to the development of deafness. However, it remains unknown about the molecular mechanism of deafness caused by PLS1 gene variants. Methodswhole exome sequencing was performed on the affected family members and healthy ones to identify the pathogenic variants, followed by sanger sequencing. Minigene assay was conducted to investigate the impact of the variant on PLS1 mRNA splicing. The pathogenicity of the variant was further investigated in zebrafish. RNA-sequencing (RNA-seq) was done for analyzing the dysregulated downstream signaling pathways caused by knockdown of PLS1 expression. ResultsWe identified a novel variant PLS1 c.981+1G>A in a large Chinese family with hearing loss and demonstrated that the variant is responsible for the occurrence of hearing loss by inducing Exon8 skipping or deletion of Exon8 (47bp). The variant caused abnormal inner ear phenotypes, characterized by decreased mean otolith distance, anterior otolith diameter, posterior otolith diameter, and cochlear diameter, swimming speed and distance in zebrafish. Furthermore, silencing PLS1 expression significantly upregulated genes in the PI3K-Akt signaling pathway, including Col6a3, Spp1, Itgb3 and Hgf. ConclusionsPLS1 c.981+1G>A is a novel pathogenic variant for hearing loss by inducing Exon8 skipping or deletion of Exon8 (47bp). Up-regulation of the PI3K-Akt signaling pathway plays an important role in the pathogenesis of PLS-1 gene.

genetics↗

bioRxiv2022

A-type FHFs mediate resurgent currents through TTX-resistant voltage-gated sodium channels

Resurgent currents (INaR) produced by voltage-gated sodium channels are required for many neurons to maintain high-frequency firing, and contribute to neuronal hyperexcitability and disease pathophysiology. Here we show, for the first time, that INaR can be reconstituted in a heterologous system by co-expression of sodium channel -subunits and A-type fibroblast growth factor homologous factors (FHFs). Specifically, A-type FHFs induces INaR from Nav1.8, Nav1.9 tetrodotoxin-resistant neuronal channels and, to a lesser extent, neuronal Nav1.7 and cardiac Nav1.5 channels. Moreover, we identified the N-terminus of FHF as the critical molecule responsible for A-type FHFs-mediated INaR. Among the FHFs, FHF4A is the most important isoform for mediating Nav1.8 and Nav1.9 INaR. In nociceptive sensory neurons, FHF4A knockdown significantly reduces INaR amplitude and the percentage of neurons that generate INaR, substantially suppressing excitability. Thus, our work reveals a novel molecular mechanism underlying TTX-resistant INaR generation and provides important potential targets for pain treatment.

neuroscience↗

bioRxiv2022

Macrophage-derived VEGF-C decreases hematogenous metastatic dissemination by normalizing the tumor vasculature

Expression of pro-lymphangiogenic vascular endothelial growth factor C (VEGF-C) in primary tumors correlates with the occurrence of proximal lymph node metastasis in most solid cancer types. However, the role of VEGF-C in regulating tumor cell dissemination to distant organs is currently unclear. Perivascular tumor-associated macrophages (TAMs) are key regulators of hematogenous cancer cell spreading, forming tumor microenvironment of metastasis (TMEM) doorways for breast cancer cells to intravasate tumor blood vessels and fuel distant metastases. Using an experimental breast cancer (BC) model, we show here that TAMs expressing VEGF-C decrease cancer cell dissemination to the lung while enhancing lymph node metastasis. These TAMs express podoplanin and associate with normalized tumor blood vessels expressing VEGFR3. Further clinical data reveal that VEGF-C+ TAMs correlate inversely with malignant grade and with the occurrence of TMEM complexes in a cohort of BC patients. Thus, our study displays an apparently paradoxical role of VEGF-C expressing TAMs in redirecting cancer cells to preferentially disseminate to the lymph nodes, at least in part, by normalizing tumor blood vessels and promoting lymphangiogenesis.

cancer biology↗

bioRxiv2022

Interactive effect matters: a combination of herbivory degree and the ratio of generalist to specialist better predicts evolution of plant defense

Herbivory degree and the ratio of generalist to specialist herbivores have long been treated as two important but independent factors in shaping the evolution of plant defense. However, this assumption of independency is poorly supported and has resulted in great controversy in explaining the patterns of plant defense. Here we investigated the possible interaction between herbivory degree and generalist-to-specialist ratio using a cost-benefit model of defense evolution in plants. Our results showed that, with increasing generalist herbivore proportion, plant defense investment increases when herbivory degree is low and decreases when herbivory degree is high. These results provide the first theoretical support for the interactive effect of herbivory degree and ratio of generalist/specialist affecting plant defense, which integrate many of the previous results (e.g. latitudinal patterns of plant defense and defense evolution of invasive plants) and put them into a more general theoretical context.

