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Yao, J.

Publications and source records attributed to Yao, J..

At least 145 records · Page 8Linked to original sources

Activation of an injury-associated transient progenitor state in the epicardium is required for zebrafish heart regeneration

The epicardium, a mesothelial cell tissue that encompasses vertebrate hearts, supports heart regeneration after injury through paracrine effects and as a source of multipotent progenitors. However, the progenitor state in the adult epicardium has yet to be defined. Through single-cell RNA-sequencing of isolated epicardial cells from uninjured and regenerating adult zebrafish hearts, we defined the epithelial and mesenchymal subsets of the epicardium. We further identified a transiently activated epicardial progenitor cell (aEPC) subpopulation marked by ptx3a and col12a1b expression. Upon cardiac injury, aEPCs emerge from the epithelial epicardium, migrate to enclose the wound, undergo epithelial-mesenchymal transition (EMT), and differentiate into mural cells and pdgfra+hapln1a+ mesenchymal epicardial cells. These EMT and differentiation processes are regulated by the Tgf{beta} pathway. Conditional ablation of aEPCs blocked heart regeneration through reduced Nrg1 expression and mesenchymal cell number. Our findings identify a transient progenitor population of the adult epicardium that is indispensable for heart regeneration and highlight it as a potential target for enhancing cardiac repair.

developmental biology↗

Microbial nanowires with genetically modified peptide ligands to sustainably fabricate electronic sensing devices

Nanowires have substantial potential as the sensor component in electronic sensing devices. However, surface functionalization of traditional nanowire and nanotube materials with short peptides that increase sensor selectivity and sensitivity requires complex chemistries with toxic reagents. In contrast, microorganisms can assemble pilin monomers into protein nanowires with intrinsic conductivity from renewable feedstocks, yielding an electronic material that is robust and stable in applications, but also biodegradable. Here we report that the sensitivity and selectivity of protein nanowire-based sensors can be modified with a simple plug and play genetic approach in which a short peptide sequence, designed to bind the analyte of interest, is incorporated into the pilin protein that is microbially assembled into nanowires. We employed a scalable Escherichia coli chassis to fabricate protein nanowires that displayed either a peptide previously demonstrated to effectively bind ammonia, or a peptide known to bind acetic acid. Sensors comprised of thin films of the nanowires amended with the ammonia-specific peptide had a ca. 100-fold greater response to ammonia than sensors made with unmodified protein nanowires. Protein nanowires with the peptide that binds acetic acid yielded a 4-fold higher response than nanowires without the peptide. The results demonstrate that protein nanowires with enhanced sensor response for analytes of interest can be fabricated with a flexible genetic strategy that sustainably eliminates the energy, environmental, and health concerns associated with other common nanomaterials.

bioengineering↗

DeepAIR: a deep-learning framework for effective integration of sequence and 3D structure to enable adaptive immune receptor analysis

Structural docking between the adaptive immune receptors (AIRs), including T cell receptors (TCRs) and B cell receptors (BCRs), and their cognate antigens is one of the most fundamental processes in adaptive immunity. However, current methods for predicting AIR-antigen binding largely rely on sequence-derived features of AIRs, omitting the structure features that are essential for binding affinity. In this study, we present a deep-learning framework, termed DeepAIR, for the accurate prediction of AIR-antigen binding by integrating both sequence and structure features of AIRs. DeepAIR consists of three feature encoders (a trainable-embedding-layer-based gene encoder, a transformer-based sequence encoder, and a pre-trained AlphaFold2-based structure encoder), a gating-based attention mechanism to extract important features, and a tensor fusion mechanism to integrate obtained features. We train and evaluate DeepAIR on three downstream prediction tasks, including the prediction of AIR-antigen binding affinity, the prediction of AIR-antigen binding reactivity, and the classification of the immune repertoire. On five representative datasets, DeepAIR shows outstanding prediction performance in terms of AUC (area under the ROC curve) in predicting the binding reactivity to various antigens, as well as the classification of immune repertoire for nasopharyngeal carcinoma (NPC) and inflammatory bowel disease (IBD). DeepAIR is freely available for academic purposes at https://github.com/TencentAILabHealthcare/DeepAIR. We anticipate that DeepAIR can serve as a useful tool for characterizing and profiling antigen binding AIRs, thereby informing the design of personalized immunotherapy. HighlightsO_LIIntegrating predicted AIR structures using AlphaFold2 significantly improves the prediction accuracy of the binding reactivity between AIRs and antigens. C_LIO_LIDeepAIR is featured by a novel deep learning architecture that leverages both the gating-based attention mechanism and tensor fusion mechanism to effectively extract and integrate informative features from three feature encoders, including a trainable embedding-layer-based gene encoder, a transformer-based sequence encoder, and a pre-trained AlphaFold2-based structure encoder. C_LIO_LIDeepAIR is implemented as a biologically interpretable deep learning framework that highlights the key residues in both and {beta} chains that are critical for predicting the AIR-antigen binding. C_LI

