Biology subjects

Wang, D.

Publications and source records attributed to Wang, D..

At least 469 records · Page 26Linked to original sources

bioRxiv2022

An HBV mRNA vaccine with favorable virological suppression and superior immunity

BRIEF ABSTRACTHere we report on the development and comprehensive evaluations of an mRNA vaccine for chronic hepatitis B (CHB) treatment. In two different HBV carrier mouse models generated by viral vector-mediated HBV transfection (pAAV-HBV1.2 and rAAV8-HBV1.3), this vaccine demonstrates sufficient and persistent virological suppression, and robust immunogenicity in terms of induction of strong innate immune activation, high-level virus-specific antibodies, memory B cells and T cells. mRNA platform therefore holds prospects for therapeutic vaccine development to combat CHB.

immunology↗

bioRxiv2022

Systematic mining and genetic characterization of regulatory factors for wheat spike development

The spike architecture of wheat plays a crucial role in determining grain number, making it a key trait to optimize in wheat breeding programs. In this study, through a multi-omic approach, we analyzed the transcriptome and epigenome profiles of the shoot apex at eight developmental stages, revealing coordinated changes in chromatin accessibility and H3K27me3 abundance during the flowering transition. We constructed a core transcriptional regulatory network (TRN) that drives wheat spike formation, and experimentally validated a multi-layer regulatory module involving TaSPL15, TaAGLG1, and TaFUL2. By integrating the TRN with genome-wide association analysis (GWAS), we identified 227 transcription factors (TFs), including 42 with known functions and 185 with unknown functions. Further investigation of 61 novel TFs using multiple homozygous mutant lines uncovered 36 TFs with altered spike architecture or flowering time, such as TaMYC2-A1, TaMYB30-A1, and TaWRKY37-A1. Of particular interest, TaMYB30-A1, downstream and repressed by WFZP, was found to regulate fertile spikelet number. Notably, during the domestication and breeding process in China, the excellent haplotype of TaMYB30-A1 containing a C allele at the WFZP binding site was enriched, leading to improved agronomic traits. Our study presents novel and high-confidence regulators and offers an effective strategy for understanding the genetic basis of wheat spike development, with practical impact for wheat breeding applications.

plant biology↗

bioRxiv2022

Altering stimulus timing via fast rhythmic sensory stimulation induces STDP-like recall performance in human episodic memory

Animal studies suggest that the strength of synaptic modification depends on spike timing between pre- and post-synaptic neurons on the order of tens of milliseconds, which is termed spike-timing-dependent plasticity (STDP). However, evidence for STDP in human episodic memory is lacking. We investigated this using rhythmic sensory stimulation to drive visual and auditory cortices at 37.5 Hz with four phase offsets. Visual relative to auditory cued recall accuracy was significantly enhanced in the 90{degrees} condition since the visual stimulus led at the shortest delay (6.67 ms). This pattern was reversed in the 270{degrees} condition when the auditory stimulus led the shortest delay. Within cue modality, recall was enhanced when a stimulus of the corresponding modality led the shortest delay as compared to the longest delay (20 ms). Our findings provide novel evidence for STDP in human memory, which builds an important bridge from in-vitro studies in animals to human behaviour.

neuroscience↗

bioRxiv2022

Ratio-based quantitative multiomics profiling using universal reference materials empowers data integration

Multiomics profiling is a powerful tool to characterize the same samples with complementary features orchestrating the genome, epigenome, transcriptome, proteome, and metabolome. However, the lack of ground truth hampers the objective assessment of and subsequent choice from a plethora of measurement and computational methods aiming to integrate diverse and often enigmatically incomparable omics datasets. Here we establish and characterize the first suites of publicly available multiomics reference materials of matched DNA, RNA, proteins, and metabolites derived from immortalized cell lines from a family quartet of parents and monozygotic twin daughters, providing built-in truth defined by family relationship and the central dogma. We demonstrate that the "ratio"-based omics profiling data, i.e., by scaling the absolute feature values of a study sample relative to those of a concurrently measured universal reference sample, were inherently much more reproducible and comparable across batches, labs, platforms, and omics types, thus empower the horizontal (within-omics) and vertical (cross-omics) data integration in multiomics studies. Our study identifies "absolute" feature quantitation as the root cause of irreproducibility in multiomics measurement and data integration, and urges a paradigm shift from "absolute" to "ratio"-based multiomics profiling with universal reference materials.