evolutionary biology↗

bioRxiv2022

Cell- and non-cell-autonomous ARF3 coordinates meristem proliferation and organ patterning in Arabidopsis

In cell-cell communication, non-cell-autonomous transcription factors play vital roles in controlling plant stem cell fate. We previously reported that AUXIN RESPONSE FACTOR 3 (ARF3), a member of the ARF family with critical roles in floral meristem maintenance and determinacy, has a distinct accumulation pattern that differs from the expression domain of its encoding gene in the shoot apical meristem (SAM). However, the biological meaning of this difference is obscure. Here, we demonstrate that ARF3 expression is mainly activated at the periphery of the SAM by auxin, where ARF3 cell-autonomously regulates the expression of meristem-organ boundary-specific genes, such as CUP-SHAPED COTYLEDON1-3 (CUC1-3), BLADE ON PETIOLE1-2 (BOP1-2) and TARGETS UNDER ETTIN CONTROL3 (TEC3) to determine organ patterning. We also show that ARF3 is translocated into the organizing center, where it represses cytokinin activity and WUSCHEL expression to regulate meristem activity non-cell-autonomously. Therefore, ARF3 acts as a molecular link that mediates the interaction of auxin and cytokinin signaling in the SAM while coordinating the balance between meristem maintenance and organogenesis. Our findings reveal an ARF3-mediated coordination mechanism through cell-cell communication in dynamic SAM maintenance.

developmental biology↗

bioRxiv2022

Reduced mesophyll conductance by cell wall thickening and chloroplasts decreasing driven the decline of photosynthesis under sole NH4+ supply

The relationship between nitrogen (N) sources and photosynthetic capacity of leaf differs between species. However, the leaf anatomical variabilities related to photosynthesis (A) of shrubs under different forms of N remain imperfectly known. Here, Lonicera Japonica (a shrub) was grown hydroponically in the presence of three forms of N (sole NH4+, 50%/50% NH4+/NO3- and sole NO3-). A and photosynthetic N use efficiency significantly decreased under sole NH4+ supply, in parallel with down-regulated stomatal conductance (gs), mesophyll conductance (gm), and electron transfer rate (J). Up to the total A decline of 41.28% in sole NH4+ supply (compare with sole NO3-), the gm attributed to 60.3% of the total limitations. Besides, the decreased internal air space explained the increase of gas-phase resistance, and the increased liquid-phase resistance in sole NH4+ supply was ascribed to the thicker cell wall thickness (Tcw) and decreased chloroplasts exposed surface area per unit leaf area (Sc/S). The discrepancy of Sc/S could be interpreted by the altered chloroplasts numbers and the distance between adjacent chloroplasts (Dchl-chl). These results indicate the alteration of Tcw and chloroplast numbers were the main causes of the difference in gm in coping with varied N sources. HighlightCell wall and chloroplast variability determining the mesophyll conductance under different nitrogen forms

physiology↗

bioRxiv2021

Construction of a potent pan-vaccine based on the evolutionary tendency of SARS-CoV-2 spike protein.

SARS-CoV-2 continued to spread globally along with different variants. Here, we systemically analyzed viral infectivity and immune-resistance of SARS-CoV-2 variants to explore the underlying rationale of viral mutagenesis. We found that the Beta variant harbors both high infectivity and strong immune resistance, while the Delta variant is the most infectious with only a mild immune-escape ability. Remarkably, the Omicron variant is even more immune-resistant than the Beta variant, but its infectivity increases only in Vero E6 cells implying a probable preference for the endocytic pathway. A comprehensive analysis revealed that SARS-CoV-2 spike protein evolved into distinct evolutionary paths of either high infectivity plus low immune resistance or low infectivity plus high immune resistance, resulting in a narrow spectrum of the current single-strain vaccine. In light of these findings and the phylogenetic analysis of 2674 SARS-CoV-2 S-protein sequences, we generated a consensus antigen (S6) taking the most frequent mutations as a pan-vaccine against heterogeneous variants. As compared to the ancestry SWT vaccine with significantly declined neutralizations to emerging variants, the S6 vaccine elicits broadly neutralizing antibodies and full protections to a wide range of variants. Our work highlights the importance and feasibility of a universal vaccine strategy to fight against antigen drift of SARS-CoV-2.