immunology↗

Nardilysin-Regulated Scission Mechanism Activates Polo-like Kinase 3 to Suppress the Development of Pancreatic Cancer

Pancreatic ductal adenocarcinoma (PDAC) develops through step-wise genetic and molecular alterations including Kras mutation and inactivation of apoptotic pathways. Here, we find that development of anoikis resistance and metastasis of KrasG12D-driven PDAC in mice is accelerated by deleting Plk3, explaining the often reduced Plk3 expression in human PDAC. Importantly, a 41 kDa Plk3 (p41Plk3) that contained the entire kinase domain at the N-terminus (1-353 aa) is activated by scission of the precursor p72Plk3 at Arg354 by metalloendopeptidase Nardilysin (NRDC), and the resulting p32Plk3 C-terminal Polo-box domain (PBD) was quickly removed by proteasome degradation preventing the p41Plk3 inhibition by PBD. We found that p41Plk3 is the activated form of Plk3 that regulates a feedforward mechanism to promote anoikis and suppress PDAC and metastasis. p41Plk3 phosphorylates c-Fos on Thr164, which in turn, induces expression of Plk3 and pro-apoptotic genes. These findings uncovered an NRDC-regulated post-translational mechanism (PTM) that activates Plk3, establishing a prototypic regulation by scission mechanism.

cancer biology↗

Multi-Molecular Hyperspectral PRM-SRS Imaging

Lipids play crucial roles in many biological processes under physiological and pathological conditions. Mapping spatial distribution and examining metabolic dynamics of different lipids in cells and tissues in situ are critical for understanding aging and diseases. Commonly used imaging methods, including mass spectrometry-based technologies or labeled imaging techniques, tend to disrupt the native environment of cells/tissues and have limited spatial or spectral resolution, while traditional optical imaging techniques still lack the capacity to distinguish chemical differences between lipid subtypes. To overcome these limitations, we developed a new hyperspectral imaging platform that integrates a Penalized Reference Matching algorithm with Stimulated Raman Scattering (PRM-SRS) microscopy. With this new approach, we directly visualized and identified multiple lipid species in cells and tissues in situ with high chemical specificity and subcellular resolution. High density lipoprotein (HDL) particles containing non-esterified cholesterol was observed in the kidney, indicating that these pools of cholesterol are ectopic deposits, or have yet to be enriched. We detected a higher Cholesterol to phosphatidylethanolamine (PE) ratio inside the granule cells of hippocampal samples in old mice, suggesting altered membrane lipid synthesis and metabolism in aging brains. PRM-SRS imaging also revealed subcellular distributions of sphingosine and cardiolipin in the human brain sample. Compared with other techniques, PRM-SRS demonstrates unique advantages, including faster data processing and direct user-defined visualization with enhanced chemical specificity for distinguishing clinically relevant lipid subtypes in different organs and species. Our method has broad applications in multiplexed cell and tissue imaging.

bioengineering↗

Natural products lysobactin and sorangicin A show in vitro activity against Mycobacterium abscessus complex

The prevalence of lung disease caused by Mycobacterium abscessus is increasing among patients with cystic fibrosis. M. abscessus is a multidrug resistant opportunistic pathogen that is notoriously difficult to treat due to a lack of efficacious therapeutic regimens. Currently, there are no standard regimens, and treatment guidelines are based empirically on drug susceptibility testing. Thus, novel antibiotics are required. Natural products represent a vast pool of biologically active compounds that have a history of being a good source of antibiotics. Here, we screened a library of 517 natural products purified from fermentations of various bacteria and fungi against M. abscessus ATCC 19977. Lysobactin and sorangicin A were active against the M. abscessus complex and drug resistant clinical isolates. These natural products merit further consideration to be included in the M. abscessus drug pipeline.