systems biology↗

bioRxiv2022

CMOT: Cross Modality Optimal Transport for multimodal inference

Biological mechanisms are complex spanning multiple facets, each providing a unique view of the underlying mechanism. Recent single-cell technologies such as scRNA-seq and scATAC-seq have facilitated parallel probing into each of these facets, providing multimodal measurements of individual cells. An integrative analysis of these single-cell modalities can therefore provide a comprehensive understanding of specific cellular and molecular mechanisms. Despite the technological advances, simultaneous profiling of multiple modalities of single cells continues to be challenging as opposed to single modality measurements, and therefore, it may not always be feasible to conduct such profiling experiments (e.g., missing modalities). Furthermore, even with the available multimodalities, data integration remains elusive since modalities may not always have paired samples, leaving partial to no correspondence information. To address those challenges, we developed Cross-Modality Optimal Transport (CMOT), a computational approach to infer missing modalities of single cells based on optimal transport (OT). CMOT first aligns a group of cells (source) within available multi-modal data onto a common latent space. Then, it applies optimal transport to map the cells with a single modality (target) to the aligned cells in source from the same modality by minimizing their cost of transportation using Wasserstein distance. This distance can be regularized by prior knowledge (e.g., cell types) or induced cells clusters to improve mapping, and an entropy of transport to speed up OT computations. Once transported, CMOT uses K-Nearest-Neighbors to infer the missing modality for the cells in target from another modality of mapped cells in source. Furthermore, the alignment of CMOT works for partially corresponding information from multi-modalities, i.e., allowing a fraction of unmatched cells in source. We evaluated CMOT on several emerging multi-modal datasets, e.g., gene and protein expression and chromatin accessibility in developing brain, cancers, and immunology. We found that not only does CMOT outperform existing state-of-art methods, but its inferred gene expression is biologically interpretable such as classifying cell types and cancer types. Finally, CMOT is open source and available on our github: https://github.com/daifengwanglab/CMOT

bioinformatics↗

bioRxiv2022

JAMIE: Joint Variational Autoencoders for Multi-Modal Imputation and Embedding

Single-cell multimodal datasets have measured various characteristics of individual cells, enabling a deep understanding of cellular and molecular mechanisms. However, multimodal data generation remains costly and challenging, and missing modalities happen frequently. Recently, machine learning approaches have been developed for data imputation but typically require fully matched multimodalities to learn common latent embeddings that potentially lack modality specificity. To address these issues, we developed an open-source machine learning model, Joint Variational Autoencoders for multimodal Imputation and Embedding (JAMIE). JAMIE takes single-cell multimodal data that can have partially matched samples across modalities. Variational autoencoders learn the latent embeddings of each modality. Then, embeddings from matched samples across modalities are aggregated to identify joint cross-modal latent embeddings before reconstruction. To perform cross-modal imputation, the latent embeddings of one modality can be used with the decoder of the other modality. For interpretability, Shapley values are used to prioritize input features for cross-modal imputation and known sample labels. We applied JAMIE to both simulation data and emerging single-cell multimodal data including gene expression, chromatin accessibility, and electrophysiology in human and mouse brains. JAMIE significantly outperforms existing state-of-the-art methods in general and prioritized multimodal features for imputation, providing potentially novel mechanistic insights at cellular resolution.

bioinformatics↗

bioRxiv2022

Combined Developmental Toxicity Of Cyhalofop-butyl And Quizalofop-p-ethyl On The Zebrafish (Danio rerio) Embryos