microbiology↗

bioRxiv2021

Three heads are better than one: Cooperative learning brains wire together when a consensus is reached

Theories of human learning converge on the view that individuals working together learn better than do those working alone. Little is known, however, about the neural mechanisms of learning through cooperation. We addressed this research gap by leveraging functional near-infrared spectroscopy (fNIRS) to record the brain activity of triad members in a group simultaneously. Triads were instructed to analyze an ancient Chinese poem either cooperatively or independently. Four main findings emerged. First, we observed significant within-group neural synchronization (GNS) in the left superior temporal cortex, supramarginal gyrus, and postcentral gyrus during cooperative learning compared to independent learning. Second, the enhancement of GNS in triads was amplified when a consensus was reached (vs. elaboration or argument) during cooperative learning. Third, GNS was predictive of learning outcome at an early stage (156-170 s after learning was initiated). Fourth, social factors such as social closeness (e.g., how much learners liked one other) were reflected in GNS and co-varied with learning engagement. These results provide neurophysiological support for Piagets theory of cognitive development and favor the notion that successful learning through cooperation involves dynamic consensus building, which is captured in neural patterns shared across learners in a group. Significance StatementConverging evidence has shown that cooperative learning is more effective than independent learning. An influential pedagogical theory postulates that learners benefit from cooperation through different forms of cognitive elaboration, such as providing elaborated clarifications to others. Alternatively, Piagets theory of cognitive development posits that cooperation encourages learners with diverse opinions to reach a consensus during the learning process. Here, we report that unlike individuals who worked alone, the brains of students who worked cooperatively with one another became synchronized. This within-group neural synchronization (GNS) was magnified when learners built mutual consensuses. These findings suggest that successful cooperative learning involves dynamic consensus building, which is reflected in the interpersonal coordination of cerebral activity.

neuroscience↗

bioRxiv2021

Structure Insight into Photosystem I Octamer from Cyanobacteria

Diversity of photosystem oligomers is essential to understand how photosynthetic organisms adopted to light conditions. Given by the structural and physiological significance, the assemblies of PSI supercomplex is of great interest in both chloroplast and cyanobacteria recently. In this study, two novel photosystem I supercomplexes were isolated for the first time from the low light incubated culture of filamentous cyanobacterium Anabaena sp. PCC 7120. These complexes were defined as PSI hexamers and octamers through biochemical and biophysical characterization. Their 77K emission spectra indicated that the red forms of chlorophylls seemed not to be affected during oligomerization. By cryo-EM single particle analysis, a near-atomic (7.0 [A]) resolution structure of PSI octamer was resolved, and the molecular assemblies of stable PSI octamer was revealed.

biophysics↗

bioRxiv2021

Intronization enhances expression of S-protein and other transgenes challenged by cryptic splicing

The natural habitat of SARS-CoV-2 is the cytoplasm of a mammalian cell where it replicates its genome and expresses its proteins. While SARS-CoV-2 genes and hence its codons are presumably well optimized for mammalian protein translation, they have not been sequence optimized for nuclear expression. The cDNA of the Spike protein harbors over a hundred predicted splice sites and produces mostly aberrant mRNA transcripts when expressed in the nucleus. While different codon optimization strategies increase the proportion of full-length mRNA, they do not directly address the underlying splicing issue with commonly detected cryptic splicing events hindering the full expression potential. Similar splicing characteristics were also observed in other transgenes. By inserting multiple short introns throughout different transgenes, significant improvement in expression was achieved, including >7-fold increase for Spike transgene. Provision of a more natural genomic landscape offers a novel way to achieve multi-fold improvement in transgene expression.

genetics↗

bioRxiv2021

Impaired photoprotection in Phaeodactylum tricornutum KEA3 mutants reveals the proton regulatory circuit of diatoms light acclimation.