microbiology↗

The Optimal Combination of Scanning Speed and Fiber-to-Stone Distance for Effective and Efficient Dusting during Holmium: YAG Laser Lithotripsy

ObjectivesTo investigate mechanistically the effects of fiber scanning speed (vfiber) and fiber tip-to-stone standoff distance (SD) on dusting efficiency during Holmium (Ho): YAG laser lithotripsy (LL) Materials and MethodsPre-soaked BegoStone samples (23 x 23 x 4 mm, W x L x H) were treated in water using a clinical Ho:YAG laser in dusting mode (0.2 J pulse energy delivered at 20 Hz frequency) at three different SDs (0.10, 0.25 and 0.50 mm) with vfiber in the range of 0 to 10 mm/s. Stone damage was quantified by optical coherence tomography, bubble dynamics were captured by high-speed imaging, and associated pressure transients were measured using a needle hydrophone. To compare photothermal ablation vs. cavitation in stone dusting, the experiments were further repeated in air (photothermal ablation only), and in water with the fiber tip advanced at a short (0.25 mm) offset distance (OSD) from a ureteroscope to mitigate the bubble collapse toward the stone surface, thus eliminating cavitation-induced damage. ResultsCompared to the craters produced by a stationary fiber, the damage troughs produced by a scanning fiber after 100 pulses were significantly larger in volume. The optimal vfiber for maximum dusting efficiency was found to be 3.5 mm/s for SD = 0.10 [~] 0.25 mm, resulting in long (17.5 mm), shallow (0.14 - 0.15 mm) and narrow (0.3 - 0.4 mm) troughs. In contrast, the maximum stone damage was produced at an optimal vfiber of 0.5 mm/s for SD = 0.50 mm, which generates much shorter (2.5 mm), yet deeper (0.35 mm) and wider (1.4 mm) troughs. Greater stone damage was produced in water than in air, especially at vfiber = 0 - 3.5 mm/s. With the scope end placed near the fiber tip, stone damage could be significantly reduced in water by 29% - 58% for SD = 0.10 mm, by 51% - 82% for SD = 0.25 mm, and by 66% - 100 % for SD = 0.50 mm, compared to those produced without the scope. Together, these findings suggest that cavitation plays an indispensable role in stone dusting by scanning treatment. Moreover, under clinically relevant vfiber (1 [~] 3 mm/s), dusting at SD = 0.5 mm (i.e., non-contact mode) may leverage higher frequency of the laser (e.g., 40 to 120 Hz) to harvest the full potential of cavitation damage while significantly reducing the procedure time, compared to its counterpart at SD = 0.1 mm (i.e., contact mode) that promotes photothermal ablation. ConclusionDusting efficiency during Ho:YAG LL may be substantially improved by utilizing the optimal combination of vfiber and SD for a given frequency.

bioengineering↗

Spatial-ID: a cell typing method for spatially resolved transcriptomics via transfer learning and spatial embedding

Spatially resolved transcriptomics (SRT) provides the opportunity to investigate the gene expression profiles and the spatial context of cells in naive state. Cell type annotation is a crucial task in the spatial transcriptome analysis of cell and tissue biology. In this study, we propose Spatial-ID, a supervision-based cell typing method, for high-throughput cell-level SRT datasets that integrates transfer learning and spatial embedding. Spatial-ID effectively incorporates the existing knowledge of reference scRNA-seq datasets and the spatial information of SRT datasets. A series of quantitative comparison experiments on public available SRT datasets demonstrate the superiority of Spatial-ID compared with other state-of-the-art methods. Besides, the application of Spatial-ID on a SRT dataset with 3D spatial dimension measured by Stereo-seq shows its advancement on the large field tissues with subcellular spatial resolution.

genomics↗

BigNeuron: A resource to benchmark and predict best-performing algorithms for automated reconstruction of neuronal morphology