Aryloxyphenoxypropionate herbicides have the characteristics of high efficiency, low toxicity, and safety to subsequent crops, and occupy an important position in the world herbicide market. Cyhalofop-butyl and quizalofop-p-ethyl are two representative herbicides, which are widely used in weed control. However, there is limited information on their combined toxicity to aquatic organisms. In this study, the developmental toxicity of cyhalofop-butyl and quizalofop-p-ethyl exposure in combination on zebrafish embryos was valuated to better understand the interaction between the that. The 96 h-LC50 (50% lethal concentration) of cyhalofop-butyl and quizalofop-p-ethyl on zebrafish embryos were 0.637 mg{middle dot}L-1 and 0.248 mg{middle dot}L-1, respectively. The combined effect of cyhalofop-butyl and quizalofop-p-ethyl was an antagonistic effect, and the 96 h-LC50 of zebrafish embryos was 1.043 mg{middle dot}L-1. Morphologically distinct pericardial edema and yolk cysts were observed after combined exposure, with significant effects on body length and heart rate in zebrafish embryos. At the same time, the mRNA levels of gene related to apoptosis and cardiac development also changed significantly. Therefore, we speculate that changes in genes related to apoptosis and cardiac development should be responsible for the abnormal development during embryonic development following co-exposure of cyhalofop-butyl and quizalofop-p-ethyl. HighlightsO_LICombined exposure caused deformities in zebrafish. C_LIO_LICombined exposure caused apoptosis in zebrafish. C_LIO_LICombined exposure altered the expression of apoptosis and cardiac-related genes in zebrafish. C_LI

pharmacology and toxicology↗

bioRxiv2022

Efficient Multi-Label Attribute Classification and Recognition of Microbiological Bacteria Based on Deep Learning and model fine-tuning

Bacterial vaginosis (BV) is the most common gynecological complaint affecting health of a large percentage of women worldwide. Traditional manual microscopy methods are expensive and time-consuming, to improve accuracy and efficiency, automated bacterial identification devices with detection intelligence algorithms are urgently needed. We propose a Fine-tuned SmallerVGG (FTS-VGG) deep convolutional network model based multi-label classification method for bacteria. Comparison experiments were deployed on several advanced backbone networks, including transfer learning on pre-trained VGG19, demonstrating that the proposed method achieves the advantages of being lighter, faster, more accurate and more efficient. Due to the high cost of time and expertise of experienced clinicians, we use random erasing for data augmentation to address the challenge of dataset collection and annotation, experiments demonstrate its robustness to occlusion. The proposed method has theoretical and practical implications, as well as the potential to be widely extended to other microscopic imaging applications.

biochemistry↗

bioRxiv2022

Inclusion Complexation of S-Nitrosoglutathione for Sustained NO Release and Reduced Device Infection

S-nitrosoglutathione (GSNO) is a non-toxic nitric oxide (NO)-donating compound that occurs naturally in the human body. The use of GSNO to deliver exogenous NO for therapeutic and protective applications is limited by the high lability of dissolved GSNO in aqueous formulations. In this paper, we report a host-guest chemistry-based strategy to modulate the GSNO reactivity and the NO release kinetics. Cyclodextrins (CDs) are host molecules that are typically used to encapsulate hydrophobic guest molecules into their hydrophobic cavities. However, we found that CDs form inclusion complexes with GSNO, an extremely hydrophilic molecule with a solubility of over 1 M at physiological pH. More interestingly, the host-guest complexation reduces the decomposition reactivity of GSNO in the order of CD > {gamma}CD > hydroxypropyl {beta}CD. The lifetime of 0.1 M GSNO is increased to up to 15 days in the presence of CDs at 37{degrees}C, which is more than twice the lifetime of free GSNO. Quantum chemistry calculations indicate that GSNO in CD undergoes a conformational change that significantly reduces the S-NO bond distance and increases its stability. The calculated S-NO bond dissociation enthalpies of free and complexed GSNO well agree with the experimentally observed GSNO decomposition kinetics. The NO release from GSNO-CD solutions, compared to GSNO solutions, has suppressed initial bursts and extended durations, enhancing the safety and efficacy of NO-based therapies and device protections. In an example application as an anti-infective lock solution for intravascular catheters, the GSNO-CD solution exhibits potent antibacterial activities for both planktonic and biofilm bacteria, both intraluminal and extraluminal environments, both prevention and treatment of infections, and against multiple bacterial strains including a multidrug-resistant strain. In addition to solutions, the inclusion complexation also enables the preparation of GSNO hydrogels with enhanced stability and improved antibacterial efficacy. Since methods to suppress and control the GSNO decomposition rate are rare, this supramolecular strategy provides new opportunities for the formulation and application of this natural NO donor.

