bioRxiv Science⌕ Search

Biology subjects

Zheng, M.

Publications and source records attributed to Zheng, M..

At least 73 records · Page 4Linked to original sources

An RGB based deep neural network for high fidelity Fusarium head blight phenotyping in wheat

Fusarium head blight (FHB) in wheat is an economically important disease, which can cause yield losses exceeding 50% and the causal pathogen that infects spikes produces harmful mycotoxins. Breeding for host resistance remains the most effective disease control method; but time, labor, and human subjectivity during disease scoring limits selection advancements. In this study we describe an innovative, high-throughput phenotyping rover for capturing in-field RGB images and a deep neural network pipeline for wheat spike detection and FHB disease quantification. The image analysis pipeline successfully detects wheat spikes from images under variable field conditions, segments spikes and diseased tissue in the spikes, and quantifies disease severity as the region of intersection between spike and disease masks. Model inferences on an individual spike and plot basis were compared to human visual disease scoring in the field and on imagery for model evaluation. The precision and throughput of the model surpassed traditional field rating methods. The accuracy of FHB severity assessments of the model was equivalent to human disease annotations of images, however individual spike disease assessment was influenced by field location. The model was able to quantify FHB in images taken with different camera orientations in an unseen year, which demonstrates strong generalizability. This innovative pipeline represents a breakthrough in FHB phenotyping, offering precise and efficient assessment of FHB on both individual spikes and plot aggregates. The model is robust to different conditions and the potential to standardize disease evaluation methods across the community make it a valuable tool for studying and managing this economically significant fungal disease.

plant biology↗

Hippo-deficient cardiac fibroblasts differentiate into osteochondroprogenitors

Cardiac fibrosis, a common pathophysiology associated with various heart diseases, occurs from the excess deposition of extracellular matrix (ECM)1. Cardiac fibroblasts (CFs) are the primary cells that produce, degrade, and remodel ECM during homeostasis and tissue repair2. Upon injury, CFs gain plasticity to differentiate into myofibroblasts3 and adipocyte-like4,5 and osteoblast-like6 cells, promoting fibrosis and impairing heart function7. How CFs maintain their cell state during homeostasis and adapt plasticity upon injury are not well defined. Recent studies have shown that Hippo signalling in CFs regulates cardiac fibrosis and inflammation8-11. Here, we used single-nucleus RNA sequencing (snRNA-seq) and spatially resolved transcriptomic profiling (ST) to investigate how the cell state was altered in the absence of Hippo signaling and how Hippo-deficient CFs interact with macrophages during cardiac fibrosis. We found that Hippo-deficient CFs differentiate into osteochondroprogenitors (OCPs), suggesting that Hippo restricts CF plasticity. Furthermore, Hippo-deficient CFs colocalized with macrophages, suggesting their intercellular communications. Indeed, we identified several ligand-receptor pairs between the Hippo-deficient CFs and macrophages. Blocking the Hippo-deficient CF-induced CSF1 signaling abolished macrophage expansion. Interestingly, blocking macrophage expansion also reduced OCP differentiation of Hippo-deficient CFs, indicating that macrophages promote CF plasticity.

developmental biology↗

Synergistic efficacy of tigecycline combined with apramycin against tet(X)-harboring Acinetobacter spp.

The emergence of the wide variety of novel tigecycline resistance tet(X) variants including tet(X3), tet(X4), tet(X5) and tet(X6) has posed a significant challenge to the clinical treatment of multidrug-resistant bacterial infections and represents a serious threat to global public health. The purpose of this study was to evaluate the synergism of tigecycline combined with other antibiotics as a means of overcoming tet(X)-mediated resistance in Acinetobacter spp. We found that the combinations of tigecycline with apramycin or amikacin exhibited synergistic activity against tet(X)-harboring Acinetobacter spp. with FICI values of 0.088 and 0.625, respectively. The MICTGC decreased >5-fold decrease in the presence of subinhibitory levels of apramycin. This combination was shown to be a therapeutically effective synergism using both in vitro and in vivo (mouse thigh infection model) assays and delayed the increase of MIC values over time. This study highlights the synergism of tigecycline in combination with apramycin which offers a viable therapeutic alternative for infections caused by tet(X)-harboring Acinetobacter.

pharmacology and toxicology↗

EquiScore: A generic protein-ligand interaction scoring method integrating physical prior knowledge with data augmentation modeling

