Biology subjects

Du, Z.

Publications and source records attributed to Du, Z..

At least 55 records · Page 3Linked to original sources

bioRxiv2024

Experimental method for creating skin with acquired appendage dysfunction

Mammalian skin appendages, such as hair follicles and sweat glands, are essential for both esthetic and functional purposes. Conditions such as burns and ulcers can lead to dysfunction or loss of skin appendages and result in hair loss and dry skin, posing challenges in their regeneration. Existing animal models are insufficient for studying acquired dysfunction of skin appendages without underlying genetic causes. This study aimed to develop more clinically relevant mouse models by evaluating two approaches: keratinocyte transplantation and grafting of skin at varying thicknesses. GFP-expressing keratinocytes were transplanted into ulcers on nude mice, leading to re-epithelialization with minimal skin appendages at 4 weeks after transplantation. However, the re-epithelialized area was largely derived from recipient cells, with the grafted cells contributing to only 1.31% of the area. In the skin grafting model, donor skin from GFP transgenic mice was grafted onto nude mice at three thicknesses: full thickness, 10/1000 inch, and 5/1000 inch. The grafted area of the 5/1000-inch grafts remained stable at 89.5% of its original size 5 weeks after transplantation, ensuring a sufficiently large skin area. The 5/1000-inch grafts resulted in a significant reduction in skin appendages, with a mean of only 3.73 hair follicles per 5 mm, compared with 69.7 in the control group. The 5/1000-inch skin grafting in orthotopic autologous transplantation also showed the achievement of skin surfaces with a minimal number of skin appendages. Therefore, a mouse model with skin grafting demonstrated stability in producing large areas of skin with minimal appendages. In conclusion, these two models with acquired skin appendage dysfunction and no underlying genetic causes provide valuable tools for researching skin appendage regeneration, offering insights into potential therapeutic strategies for conditions involving skin appendage loss.

bioengineering↗

bioRxiv2024

Long read sequencing and assembly of wild diploid relatives and cultivars in support of banana breeding programs

Banana is an important fruit and staple crop, which is vital for food and income security in developing countries. A genomics initiative was undertaken as part of the Global Alliance against TR4 (Tropical Race 4 of Fusarium Wilt of Banana) Alliance, with Bayer Crop Science, International Institute of Tropical Agriculture, and University of Queensland to collectively accelerate the breeding efforts in Eastern Africa. The goal of this project is to develop genomics resources to improve banana breeding, productivity, and quality traits amid a changing climate and shifting disease pressures for breeding. Here, we present the PacBio HiFi sequencing, assembly, and comparative analysis of seven genomes of wild and edible diploid banana accessions belonging to subspecies considered important progenitors to cultivated banana varieties and part of breeding programs. This banana genome resource will help power genome editing, a pangenome effort, and conventional breeding programs for germplasm improvement.

genomics↗

bioRxiv2024

Stacked MXene/PEDOT-PSS Electrode Fiber for High-Performance Recording and Stimulation

The development of microelectrodes with high electrical performance is imperative, particularly for invasive interfaces such as deep brain stimulation (DBS) electrodes. MXene, a new family of 2D early transition metal carbides or nitrides, exhibits outstanding electrical properties and has been researched to improve bioelectronic interface. Through a wet spinning process, we fabricate MXene/PEDOT-PSS electrode fibers measuring 30 m in diameter, exhibiting an electrical conductivity of 2.16 {+/-} 1.46 x 10^5 S/m and notably low interfacial impedance. The excellent cathodic charge storage capacity (CSCc) and charge injection capacity (CIC) lead to their high performance in recording or stimulation. The electrode fibers are electrochemically stable, biocompatible, magnetic resonance imaging (MRI)-compatible, and demonstrate excellent performance in electromyography (EMG), electrocardiograph (ECG), cortical recording and subthalamic nuclei deep brain stimulation (STN-DBS) experiments.

bioengineering↗

bioRxiv2024

Enhancing Variant Calling in Whole Exome Sequencing (WES) Data Using Population-Matched Reference Genomes