biochemistry↗

bioRxiv2022

Correlation analysis between drug resistance and virulence genes of carbapenem-resistant Acinetobacter baumannii In Western Guilin

BackgoundIn order to detect the resistance of Acinetobacter baumannii to {beta}-lactam antibiotics in western Guilin, analyze the reasons for its resistance, and provide laboratory basis for clinical treatment; method for the {beta}-lactamase gene of Acinetobacter baumannii, and to explore the relationship between the presence of the {beta}-lactamase gene of Acinetobacter baumannii and multidrug resistance. MethodsFrom November 2020 to June 2022, 78 non-repeated Acinetobacter baumannii strains from the Second Affiliated Hospital of Guilin Medical University were collected, and their resistance to carbapenem antibiotics was analyzed. PCR was used to detect resistance-related genes (blaOXA-23, blaOXA-51, blaOXA-58, blaOXA-24, blaIMP and blaSIM) and virulence genes (cusE, abaI and bfmS). To analyze the relationship between drug resistance and virulence genes of Acinetobacter baumannii. ResultsMost of the 165 non-enterobacteriaceae bacteria we collected from the hospital were Acinetobacter baumannii and Pseudomonas aeruginosa, and most of the specimen types were from sputum and secretions, and most of them were from respiratory and critical care diseases area and intensive care unit, among them, there are 78 strains of Acinetobacter baumannii studied this time. After screening, 78 Acinetobacter baumannii strains were resistant to Cefazolin, Ampicillin, Amoxicillin/Clavulanate, Aztreonam, Chloramphenicol, Tetracycline, Cefotaxime, Ampicillin/Sulbactam, Piperacillin, Gentamicin, Ciprofloxacin, Levofloxacin, Moxifloxacin, Cefepime, Ceftazidime, Piperacillin/Tazobactam, Compound Sulfonamide, Meropenem, Imipenem, Amikacin, Polymyxin, resistance rates were 98.72%, 98.72%, 96.16%, 96.15%, 96.15%, 66.67%, 60.26%, 58.98%, 58.97%, 57.69%, 57.69%, 57.69%, 57.69%, 57.69%, 56.41%, 55.13%, 53.85%, 52.56%, 52.56%, 50%, 0%. Among them, 17 strains with drug resistance gene blaOXA-51 were detected,accounting for 21.79%; drug gene blaOXA-23, blaOXA-24, blaIMP, blaOXA-58, blaSIM gene were not detected; 17 strains with virulence gene bfmS was detected, accounting for 21.79%; abaI, csuE virulence gene was not detected. ConclusionAcinetobacter baumannii in the hospital is highly resistant to carbapenems, mainly carrying blaOXA-51 resistance genes. Drug resistance is closely related to the virulence gene bfmS.

microbiology↗

bioRxiv2022

Large scale interrogation of retinal cell functions by 1-photon light-sheet microscopy

Visual processing in the retina depends on the collective activity of large ensembles of neurons organized in different layers. Current techniques for measuring activity of layer-specific neural ensembles rely on expensive pulsed infrared lasers to drive 2-photon activation of calcium-dependent fluorescent reporters. Here, we present a 1-photon light-sheet imaging system that can measure the activity in hundreds of ex vivo retinal neurons over a large field of view while simultaneously presenting visual stimuli. This allowed for a reliable functional classification of different retinal ganglion cell types. We also demonstrate that the system has sufficient resolution to image calcium entry at individual synaptic release sites across the axon terminals of dozens of simultaneously imaged bipolar cells. The simple design, a large field of view, and fast image acquisition, make this a powerful system for high-throughput and high-resolution measurements of retinal processing at a fraction of the cost of alternative approaches.