Diatoms are amongst the most successful clades of oceanic phytoplankton, significantly contributing to photosynthesis on Earth. Their ecological success likely stems from their ability to acclimate to changing environmental conditions, including e.g. variable light intensity. Diatoms are outstanding at dissipating light energy exceeding the maximum photosynthetic electron transfer (PET) capacity of via Non Photochemical Quenching (NPQ). While the molecular effectors of this process, as well as the role of the Proton Motive Force (PMF) in its regulation are known, the putative regulators of the PET/PMF relationship in diatoms remain unidentified. Here, we demonstrate that the H+/K+ antiporter KEA3 is the main regulator of the coupling between PMF and PET in the model diatom Phaeodactylum tricornutum. By controlling the PMF, it modulates NPQ responses at the onset of illumination, during transients and in steady state conditions. Under intermittent light KEA3 absence results in reduced fitness. Using a parsimonious model including only two components, KEA3 and the diadinoxanthin de-epoxidase, we can describe most of the feedback loops observed between PET and NPQ. This two-components regulatory system allows for efficient responses to fast (minutes) or slow (e.g. diel) changes in light environment, thanks to the presence of a regulatory Ca2+-binding domain in KEA3 that controls its activity. This circuit is likely finely tuned by the NPQ effector proteins LHCX, providing diatoms with the required flexibility to thrive in different ocean provinces. One sentence summaryThe author(s) responsible for distribution of materials integral to the findings presented in this article in accordance with the policy described in the Instructions for Authors (https://academic.oup.com/plcell/pages/General-Instructions) is Giovanni Finazzi.

plant biology↗

bioRxiv2021

Spermidine dampens inflammation by directly inhibiting Th17 cytokine production through a PRDX1 associated antioxidant pathway

The activation of IL-17 signaling has been linked to the pathogenesis of many chronic, inflammatory lung diseases including Cystic Fibrosis (CF). Through unbiased single-cell RNAseq screening, we found that IL-17+ T cells highly express Srm and Smox, which encode two key enzymes for spermidine synthesis. Spermidine has been shown to reduce inflammation by regulating macrophage activation and balancing Th17/Treg differentiation, but its direct effects on Th17 cytokine production has not been carefully investigated. Here, using already differentiated Th17 cells from cultured mouse splenocytes, we found that exogenous spermidine directly inhibits IL-1{beta}/IL-23 induced IL-17 production. Blockade of endogenous spermidine synthesis enhanced IL-17 production above native levels, further supporting that spermidine is a direct regulator of cytokine secretion independent of differentiation. In vivo, spermidine alleviates lung inflammation in both PA infection and LPS induced acute lung injury models. Further RNA-seq analysis suggests spermidine suppression of Th17 cytokine production is mediated through its PRDX1 dependent antioxidant activity. Our data establishes that spermidine is a direct regulator of Type-17 T cell cytokine production and has potent anti-inflammatory effects against lung inflammation.

immunology↗

bioRxiv2021

The Need for Transfer Learning in CRISPR-Cas Off-Target Scoring

MotivationThe scalable design of safe guide RNA sequences for CRISPR gene editing depends on the computational "scoring" of DNA locations that may be edited. As there is no widely accepted benchmark dataset to compare scoring models, we present a curated "TrueOT" dataset that contains thoroughly validated datapoints to best reflect the properties of in vivo editing. Many existing models are trained on data from high throughput assays. We hypothesize that such models may suboptimally transfer to the low throughput data in TrueOT due to fundamental biological differences between proxy assays and in vivo behavior. We developed new Siamese convolutional neural networks, trained them on a proxy dataset, and compared their performance against existing models on TrueOT. ResultsOur simplest model with a single convolutional and pooling layer surprisingly exhibits state-of-the-art performance on TrueOT. Adding subsequent layers improved performance on a proxy dataset while compromising performance on TrueOT. We demonstrate improved generalization on TrueOT with a Siamese model of higher complexity when we apply transfer learning techniques. These results suggest an urgent need for the CRISPR community to agree upon a benchmark dataset such as TrueOT and highlight that various sources of CRISPR data cannot be assumed to be equivalent. Availability and ImplementationOur code base and datasets are available on GitHub at github.com/baolab-rice/CRISPR_OT_scoring.

bioinformatics↗

bioRxiv2021

ITRAQ-based quantitative proteomic analysis of japonica rice seedling during cold stress

Low temperature is one of the important environmental factors that affect rice growth and yield. To better understand the japonica rice responses to cold stress, isobaric tags for relative and absolute quantification (iTRAQ) labeling based quantitative proteomics approach was used to detected changes in protein level. Two-week-old seedlings of the cold tolerance rice variety Kongyu131 were treated at 8{degrees}C for 24, 48 and 72 h, then the total proteins were extracted from tissues and used for quantitative proteomics analysis. A total of 5082 proteins were detected for quantitative analysis, of which 289 proteins were significantly regulated, consisting of 169 uniquely up-regulated proteins and 125 uniquely down-regulated proteins in cold stress groups relative to control group. Functional analysis revealed most of regulation proteins involved in photosynthesis, metabolic pathway, biosynthesis of secondary metabolites and carbon metabolism. Western blot analysis showed that protein regulation was consistent with the iTRAQ data. The corresponding genes of 25 regulation proteins were used for quantitative real time PCR analysis, and the results showed that the mRNA level was not always parallel to the corresponding protein level. The importance of our study is providing new insights into cold stress responses in rice on proteomic aspect.