BigNeuron is an open community bench-testing platform combining the expertise of neuroscientists and computer scientists toward the goal of setting open standards for accurate and fast automatic neuron reconstruction. The project gathered a diverse set of image volumes across several species representative of the data obtained in most neuroscience laboratories interested in neuron reconstruction. Here we report generated gold standard manual annotations for a selected subset of the available imaging datasets and quantified reconstruction quality for 35 automatic reconstruction algorithms. Together with image quality features, the data were pooled in an interactive web application that allows users and developers to perform principal component analysis, t-distributed stochastic neighbor embedding, correlation and clustering, visualization of imaging and reconstruction data, and benchmarking of automatic reconstruction algorithms in user-defined data subsets. Our results show that image quality metrics explain most of the variance in the data, followed by neuromorphological features related to neuron size. By benchmarking automatic reconstruction algorithms, we observed that diverse algorithms can provide complementary information toward obtaining accurate results and developed a novel algorithm to iteratively combine methods and generate consensus reconstructions. The consensus trees obtained provide estimates of the neuron structure ground truth that typically outperform single algorithms. Finally, to aid users in predicting the most accurate automatic reconstruction results without manual annotations for comparison, we used support vector machine regression to predict reconstruction quality given an image volume and a set of automatic reconstructions.

bioinformatics↗

Genetic admixture history and forensic characteristics of Tibeto-Burman-speaking Qiang people explored via the newly developed Y-STR panel and genome-wide SNP data

Fine-scale patterns of population genetic structure and diversity of ethnolinguistically diverse populations are important for biogeographical ancestry inference, kinship testing and also for the development and validation of new kits focused on forensic personal identification. Analyses focused on forensic markers and genome-wide SNP data can provide new insights into the origin, admixture processes and forensic characteristics of targeted populations. Qiang people with a large sample size among Tibeto-Burman-speaking populations widely reside in the middle latitude of the Tibetan Plateau. However, their genetic structure and forensic features have remained uncharacterized due to the paucity of comprehensive genetic analyses. Here, we first developed and validated the AGCU-Y30 Y-STR panel, which contains slowly and moderately mutating Y-STRs, and then we conducted comprehensive population genetic analyses based on Y-STRs and genome-wide SNPs to explore the admixture history of Qiang people and their neighbours. The validated results of this panel showed that the new Y-STR kit was sensitive and robust enough for forensic applications. Haplotype diversity (HD) ranging from 0.9932 to 0.9996 and allelic frequencies ranging from 0.001946 to 0.8326 in 514 Qiang people demonstrated that all included markers were highly polymorphic in Tibeto-Burman people. Population genetic analyses based on Y-STRs (RST, FST, MDS, NJ, PCA and MJNs) revealed that the Qiang people harboured a paternally close relationship with lowland Tibetan-Yi corridor populations. Furthermore, we made a comprehensive population admixture analysis among Eurasian modern and ancient populations based on the shared alleles. We determined that the Qiang people were a genetically admixed population and showed the closest relationship with Tibetan and Neolithic Yellow River farmers. Admixture modelling showed that Qiang people shared the primary ancestry with Tibetan and was derived from North China, supporting the hypothesis of common origin between Tibetan and Qiang people.

genetics↗

Group II Intron-Like Reverse TranscriptasesFunction in Double-Strand Break Repair by Microhomology-Mediated End Joining

Bacteria encode free-standing reverse transcriptases (RTs) of unknown function that are closely related to group II intron-encoded RTs. Here, we found that a Pseudomonas aeruginosa group II intron-like RT (G2L4 RT) with YIDD instead of YADD at its active site functions in DNA repair in its native host and when transferred into Escherichia coli. G2L4 RT has biochemical activities strikingly similar to those of human DNA repair polymerase{theta} and uses them for translesion DNA synthesis and double-strand break repair (DSBR) via microhomology-mediated end-joining (MMEJ) in vitro and in vivo. We also found that a group II intron RT can function similarly to G2L4 RT in DNA repair, with reciprocal substitutions at the active site showing an I residue favors MMEJ and an A residue favors primer extension in both enzymes. The DNA repair functions of these enzymes utilize conserved structural features of non-LTR-retroelement RTs, including human LINE-1 and other eukaryotic non-LTR-retrotransposon RTs, suggesting such enzymes may have an inherent ability to function in DSBR in a wide range of organisms.

molecular biology↗

Tyrosine phosphorylation tunes chemical and thermal sensitivity of TRPV2 ion channel