neuroscience↗

bioRxiv2022

Control of lipolysis by a population of oxytocinergic sympathetic neurons

Oxytocin (OXT), a nine amino acid peptide produced in the hypothalamus and released by the posterior pituitary, has well-known actions in parturition, lactation, and social behavior1, and has become an intriguing therapeutic target for diseases like autism and schizophrenia2. Exogenous OXT has also been shown to promote weight loss, among other beneficial metabolic effects1,3, suggesting that its therapeutic potential may extend to diabetes and obesity1,4. It is unclear, however, whether endogenous OXT participates in metabolic homeostasis. Here we show that OXT is a critical regulator of adipose tissue lipolysis in both mice and humans. In addition, OXT serves to license the ability of {beta}- adrenergic agonists to fully promote lipolysis. Most surprisingly, the relevant source of OXT in these metabolic actions is a previously unidentified subpopulation of tyrosine hydroxylase (TH)-positive sympathetic neurons. Our data reveal that OXT from the peripheral nervous system is an endogenous regulator of adipose and systemic metabolism.

physiology↗

bioRxiv2022

Quartet DNA reference materials and datasets for comprehensively evaluating germline variants calling performance

Current methods for evaluating the accuracy of germline variant calls are restricted to easy-to-detect high-confidence regions, thus ignoring a substantial portion of difficult variants beyond the benchmark regions. We established four DNA reference materials from immortalized cell lines derived from a Chinese Quartet including parents and monozygotic twins. We integrated benchmark calls of 4.2 million small variants and 15,000 structural variants from multiple platforms and bioinformatic pipelines for evaluating the reliability of germline variant calls inside the benchmark regions. The genetic built-in-truth of the Quartet family design not only improved sensitivity of benchmark calls by removing additional false positive variants with apparently high quality, but also enabled estimation of the precision of variants calls outside the benchmark regions. Batch effects of variant calling in large-scale DNA sequencing efforts can be effectively identified with the concurrent use of the Quartet DNA reference materials along with study samples, and can be alleviated by training a machine learning model with the Quartet reference datasets to remove potential artifact calls. Matched RNA and protein reference materials were also established in the Quartet project, thereby enabling benchmark calls constructed from DNA reference materials for evaluation of variants calling performance on RNA and protein data. The Quartet DNA reference materials from this study are a resource for objective and comprehensive assessment of the accuracy of germline variant calls throughout the whole-genome regions.

bioinformatics↗

bioRxiv2022

Bioinformatic-based identification of 3 immune-related genes for prognostic in breast invasive carcinoma

Breast invasive carcinoma (BRCA) is the leading cause of cancer deaths in female worldwide. Immune cell infiltration is considered to be crucial factor for the success or failure of BRCA therapy. As we all known, early diagnosis of breast cancer can greatly improve the survival rate of patients. Hence, to screen effective biomarkers for breast cancer immunotherapy might be extremely important. In this research, we identified an immune-related, three-gene biomarkers for prognosis of BRCA. We obtained altogether 192 differentially expressed genes (DEGs) from GEO datasets (GSE22820, GSE36295) and GEPIA database, followed by the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. We screened 3 immune-related candidate biomarkers composing by CXCL2, CXCL9 and RBP7 that improves survival prediction outcome in BRCA. Kaplan-Meier analysis was conducted to analyze the patient survival based on 3 genes. In addition, we found that selected biomarkers were closely connected with infiltration levels of different tumor immune cells. Moreover, principal component analysis showed three biomarkers could effectively distinguish tumor samples from normal samples. In summary, these findings suggested that CXCL2, CXCL9 and RBP7 are viable prognostic and diagnostic biomarkers and provide new ideas for immunotherapy solutions of BRCA in the future.

bioinformatics↗

bioRxiv2022

Bone marrow hemogenic endothelial cells contribute multilineage hematopoietic progenitors in adult mice

During development, hematopoietic stem/progenitor cells (HSPCs) originate from a subset of hemogenic endothelial cells (ECs) through a process of endothelial-to-hematopoietic transition (EHT). This process is temporally restricted to short developmental windows and generates HSPC with distinct capabilities for hematopoiesis. Although it is generally thought that adult hematopoiesis is sustained by HSCs derived from hemogenic endothelium during development, some observations point to EHT persistence in the late fetus/perinatally. Here we use lineage tracking and bioinformatics analysis to assess the presence of hemogenic endothelial cells in the adult mouse. Our analysis identifies a subset of bone marrow-resident adult endothelial cells, characterized by the expression of VE-Cadherin and the transcription factor RUNX1, that produce CD45+ hematopoietic cells. This EHT generates hematopoietic progenitors, and mature myeloid and lymphoid cells in the adult mouse. Our results reveal the identification of a distinct source of adult blood.