Whole exon sequencing (WES) data are frequently used for cancer diagnosis and genome-wide association studies (GWAS), hinging upon high-coverage read mapping, informative variant calling, and high-quality reference genomes. The center position of the currently used genome assembly, GRCh38, is now challenged by two newly publicized telomere-to-telomere or T2T genomes, T2T-CHM13 and T2T-YAO, and it becomes urgent to have a comparative study to test population specificity using the three reference genomes based on real case WES data. We here report our analysis along this line for 19 tumor samples collected from Chinese patients. The primary comparison of the exon regions among the three references reveals that the sequences in up to [~]1% target regions in YAO are widely diversified from GRCh38 and may lead to off-target in sequence capture. However, YAO still outperforms GRCh38 genomes by obtaining 7.41% more mapped reads. Due to more reliable read-mapping and closer phylogenetic relationship with the samples than GRCh38, YAO reduces half of variant calls of clinical significance which are mostly benign while keeping sensitivity in identifying pathogenic variants. YAO also outperforms CHM13 in reducing calls of Chinese-specific variants. Our findings highlight the critical need for employing population-specific reference genomes in genomic analysis to ensure accurate variant analysis and the significant benefits of tailoring these approaches to the unique genetic backgrounds of each ethnic group.

genomics↗

bioRxiv2024

CLR_ESP: Improved enzyme-substrate pair prediction using contrastive learning

To reduce the cost of experimental characterization of the potential substrates for enzymes, machine learning prediction model offers an alternative solution. Pretrained language models, as powerful approaches for protein and molecule representation, have been employed in the development of enzyme-substrate prediction models, achieving promising performance. In addition to continuing improvements in language models, effectively fusing encoders to handle multimodal prediction tasks is critical for further enhancing model performance using available representation methods. Here, we present FusionESP, a multimodal architecture that integrates protein and chemistry language models with a newly designed contrastive learning strategy for predicting enzyme-substrate pairs. Our best model achieved state-of-the-art performance with an accuracy of 94.77% on independent test data and exhibited better generalization capacity while requiring fewer computational resources and training data, compared to previous studies of finetuned encoder or employing more encoders. It also confirmed our hypothesis that embeddings of positive pairs are closer to each other in high-dimension space, while negative pairs exhibit the opposite trend. The proposed architecture is expected to be further applied to enhance performance in additional multimodality prediction tasks in biology. A user-friendly web server of FusionESP is established and freely accessible at https://rqkjkgpsyu.us-east-1.awsapprunner.com/.

bioinformatics↗

bioRxiv2024

Intraperitoneal programming of tailored CAR macrophages via mRNA-LNP to boost cancer immunotherapy

Therapeutic strategies for peritoneal metastasis in solid tumors are urgently needed in the clinic. Programming chimeric antigen receptor macrophages (CAR-Ms) in situ offers opportunities for an unmet demand. However, potential intracellular domains (ICDs) for CAR design and their antitumor mechanisms for macrophage empowerment remain to be explored systematically. By developing a targeted mRNA-LNP delivery system for macrophages, we have investigated 36 CAR combinations to determine the impact of CAR-Ms on immune regulation in vitro and in vivo. In two solid tumor mouse models, intraperitoneal programming of CAR-Ms was shown to elicit robust adaptive immune activation and significantly synergize with PD-1/L1 therapy. Single-cell RNA sequencing (scRNA-seq) analysis revealed that CAR-Ms could reshape the immunosuppressive tumor microenvironment (TME) and boost the TCF1+PD-1+ progenitor- exhausted CD8+ T cells (Tpex) population. Meanwhile, we found that tailored CAR-M with CD3{zeta}/TLR4 ICDs could favorably maintain proinflammatory phenotype and simultaneously upregulate MHC I and PD-L1 expression by perturbing NF-{kappa}B pathways. Moreover, the synergism between macrophage PD-L1 knockdown and CAR-M therapy highlighted the need to block the PD-1/L1 axis in antigen cross-presentation. In short, we developed an mRNA-LNP delivery system for intraperitoneal programming of tailored CAR-Ms in vivo and broadened understanding of both regulatory and feedback mechanisms for CAR-M therapies against solid tumors.

bioengineering↗

bioRxiv2024

PhaSeDis: A Manually Curated Database of Phase Separation-Disease Associations and Corresponding Small Molecules