plant biology↗

bioRxiv2021

Enhanced soil quality after forest conversion to vegetable cropland and tea plantation has contrasting effects on soil microbial structure and functions

Land-use changes could potentially exert a strong influence on soil quality and soil microbial communities. Moreover, microbial taxa are also important drivers of soil ecological functions. However, the linkage between soil quality and soil microbial communities is in need of deeper understanding. In this study, we examined the effects of soil quality on microbial community structure and functions after forest conversion to vegetable cropland and tea plantations. Soil quality index was significantly increased after natural forest conversion to vegetable cropland and tea plantations. Soil bacterial beta diversity significantly correlated to soil quality, but the sensitivity of individual microbial groups varied in response to changes in soil quality. Higher soil quality promoted bacterial diversity in vegetable cropland but decreased it in tea plantations, which implied soil quality was a structural factor in bacterial community composition but had contrasting effects for croplands versus plantations. Agricultural management played a negative role in maintaining microbial interactions, as identified by the network analysis, and furthermore the analysis revealed key functions of the microbial communities. After land-use change, the abundance (e.g., level, intensity) of microbial N-cycling function increased in tea plantations but decreased in vegetable cropland. The abundance of C-cycling function featured an opposite trend. Higher level of N-fixation in tea plantations but the higher abundance of N-oxidation in vegetable cropland was demonstrated. Higher abundance of ammonia-oxidizing bacteria and ammonia-oxidizing archaea as identified by qPCR in vegetable cropland corroborated the FAPROTAX function prediction. Therefore, the key taxa of soil microbial communities and microbial functions were largely dependent on changes in soil quality and determined responses to specific agricultural management.

ecology↗

bioRxiv2021

Genome-wide identification and characterization of DNA/RNA differences associated with Fusarium graminearum infection in wheat

RNA editing (DNA/RNA differences) as a post-transcriptional modification approach to enrich genetic information, plays the crucial role in regulating diverse biological processes in eukaryotes. Although it has been extensively studied in plant chloroplast and mitochondria genome, RNA editing in plant nuclear genome, especially those associated with Fusarium head blight (FHB), is not well studied at present. Here, we investigated the DNA/RNA differences associated with FHB through a novel method by comparing the RNA-seq data from Fusarium-infected and control samples from 4 wheat genotypes. A total of 187 DNA/RNA differences were identified in 36 wheat genes, representing the first landscape of the FHB-responsive RNA editome in wheat. Furthermore, all of these 36 edited genes were located in the FHB related co-expression gene modules, which may involve in regulating FHB response. Finally, the effects of DNA/RNA differences were systematically investigated to show that they could cause the change of RNA structure and protein structure in edited genes. In particular, the G to C editing (chr3A_487854715) in TraesCS3A02G263900, which is the orthology of OsRACK1, resulted that it was targeted by tae-miR9664-3p to control its expression in different genotype through different editing efficiency, suggesting RNA editing could mediate miRNA to participate in the regulation network of FHB tolerance. This study reported the first wheat DNA/RNA differences associated with FHB, which not only contribute to better understand the molecular basis underlying FHB tolerance, but also shed light on improving FHB tolerance through epigenetic method in wheat and beyond.

plant biology↗

bioRxiv2021

Foot scales in the Early Cretaceous bird Gansus yumenensis from China

Most modern birds have scales covering the foot and feathers elsewhere. Discoveries of fossil feathers attached to the metatarsus in non-avian dinosaurs and basal birds suggests that the avian scales are secondarily derived from feathers. However, our knowledge of early avian scales and their taphonomy is still limited, due to the scarcity of fossil record. Here we employ multiple techniques to characterize the morphological and chemical details preserved and investigate how they are preserved in the skin of IVPP V15077, a referred specimen of the Early Cretaceous Gansus yumenensis. Results show that two types of scales, scutellate and interstitial scales, are preserved in IVPP V15077, which, in combination with previous discovery of scutate and reticulate scales in other Early Cretaceous birds, indicates that all four types of scales present in modern birds have appeared in the Early Cretaceous. SEM observations and Raman analysis suggest that the skin of Gansus yumenensis may be pigmented. Elemental mapping indicates that aluminosilicates and calcium phosphate are involved in the mineralization of the skin.

paleontology↗