Developing robust methods for evaluating protein-ligand interactions has been a long-standing problem. Here, we propose a novel approach called EquiScore, which utilizes an equivariant heterogeneous graph neural network to integrate physical prior knowledge and characterize protein-ligand interactions in equivariant geometric space. To improve generalization performance, we constructed a dataset called PDBscreen and designed multiple data augmentation strategies suitable for training scoring methods. We also analyzed potential risks of data leakage in commonly used data-driven modeling processes and proposed a more stringent redundancy removal scheme to alleviate this problem. On two large external test sets, EquiScore outperformed 21 methods across a range of screening performance metrics, and this performance was insensitive to binding pose generation methods. EquiScore also showed good performance on the activity ranking task of a series of structural analogs, indicating its potential to guide lead compound optimization. Finally, we investigated different levels of interpretability of EquiScore, which may provide more insights into structure-based drug design.

bioinformatics↗

Transfer Learning Enhanced Graph Neural Network for Aldehyde Oxidase Metabolism Prediction and Its Experimental Application

Aldehyde oxidase (AOX) is a molybdoenzyme that is primarily expressed in the liver and is involved in the metabolism of drugs and other xenobiotics. AOX-mediated metabolism can result in unexpected outcomes, such as the production of toxic metabolites and high metabolic clearance, which can lead to the clinical failure of novel therapeutic agents. Computational models can assist medicinal chemists in rapidly evaluating the AOX metabolic risk of compounds during the early phases of drug discovery and provide valuable clues for manipulating AOX-mediated metabolism liability. In this study, we developed a novel graph neural network called AOMP for predicting AOX-mediated metabolism. AOMP integrated the tasks of metabolic substrate/non-substrate classification and metabolic site prediction, while utilizing transfer learning from 13C nuclear magnetic resonance data to enhance its performance on both tasks. AOMP significantly outperformed the benchmark methods in both cross-validation and external testing. Using AOMP, we systematically assessed the AOX-mediated metabolism of common fragments in kinase inhibitors and successfully identified four new scaffolds with AOX metabolism liability, which were validated through in vitro experiments. Furthermore, for the convenience of the community, we established the first online service for AOX metabolism prediction based on AOMP, which is freely available at https://aomp.alphama.com.cn.

bioinformatics↗

Isolation and nitrogen removal characteristics of a novel aerobic denitrifying strain Achromobacter xylosoxidans GR7397

Aerobic denitrifying bacteria have the potential for engineering applications due to the efficient nitrate removal capacity from wastewater. In this study, a novel aerobic denitrifying strain was isolated and identified as Achromobacter xylosoxidans GR7397 from the activated sludge of a wastewater treatment plant, which possessed efficient nitrate removal capacity. Moreover, the denitrification capacity and properties of the strain were investigated in the presence of nitrate as the only nitrogen source. Five denitrification reductases encoding genes were harbored by strain GR7397 determined by electrophoretic analysis of PCR amplification products, consisting of periplasmic nitrate reductase (NAP), nitrate reductase (NAR), nitrite reductase (NIR), nitrous oxide reductase (NOS), and nitric oxide reductase (NOR), demonstrating that the strain has a complete denitrification metabolic pathway. The optimum denitrifying condition of strain GR7397 included sodium acetate adopted as the electron donor, COD/TN ratio at 4, pH at 8, temperature at 30{degrees}C, under which condition, the nitrate removal rate reached 14.86 mg {middle dot} L-1 {middle dot} h-1 that the [Formula] concentration decreased from 93.90 mg/L to 4.73 mg/L within 6 h with no accumulation of nitrite. In addition, the bioaugmentation performance of strain GR7397 to enhance nitrate removal was evaluated to be effective and stabilized in a sequential batch reactor (SBR). The removal rate of [Formula] was the highest during each cycle with a range of 15.48-28.56 mg{middle dot}L-1{middle dot}h-1 in the SBR with inoculating 30% of the strain concentrate. The current research demonstrated that strain GR7397 has significant potential for application in enhancing nitrogen removal in wastewater treatment.

bioengineering↗

Integration of microbial and chemical synthesis for the efficient production of plitidepsin, a promising anticancer and antiviral agent

Plitidepsin, a marine-derived anticancer medicine, is being tested in phase III clinical trials for treating COVID-19. However, the current supply of plitidepsin relies on laborious chemical synthesis processes. Here, we present a new approach that combines microbial and chemical synthesis to produce plitidepsin. We screened a Tistrella strain library to identify a high-yield didemnin B producer, and then introduced a second copy of the didemnin biosynthetic gene cluster into its genome, resulting in the highest yield of didemnin B reported in the literature. Next, we developed two straightforward chemical strategies to convert didemnin B to plitidepsin, one of which involved a one-step synthetic route giving over 90% overall yield. We also synthesized two new didemnin analogues and assessed their anticancer and antiviral activities. Our findings offer a practical and sustainable solution for producing plitidepsin and its derivatives, potentially expediting didemnin drug development.