Biomacromolecules form membraneless organelles through liquid-liquid phase separation in order to regulate the efficiency of particular biochemical reactions. Dysregulation of phase separation might result in pathological condensation or sequestration of biomolecules, leading to diseases. Thus, phase separation and phase separating factors may serve as drug targets for disease treatment. Nevertheless, such associations have not yet been integrated into phase separation related databases. Therefore, based on MloDisDB, a database for membraneless organelle factor-disease association previously developed by our lab, we constructed PhaSeDis, the phase separation-disease association database. We increased the number of phase separation entries from 52 to 185, and supplemented the evidence provided by the original article verifying the phase separation nature of the factors. Moreover, we included the information of interacting small molecules with low or high-throughput evidence that might serve as potential drugs for phase separation entries. PhaSeDis strives to offer comprehensive descriptions of each entry, elucidating how phase separating factors induce pathological conditions via phase separation and the mechanisms by which small molecules intervene. We believe that PhaSeDis would be very important in the application of phase separation regulation in treating related diseases. PhaSeDis is available at http://mlodis.phasep.pro.

bioinformatics↗

bioRxiv2024

Global invasion history and genomic signatures of adaptation of a highly invasive lace bug

Invasive species cause enormous economic and ecological damage. Climate change has resulted in an unprecedented increase in the number and impact of invaders. The mechanisms underlying invasions, however, are largely unclear. The sycamore lace bug, Corythucha ciliata, is a highly invasive species that originated in North America. Its population has expanded over the Northern Hemisphere since the 1960s. In this study, we assemble the lace bugs genome using high-coverage PacBio, Illumina, and Hi-C sequencing. We identify 15,278 protein-coding genes and expansion of gene families with oxidoreductase and metabolic activities. In-depth resequencing of 402 samples collected from native and nine invasive countries across three continents identified 2.74 million single nucleotide polymorphisms. We resolve two major invasion routes of this lace bug from North America through both Europe and Japan, forming a contact zone in East Asia. Genomic signatures of selection associated with invasion and long-term balancing selection in native ranges are identified. These genomic signatures overlap with each other and the expanded genes, suggesting an improvement in the oxidative stress and thermal tolerance of this species. Our findings offer valuable insights into the genomic architecture and adaptive evolution underlying the invasive capabilities of species in the face of rapid environmental changes.

evolutionary biology↗

bioRxiv2024

High-precision photoacoustic neural modulation uses a non-thermal mechanism

Neuromodulation is a powerful tool for fundamental studies in neuroscience and potential treatments of neurological disorders. Both photoacoustic (PA) and photothermal (PT) effects have been harnessed for non-genetic high-precision neural stimulation. Using a fiber-based device excitable by a nanosecond pulsed laser and a continuous wave laser for PA and PT stimulation, respectively, we systematically investigated PA and PT neuromodulation at single neuron level. Our results show that the laser energy needed for PA neurostimulaion is 1/40 of that needed for PT stimulation to achieve the same level of cell response recorded by Ca2+ imaging. The threshold energy for PA stimulation is found to be further reduced in neurons overexpressing mechano-sensitive channels, indicating the direct involvement of mechano-sensitive channels in PA stimulation. Electrophysiology study of single neurons upon PA and PT stimulation was performed by patch clamp recordings. Electrophysiological features stimulated by PA are distinct from those induced by PT, confirming that PA and PT stimulations operate through distinct mechanisms. These insights offer a foundation for rational design of more efficient and safer non-genetic neural modulation approaches.

neuroscience↗

bioRxiv2024

Discovery of Waddington's developmental canals elucidates the embryogenesis stability in Caenorhabditis elegans