Transient receptor potential vanilloid 2 (TRPV2) is a multimodal ion channel widely regulating central and peripheral functions. Its important involvement in immune responses has been suggested such as in the macrophages phagocytosis process. However, the endogenous signaling cascades controlling the gating of TRPV2 remain to be understood. Here, we report that enhancing tyrosine phosphorylation remarkably alters the chemical and thermal sensitivities of TRPV2 endogenously expressed in rat bone marrow-derived macrophages. We identify that the protein tyrosine kinase JAK1 mediates TRPV2 phosphorylation at the molecular sites Tyr(335), Tyr(471), and Tyr(525). JAK1 phosphorylation is required for maintaining TRPV2 activity and the phagocytic ability of macrophages. We further show that TRPV2 phosphorylation is dynamically balanced by protein tyrosine phosphatase non-receptor type 1 (PTPN1). PTPN1 inhibition increases TRPV2 phosphorylation, further reducing the activation temperature threshold to [~]40 {degrees}C. Our data thus unveil an intrinsic mechanism where the phosphorylation/dephosphorylation dynamic balance sets the basal chemical and thermal sensitivity of TRPV2. Targeting this pathway will aid therapeutic interventions in physiopathological contexts.

physiology↗

Genomic insights into the phylogeny and biomass-degrading enzymes of rumen ciliates

Understanding the biodiversity and genetics of the gut microbiome has important implications for host physiology. One underexplored and elusive group is ciliated protozoa, which play crucial roles in regulating gut microbial interactions. Integrating single-cell sequencing and an assembly-and-identification pipeline, we acquired 52 high-quality ciliate genomes of 22 rumen morphospecies for all major abundant clades. With these genomes, we firstly resolved the taxonomic and phylogenetic framework that reclassified them into 19 species spanning 13 genera and reassigned the genus Dasytricha from Isotrichidae to a new family Dasytrichidae. Via extensive horizontal gene transfer and gene family expansion, rumen ciliates possess a broad array of enzymes to synergistically degrade plant and microbial carbohydrates. In particular, [~]80% of the degrading enzymes in Diplodiniinae and Ophryoscolecinae act on plant cell wall, and the high activities of their cellulase, xylanase and lysozyme reflect the potential of ciliate enzymes for biomass-conversion. Additionally, the new ciliate dataset greatly facilitated the rumen metagenomic analyses by allowing [~]12% of reads to be classified.

microbiology↗

Directed motor actions and choice signalling drive cortical acetylcholine dynamics.

Numerous cognitive functions including attention and learning are influenced by the dynamic patterns of acetylcholine release across the brain. How acetylcholine mediates these functions in cortex remains unclear, as the relationship between cortical acetylcholine and behavioral events has not been precisely measured across task learning. To dissect this relationship, we quantified motor behavior and sub-second acetylcholine dynamics in primary somatosensory and auditory cortex during rewarded sensory detection and discrimination tasks. We found that acetylcholine dynamics were directly attributable to goal-directed actions (whisker motion and licking), rather than delivery of sensory cues or rewards. As task performance improved across training, acetylcholine release associated with the first lick in a trial was strongly and specifically potentiated. These results show that acetylcholine dynamics in sensory cortex are driven by directed motor actions to gather information and act upon it.

neuroscience↗

Generating Electricity from Water Evaporation Through Microbial Biofilms

Sustainable strategies for energy production are required to reduce reliance on fossil fuels and to power electronics without generating toxic waste.1-7 Generating electricity from water evaporation through engineered materials is a promising approach,8,9 but power outputs have been low and the materials employed were not sustainably produced. Microorganisms can be mass produced with renewable feedstocks. Here, we demonstrate that it is possible to engineer microbial biofilms as a cohesive, flexible material for long-term continuous electricity production from evaporating water. The biofilm sheets were the functional component in devices that continuously produced power densities ([~]1 W/cm2) higher than that achieved with non-biological materials. Current production scaled directly with biofilm-sheet size and skin-patch devices harvested sufficient electricity from the moisture on skin to continuously power wearable devices. The results demonstrate that appropriately engineered biofilms can perform as robust functional materials without the need for further processing or maintaining cell viability. Biofilm-based hydroelectric current production was comparable to that achieved with similar sized biofilms catalyzing current production in microbial fuel cells,10,11 without the need for an organic feedstock or maintaining cell viability. The ubiquity of biofilms in nature suggests the possibility of additional sources of biomaterial for evaporation-based electricity generation and the possibility of harvesting electricity from diverse aqueous environments.