synthetic biology↗

Distinct Myeloid Derived Suppressor Cell Populations Promote Tumor Aggression in Glioblastoma

The diversity of genetic programs and cellular plasticity of glioma-associated myeloid cells, and thus their contribution to tumor growth and immune evasion, is poorly understood. We performed single cell RNA-sequencing of immune and tumor cells from 33 glioma patients of varying tumor grades. We identified two populations characteristic of myeloid derived suppressor cells (MDSC), unique to glioblastoma (GBM) and absent in grades II and III tumors: i) an early progenitor population (E-MDSC) characterized by strong upregulation of multiple catabolic, anabolic, oxidative stress, and hypoxia pathways typically observed within tumor cells themselves, and ii) a monocytic MDSC (M-MDSC) population. The E-MDSCs geographically co-localize with a subset of highly metabolic glioma stem-like tumor cells with a mesenchymal program in the pseudopalisading region, a pathognomonic feature of GBMs associated with poor prognosis. Ligand-receptor interaction analysis revealed symbiotic cross-talk between the stemlike tumor cells and E-MDSCs in GBM, whereby glioma stem cells produce chemokines attracting E-MDSCs, which in turn produce growth and survival factors for the tumor cells. Our large-scale single-cell analysis elucidated unique MDSC populations as key facilitators of GBM progression and mediators of tumor immunosuppression, suggesting that targeting these specific myeloid compartments, including their metabolic programs, may be a promising therapeutic intervention in this deadly cancer. One-Sentence SummaryAggressive glioblastoma harbors two unique myeloid populations capable of promoting stem-like properties of tumor cells and suppressing T cell function in the tumor microenvironment.

immunology↗

Time-resolved molecular measurements reveal changes in astronauts during spaceflight

From the early days of spaceflight to current missions, astronauts continue to be exposed to multiple hazards that affect human health, including low gravity, high radiation, isolation during long-duration missions, a closed environment and distance from Earth. Their effects can lead to adverse physiological changes and necessitate countermeasure development and/or longitudinal monitoring. A time-resolved analysis of biological signals can detect and better characterize potential adverse events during spaceflight, ideally preventing them and maintaining astronauts wellness. Here we provide a time-resolved assessment of the impact of spaceflight on multiple astronauts (n=27) by studying multiple biochemical and immune measurements before, during, and after long-duration orbital spaceflight. We reveal space-associated changes of astronauts physiology on both the individual level and across astronauts, including associations with bone resorption and kidney function, as well as immune-system dysregulation.

molecular biology↗

Expanding the diversity of Accumulibacter with a novel type and deciphering the transcriptional and morphological features among co-occurring strains

Accumulibacter is the major polyphosphate-accumulating organism (PAO) in global wastewater treatment systems. Its phylogenetic and functional diversity has been continuously updated in recent years. In addition to its widely recognized two sublineages, Types I and II, here we discovered a novel type enriched in laboratory bioreactors. Core gene- and machine learning-based gene feature profiling supported that Type III Accumulibacter was potential PAO with the unique function of using dimethyl sulfoxide as electron acceptor. On the basis of the correlation between the similarity of ppk1 and genome, the number of ppk1-represented Accumulibacter species was estimated to be over one hundred, suggesting that the currently recognized species are only the tip of the iceberg. Meanwhile, multiple Accumulibacter strains co-occurring in a bioreactor were investigated for their inter-strain transcriptional and morphological features. Metatranscriptomics of seven co-occurring strains indicated that the expression level and interphasic dynamics of PAO phenotype-related genes had minimal correlation with their phylogeny. In particular, expression of denitrifying and poly-P metabolism genes had higher inter-strain and interphasic divergence compared with glycogen and polyhydroxyalkanoates metabolic genes. A strategy of cloning rRNA genes from different strains based on similar genomic synteny was successfully applied to differentiate their morphology via fluorescence in situ hybridization. Our study further expanded the phylogenetic and functional diversity of Accumulibacter. We also proposed that deciphering the function and capability of certain Accumulibacter should be environment- and population-specific. ImportanceAccumulibacter, as the core functional but uncultured taxa for enhanced biological phosphorus removal, has attracted much attentions on its phylogenetic and functional diversity and intra-genus niche differentiation in the last two decades. It was well-known that this genus had two sub-lineages (Type I and II) since 2002. In this study, a novel type (Type III) with proposed novel functional feature was discovered by the metagenomic approach. By linking average nucleotide identity of Accumulibacter genomes and the similarity of the ppk1 sequences, a phylogenetic biomarker that has been largely deposited in database, we estimated that its global species-level diversity was higher than 100. Moreover, as we found the co-occurrence of multiple Accumulibacter strains in one bioreactor, the simultaneous transcriptional divergence of the co-occurring strains was interesting for understanding their niche differentiation in a single community. The results suggested the decoupling feature between transcriptional pattern with phylogeny for co-occurring strains.