During embryogenesis, the cells in an embryo need to make numerous spatiotemporal decisions. However, there is inherent noise in each decision due to genetic or environmental fluctuations. How to suppress the noise accumulation to achieve stable embryonic end-products, a process known as Waddingtons developmental canalization, has been a major puzzle in biology since the 1940s. Previous studies have focused on the molecular noise within a cell instead of the cell noise within an embryo, thus providing indirect understandings (e,g., the well-known genetic capacitor Hsp90). In this study, we applied time-lapse microscopic imaging to capturing the spatiotemporal features of single cells, including cell position and cell cycle length, during the embryogenesis of approximately 2,100 Caenorhabditis elegans embryos exposed to various genetic or environmental perturbations. By treating the deviation of a cells spatiotemporal feature from the expected value as noise, we modeled the transmission of noise from each mother cell to their daughters. We discovered pervasive mother-daughter negative feedbacks, which collectively constitute continuous and comprehensive canals for suppressing noise accumulation along the developmental cell lineages, with the steepness (measuring noise suppression efficacy) and depth (measuring noise tolerance level) of the canals quantitatively defined. The learned quantitative rules enabled us to develop a cell-noise-based model that accurately predicts the nematode hatching phenotype, revealing how embryonic stochasticity could cause phenotypic disparity. With a high-dimensional mathematical tool we then proved the system stability of embryogenesis against the cell spatiotemporal noise. We also revealed several dozen canal-maintaining genes and proposed a novel association study framework that links embryonic cells rather than genetic variants with organismal traits. In sum, this study discovered and quantitatively characterized the developmental canals that directly stabilize embryogenesis in a metazoan, illuminating an 80-year-old puzzle and paving a way for studying the phenotypic plasticity and robustness of multicellular organisms from the perspective of embryogenesis.

developmental biology↗

bioRxiv2023

Effects of fructooligosaccharides and Saccharomyces boulardii on the compositional structure and metabolism of gut microbiota in students

Fructooligosaccharides (FOS) are a common prebiotic widely used in functional foods. Meanwhile, Saccharomyces boulardii is a fungal probiotic frequenly used in the clinical treatment of diarrhea. Compared with single use, the combination of prebiotics and probiotics may be more effective in regulating gut microbiota. Hence, the combined use of prebiotics and probiotics has become a hot spot in synbiotics research in recent years. The present study aimed to investigate the effects of FOS and S. boulardii-- alone or in combination--on the structure and metabolism of the gut microbiota in healthy primary and secondary school students using an in vitro fermentation model. The results indicated that S. boulardii alone could not effectively regulate the community structure and metabolism of the microbiota. However, both FOS and the combination of FOS and S. boulardii could effectively regulate the microbiota, significantly inhibiting the growth of Escherichia-Shigella and Bacteroides, and controlling the production of the gases including H2S and NH3. In addition, both FOS and the combination could significantly promote the growth of Bifidobacteria and Lactobacillus, lower environmental pH, and enhance several physiological functions related to synthesis and metabolism. Nevertheless, the combination had more unique benefits as it promoted the growth of Lactobacillus, significantly increased CO2 production and enhanced the functional pathways of carbon metabolism and pyruvic acid metabolism. These findings provide guidance for clinical application and a theoretical basis for the development of synbiotic preparations.

microbiology↗

bioRxiv2023

Correlation of a pan-tissue epigenetic mitotic clock with tumor cell-of-origin

The cumulative number of stem cell divisions in a tissue, known as mitotic age, is thought to be a major determinant of cancer-risk. Somatic mutational and DNA methylation (DNAm) clocks are promising tools to molecularly track mitotic age, yet their relationship is underexplored and their potential for cancer risk prediction in normal tissues remains to be demonstrated. Here we build and validate an improved pan-tissue DNAm counter of total mitotic age called stemTOC. We demonstrate that stemTOCs mitotic age proxy increases with the tumor cell-of-origin fraction in each of 15 cancer-types, in precancerous lesions, and in normal tissues exposed to major cancer risk factors. Extensive benchmarking against 6 other mitotic counters shows that stemTOC compares favorably, specially in the preinvasive and normal-tissue contexts. By cross-correlating stemTOC to two clock-like somatic mutational signatures, we confirm the mitotic-like nature of only one of these. Our data points towards DNAm as a promising molecular substrate for detecting mitotic-age increases in normal tissues and precancerous lesions, and hence for developing cancer-risk prediction strategies.

cancer biology↗

bioRxiv2023

Extracting herbicide and antibiotic natural products from a plant-microbe interaction system