cell biology↗

bioRxiv2022

Life-course social disparities in body mass index trajectories across adulthood: cohort study evidence from China Health and Nutrition Survey

BackgroundThe social disparities in obesity may originate in early life and adult social class. There are various developmental trajectories of overweight/obesity in adulthood. It is unclear how the intergenerational mobility of socioeconomic status influences adult overweight/obesity in China. MethodsWe used longitudinal data from ten waves of the China Health and Nutrition Survey (CHNS) between 1989 and 2015 for our analysis. The group-based trajectory modeling was used to identify BMI trajectories in adulthood. Multinomial logistic regression was adopted to assess the associations between SES and adult BMI trajectories. ResultsAmong a total of 3,138 participants, three latent clusters, including normal-stable BMI (51.4%), progressive overweight group (39.8%), and progressive obesity group (8.8%), were identified. High fathers occupational position, high participants occupation position and educational attainment, respectively, were associated with greater obesity risk. Compared to a stable low life course SES trajectory, a stable high life course SES trajectory was associated with a 2.35-fold risk of obesity, and upward and downward social mobility trajectories increased the risk for overweight/obesity. Individuals in the highest relative to the lowest life course cumulative socioeconomic score group had around twice risk of obesity. ConclusionsThe results emphasize the role of the high SES in early life and life-course SES accumulation, in the obesity intervention in China. FundingAll the work was supported by the National Natural Science Foundation of China (Grant Nos. 72174167, 81602928) and Natural Science Foundation of Shaanxi (2021JM-031).

scientific communication and education↗

bioRxiv2022

Genomic and transcriptional profiling stratifies VQ myeloma lines into two clusters with distinct risk signatures and drug responses

Multiple myeloma (MM) is a cancer of malignant plasma cells in the bone marrow and extramedullary sites. We previously characterized a VQ model for human high-risk MM. Different VQ lines display distinct disease phenotypes and survivals, suggesting significant intra-model variation. Here, we use whole exome sequencing and copy number variation (CNV) analysis coupled with RNA-Seq to stratify VQ lines into corresponding clusters: Cluster I VQ cells carried recurrent amplification of chromosome (chr) 3 and displayed upregulation of growth pathways and high-risk myeloma gene signatures, whereas Cluster II cells had monosomy chr5 and overexpressed genes and pathways associated with positive response to bortezomib (Btz) treatment in human MM patients. Consistently, in sharp contrast to Cluster II VQ cells that showed short-term response to Btz, Cluster I VQ cells were de novo resistant to Btz in vivo. Our study highlights Cluster I VQ lines as highly representative of human high-risk MM subset.

cancer biology↗

bioRxiv2022

The effector recognition by synthetic sensor NLR receptors requires the concerted action of multiple interfaces within and outside the integrated domain

Plant sensor nucleotide-binding leucine-rich repeat (NLR) receptors detect pathogen effectors through their integrated domains (IDs). The RGA5 sensor NLR recognizes its corresponding effectors AVR-Pia and AVR1-CO39 from the blast fungus Magnaporthe oryzae through direct binding to its heavy metal-associated (HMA) ID to trigger the RGA4 helper NLR-dependent resistance in rice. Here we report a mutant of RGA5 named RGA5HMA5 that confers complete resistance in transgenic rice plants to the M. oryzae strains expressing the noncorresponding effector AVR-PikD. RGA5HMA5 carries three engineered interfaces, two of which lie in the HMA ID and the other in the C-terminal Lys-rich stretch tailing the ID. However, the RGA5 variants having one or two of the three interfaces, including replacing all the Lys residues with Glu residues in the Lys-rich stretch, failed to activate RGA4-dependent cell death of rice protoplasts. Altogether, this work demonstrates that sensor NLRs require a concerted action of multiple surfaces within and outside the IDs to both recognize noncorresponding effectors and activate helper NLR-mediated resistance, and has implications in structure-guided designing of sensor NLRs.

plant biology↗