microbiology↗

Proliferative Exhausted CD8 T Cells Exacerbate Long-lasting Anti-tumor Effects in Human Papillomavirus Positive Head and Neck Squamous Cell Carcinoma

The survival prognosis of human papillomavirus (HPV)-positive and HPV-negative head and neck squamous cell carcinoma (HNSCC) is largely different, and little is known about the anti-tumor mechanism of tumor-infiltrated CD8+ exhausted T cells (Tex) in HNSCC. We performed cell level multi-omics sequencing on human HNSCC samples to decipher the multi-dimensional characteristics of Tex cells. A proliferative exhausted CD8+ T cell cluster (P-Tex) which was beneficial to survival outcomes of patients with HPV-positive HNSCC was identified. Interestingly, P-Tex cells expressed CDK4 genes as high as cancer cells, which could be simultaneously inhibited by CDK4 inhibitors and might be a potential reason for the ineffectiveness of CDK4 inhibitors in treating HPV-positive HNSCC. P-Tex cells could aggregate in the antigen presenting cell niches and activate certain signaling pathways. Together, our findings suggest a promising role for P-Tex cells in the prognosis of patients with HPV-positive HNSCC by providing modest but persistent anti-tumor effects. Graphic abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=105 SRC="FIGDIR/small/513993v1_ufig1.gif" ALT="Figure 1"> View larger version (39K): org.highwire.dtl.DTLVardef@1f8810forg.highwire.dtl.DTLVardef@1e11d84org.highwire.dtl.DTLVardef@58fb6aorg.highwire.dtl.DTLVardef@1e20a13_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

Targeted Protein Degradation via Nanoparticles

Strategies that hijack selective proteins of interest (POIs) to the intracellular protein recycling machinery for targeted protein degradation (TPD) have recently emerged as powerful tools for undruggable targets in biomedical research and the pharmaceutical industry. However, targeting any new POI with current TPD tools requires laborious case-by-case design for different diseases and cell types, especially for those extracellular targets. Here, we observed that nanoparticles (NPs) can mediate the receptor-free internalization of hijacked protein and further developed a generic paradigm for both intra- and extracellular POI degradation, by making full use of clinically approved components. The phenomenon is general, as we found nanostructures such as lipid nanoparticle (LNP), liposomes, exosomes, polymeric nanoparticles, inorganic nanoparticles and their hybrid nanoparticles modified with POI-recognizing moiety (antibody, peptides, small molecule drugs) can mediate TPD for a wide range of extracellular/membrane and intracellular targets. The super flexible and feasible-to-synthesize TPD-NPs paradigm may revolutionize the current TPD tools development landscape and it provides fundamental knowledge to receptor mediated drug therapies. HighlightsO_LINanoparticle mediated targeted protein degradation (TPD-NP) can be constructed by "Mix-and-Match" and do not require de novo synthesis or specific internalization design. C_LIO_LITPD-NPs can be equipped with specific cell type targeting capacity, loading and controlled release of therapeutic cargos, as well as biological barrier penetration capacity. C_LIO_LIAssembling components can be clinical-approved or biodegradable for translational medicine. C_LIO_LITPD-NP highly boosted current application platforms of nano-delivery and TPD. C_LI

bioengineering↗

Cuproptosis is correlated with clinical status, tumor immune microenvironment and immunotherapy in colorectal cancer: a multi-omic analysis

Copper, like double-edged sword, either too little or too much can lead to cell death. Cuproptosis, a novel identified cell death form induced by copper, is characterized by aggregation of lipoylated mitochondrial enzymes and the destabilization of Fe-S cluster proteins. However, the function and potential clinical value of cuproptosis in colorectal cancer remains largely unknown. In this study, 16 cuproptosis-related molecules (CPRMs) were identified and analyzed by transcriptomics, genomics, and single-cell transcriptome profiling from multiple databases. We established two cuproptosis-related molecular phenotypes (CMP1 and 2) to distinguish CRC individuals, in which there were significantly differences in prognosis, biological function, somatic mutation frequency, immune cell infiltration in CRC individuals. A novel cuproptosis-related scoring system (CuproScore) was also constructed to predict the prognosis of CRC individuals, TME and the response to immunotherapy. Of notion, the value of CuproScore was also confirmed in our transcriptome cohort, demonstrating that CRC individuals in the high CuproScore group tended to have higher immune cell infiltrations and higher immune checkpoint expression. We also checked and analyzed the expression and clinical significance of 16 CPRMs in CRC cell lines and CRC tissues. This study indicated that cuproptosis and CPRMs played significant role in CRC progression and in modeling the TME. Inducing cuproptosis may be a useful tool for tumor therapy in the future.