Plants and their associated microbes live in complicated, changeable, and unpredictable environments. They usually interact with each other in many ways by proceeding in multi-dimensional, multi-scale and multi-level coupling manners, leading to challenges of the co-existence of randomness and determinism, or continuity and discreteness. Gaining a deeper understanding of these diverse interaction mechanisms can facilitate the development of new data mining theories and methods for complex systems, new coupled modelling for the system with different spatiotemporal scales and functional properties, or even universal theory of information and information interactions. In this study, we use a "close-loop" model to present a plant-microbe interaction system and describe the probable functions from the microbial natural products. Specifically, we report a rhizosphere species, Streptomyces ginsengnesis G7, which produces polyketide lydicamycins and other active metabolites. Interestingly, these distinct molecules have the potential to function both as antibiotics and herbicides for crop protection. Detailed laboratory experiments combined with comprehensive bioinformatics analysis allow us to rationalise a model for this specific plant-microbe interaction process. Our work reveals the benefits of exploring otherwise neglectable resources for the identification of novel functional molecules and provides a good reference to better understand the system biology in the complex ecosystems.

cell biology↗

bioRxiv2023

T2T-YAO: a Telomere-to-telomere Assembled Diploid Reference Genome for Han Chinese

Since its initial release in 2001, the human reference genome has been continuously improved in both continuity and accuracy, and the recently-released telomere-to-telomere version--T2T-CHM13--reaches its top quality after 20 years of effort. However, T2T-CHM13 does not represent an authentic diploid human genome, but rather one derived from a simplified, nearly homozygous genome of a hydatidiform mole cell line. To address this limitation and provide an alternative pertinent to the Chinese population, the largest ethnic group in the world, we have assembled a complete diploid human genome of a male Han Chinese, T2T-YAO, which includes telomere-to-telomere assemblies for all the 22+X+M and 22+Y chromosomes in his two haploids inherited separately from his parents. Both haplotypes contain no artificial sequences or model nucleotides and possess a high quality comparable to CHM13, with fewer than one error per [~]14 Mb. Derived from the individual who lives in the aboriginal region of Han Chinese, T2T-YAO shows clear ancestry and potential genetic continuity from the ancient ancestors of the Han population. Each haplotype of T2T-YAO possesses [~]340 Mb exclusive sequences and [~]3100 unique genes as compared to CHM13, and their genome sequences show greater genetic distance to CHM13 than to each other in terms of nucleotide polymorphism and structural variations. The construction of T2T-YAO would serve as a high-quality diploid reference that enables precise delineation of genomic variations in a haplotype-sensitive manner, which could advance our understandings in human evolution, hereditability of diseases and phenotypes, especially within the context of the unique variations of the Chinese population.

genetics↗

bioRxiv2023

Phosphorylation modulates estrogen receptor disorder by altering long-range hydrophobic interactions

Protein intrinsic disorder is coupled to a range of biological phenomena, from gene regulation to cancer progression. Phosphorylation of the estrogen receptor (ER) at Ser118 through its disordered N-terminal domain (NTD) activates its transcriptional function, but it is challenging to rationalize how this modification regulates ER activity. Using biophysical approaches of small-angle X-ray scattering and nuclear magnetic resonance spectroscopy, we demonstrate that Ser118 phosphorylation triggers long-range conformational changes in ER-NTD, particularly between two hydrophobic clusters of residual structures. Alanine substitution of hydrophobic amino acids near Ser118 produces similar conformational alterations and rescues impaired ER activity caused by a phosphorylation-deficient mutant. These findings establish a direct link between phosphorylation-induced conformational changes and the activation function of this disordered protein as a promising avenue to block ER transcriptional activation.

biophysics↗

bioRxiv2023

Pan-genome and Haplotype Map of Cultivars and Their Wild Ancestors Provides Insights into Adaptive Evolution of Cassava (Manihot esculenta Crantz)