microbiology↗

scBERT: a Large-scale Pretrained Deep Langurage Model for Cell Type Annotation of Single-cell RNA-seq Data

Annotating cell types based on the single-cell RNA-seq data is a prerequisite for researches on disease progress and tumor microenvironment. Here we show existing annotation methods typically suffer from lack of curated marker gene lists, improper handling of batch effect, and difficulty in leveraging the latent gene-gene interaction information, impairing their generalization and robustness. We developed a pre-trained deep neural network-based model scBERT (single-cell Bidirectional Encoder Representations from Transformers) to overcome the challenges. Following BERTs approach of pre-train and fine-tune, scBERT obtains a general understanding of gene-gene interaction by being pre-trained on huge amounts of unlabeled scRNA-seq data and is transferred to the cell type annotation task of unseen and user-specific scRNA-seq data for supervised fine-tuning. Extensive and rigorous benchmark studies validated the superior performance of scBERT on cell type annotation, novel cell type discovery, robustness to batch effect, and model interpretability.

bioinformatics↗

Effects of short-term salinity exposure on haemolymph osmolality, gill morphology and Na+/K+ - ATPase activity in Solenaia oleivora

In order to explore the physiological reaction to hyperosmotic environment, Solenaia oleivora were exposed to 2.23{per thousand} salinity. In 48h, the hemolymph osmolality kept increasing, and the hemolymph protein concentration increased in the first 6h and then decreased significantly, while the free amino acid content increased in the first 24h and then kept stable (P < 0.05). The activity of Na+/K+-ATPase at 0h was significantly higher than other times in most organs except intestine, which was highest at 3h (P < 0.05). The ions concentration were also influenced. The concentration of Na+ rose in haemolymph, axe foot and intestine, but decreased in gill and hepatopancreas. In hemolymph, gill, hepatopancreases and adductor muscle, the K+ concentration was the highest at 0h, while in axe foot and intestine, it showed a positive tendency. The concentration of Cl- in haemolymph, adductor muscle, intestine and axe foot were positively correlated with treatment time, while hepatopancreas showed opposite tendency. High salinity stress caused a difference in the gill histological structure, the gill structure shrunk, the gill lamellas space and shrinking degree showed an enlarging trend with salinity treatment time.

animal behavior and cognition↗

STAYGREEN-mediated chlorophyll a catabolism is critical for photosystem stability upon heat stress in ryegrass

Chlorophyll (Chl) loss is one of the most visible symptoms of heat-induced leaf senescence, especially for cool-season grass species. Suppression of the Chl a Me-dechelatase gene, SGR (also named as nye1), blocked the degradation of Chl a and resulted in the stay-green trait during leaf senescence. However, effect of Chl a catabolism on plant tolerance to long-term moderate heat stress (35-40{degrees}C) remains unclear. In this study, we suppressed the expression of Chl a catabolic gene, LpSGR, in both constitutive and inducible manners in perennial ryegrass. Constitutive suppression of LpSGR aggravated heat stress-induced chloroplast structure and photosystem damages, disrupted energy utilization/dissipation during photosynthesis, activated ROS generation with weakened ROS-scavenging enzyme activities. Transcriptome comparison among wildtype (WT) and transgenic RNAi plants under either the optimum or high temperature conditions also emphasized the effect of Chl a catabolism on expression of genes encoding photosynthesis system, ROS-generation and scavenging system, and heat shock transcription factors. Furthermore, making use of a modified ethanol-inducible system, we generated stable transgenic perennial ryegrass to suppress LpSGR in an inducible manner. Without ethanol induction, these transgenic lines exhibited the same growth and heat tolerance traits to WT, while under the induction of ethanol spray, the transgenic lines also showed compromised heat tolerance. Taken together, our data suggest that Chl a catabolism is critical for energy dissipation and electron transfer in photosynthesis, ROS-balancing and chloroplast membrane system stability upon long-term moderate heat stress.

plant biology↗