Cassava is the most important starch sources, a tropical model crop. We constructed nearly T2T genomes of cultivar AM560, wild ancestors FLA4047 and W14, pan-genome of 24 representatives and a clarified evolutionary tree with 486 accessions. Comparison of SVs and SNVs between the ancestors and cultivated cassavas revealed predominant expansion, contraction of genes and gene families. Significantly selective sweeping occurred in the cassava genomes in 122 footprints with 1,519 candidate domestication genes. We identified selective mutations in MeCSK and MeFNR3 promoting photoreaction associated with MeNADP-ME of C4 assimilation in modern cassava. Co-evolved retardation of floral primordia and initiation of storage roots arose from MeCOL5 mutants with altered bindings to MeFT1, MeFT2 and MeTFL2. MebHLHs evolved to regulate the biosynthesis, transport and endogenous remobilization of cyanogenic glucosides, with new functionalities of MeMATE1, MeGTR in selected sweet cassava. These findings enhanced comprehensive knowledge and database on the evolution and breeding of cassava. HIGHLIGHTSO_LIThree nearly T2T cassava genomes of cultivar AM560 and its wild ancestors FLA4047 and W14. C_LIO_LIA species-level cassava panSV haplotype map across 346,322 structural variations over 31,362 gene families and 96,032,008 SNPs and InDels variations globally and a clarified evolutionary tree with 486 accessions. C_LIO_LISelective mutations in MeCSK and MeFNR3 promoted photoreaction associated with MeNADP-ME of C4 assimilation shaped the C3-C4 intermediate photosynthesis of modern cassava. C_LIO_LICoevolution of floral primordia contrary to initiated storage root is pivotal for the domestication of cassava, and arose from MeCOL5 mutants altered the binding with MeFT1, MeFT2 (SP6A), and MeTFL2. C_LI

systems biology↗

bioRxiv2023

SPPUSM: An MS/MS spectra merging strategy for improved low-input and single-cell proteome identification

Single and rare cell analysis provides unique insights into the investigation of biological processes and disease progress by resolving the cellular heterogeneity that is masked by bulk measurements. Although many efforts have been made, the techniques used to measure the proteome in trace amounts of samples or in single cells still lag behind those for DNA and RNA due to the inherent non-amplifiable nature of proteins and the sensitivity limitation of current mass spectrometry. Here, we report an MS/MS spectra merging strategy termed SPPUSM (same precursor-produced unidentified spectra merging) for improved low-input and single-cell proteome data analysis. In this method, all the unidentified MS/MS spectra from multiple test files are first extracted. Then, the corresponding MS/MS spectra produced by the same precursor ion from different files are matched according to their precursor mass and retention time (RT) and are merged into one new spectrum. The newly merged spectra with more fragment ions are next searched against the database to increase the MS/MS spectra identification and proteome coverage. Further improvement can be achieved by increasing the number of test files and spectra to be merged. Up to 18.2% improvement in protein identification was achieved for 1 ng HeLa peptides by SPPUSM. Reliability evaluation by the "entrapment database" strategy using merged spectra from human and E. coli revealed a marginal error rate for the proposed method. For application in single cell proteome (SCP) study, identification enhancement of 28%-61% was achieved for proteins for different SCP data. Furthermore, a lower abundance was found for the SPPUSM-identified peptides, indicating its potential for more sensitive low sample input and SCP studies.

molecular biology↗

bioRxiv2023

Vacuolar H+-ATPase Determines Daughter Cell Fates through Asymmetric Segregation of the Nucleosome Remodeling and Deacetylase Complex

Asymmetric cell divisions (ACDs) generate two daughter cells with identical genetic information but distinct cell fates through epigenetic mechanisms. However, the process of partitioning different epigenetic information into daughter cells remains unclear. Here, we demonstrate that the nucleosome remodeling and deacetylase (NuRD) complex is asymmetrically segregated into the surviving daughter cell rather than the apoptotic one during ACDs in Caenorhabditis elegans. The absence of NuRD triggers apoptosis via the EGL-1-CED-9-CED-4-CED-3 pathway, while an ectopic gain of NuRD enables apoptotic daughter cells to survive. We identify the vacuolar H+-adenosine triphosphatase (V-ATPase) complex as a crucial regulator of NuRDs asymmetric segregation. V-ATPase interacts with NuRD and is asymmetrically segregated into the surviving daughter cell. Inhibition of V-ATPase disrupts cytosolic pH asymmetry and NuRD asymmetry. We suggest that asymmetric segregation of V-ATPase may cause distinct acidification levels in the two daughter cells, enabling asymmetric epigenetic inheritance that specifies their respective life-versus-death fates.

cell biology↗