cancer biology↗

The baseless mutant links protein phosphatase 2A with basal cell identity in the brown alga Ectocarpus

The first mitotic division of the initial cell is a key event in all multicellular organisms and is usually concomitant with the establishment of major developmental axes and cell fates. The brown alga Ectocarpus has a haploid-diploid life cycle that involves the development of two multicellular and independent generations, the sporophyte and the gametophyte. Each generation deploys a distinct developmental program autonomously from an initial cell, whose first cell division sets up the future body pattern. Here, we show that mutations in the BASELESS (BAS) gene result in multiple cellular defects during the first division of the initial cell and subsequently failure to produce basal structures (rhizoids and prostrate filaments) during both generations of the life cycle. Cloning-by-sequencing revealed that BAS encodes a type B" regulatory subunit of protein phosphatase 2A, and transcriptomic analysis of early developmental stages uncovered potential effector genes involved in setting up basal cell fate in this organism. The bas mutant phenotype is very similar to that observed in the distag (dis) mutants, which lack a functional TBCCd1 protein, at both the cellular and morphological levels. The high level of similarity of the dis and bas mutant phenotypes indicate that TBCCd1 and PP2A are two critical components of the cellular machinery that regulates the division of the initial cell and mediates the establishment of basal cell fate in the developing thallus.

developmental biology↗

Allosteric Regulation of Aptamer Affinity through Mechano-Chemical Coupling

The capacity to precisely modulate aptamer affinity is important for a wide variety of applications. However, most such engineering strategies entail laborious trial-and-error testing or require prior knowledge of an aptamers structure and ligand-binding domain. We describe here a simple and generalizable strategy for allosteric modulation of aptamer affinity by employing a double-stranded molecular clamp that destabilizes aptamer secondary structure through mechanical tension. We demonstrate the effectiveness of the approach with a thrombin-binding aptamer and show that we can alter its affinity by as much as 65-fold. We also show that this modulation can be rendered reversible by introducing a restriction enzyme cleavage site into the molecular clamp domain and describe a design strategy for achieving even more finely-tuned affinity modulation. This strategy requires no prior knowledge of the aptamers structure and binding mechanism and should thus be generalizable across aptamers.

biochemistry↗

Mechanical Deformation Behaviors and Structural Properties of Ligated DNA Crystals

DNA self-assembly has emerged as a powerful strategy for constructing complex nanostructures. While the mechanics of individual DNA strands have been studied extensively, the deformation behaviors and structural properties of self-assembled architectures are not well understood. This is partly due to the small dimensions and limited experimental methods available. DNA crystals are macroscopic crystalline structures assembled from nanoscale motifs via sticky-end association. The large DNA constructs may thus be an ideal platform to study structural mechanics. Here we have investigated the fundamental mechanical properties and behaviors of ligated DNA crystals made of tensegrity triangular motifs. We performed coarse-grained molecular dynamics simulations and confirmed the results with nanoindentation experiments using atomic force microscopy. We observed various deformation modes including un-tension, linear elasticity, duplex dissociation, and single-stranded component stretch. We found that the mechanical properties of a DNA architecture are correlated with those of its components, however the structure shows complex behaviors which may not be predicted by components alone.

biophysics↗

A Modular Chemoenzymatic Approach to C14-Functionalized Steroids

C14-functionalized steroids belong to a unique class of steroids with important biological activities. However, the lack of efficient methods to access C14-functionalized steroids impede related steroidal drug discovery. Herein we report a modular chemoenzymatic approach to access diversified C14-functionalized steroids. We first identified a novel C14-hydroxylase (CYP14A) from Cochliobolus lunatus with high catalytic efficiency and substrate promiscuity. Protein engineering of CYP14A generated three variants I111A, M115K and V124A that greatly improved the C14-hydroxy regioselectivity. Based on this efficient biocatalytic method, a range of C14-OH steroids with C17 side chain were prepared in good yields, which was then transformed into {Delta}14 olefins through a facile elimination. The newly formed {Delta}14 olefin served as a versatile handle to install diversified functional groups (e.g. epoxide, {beta}-OH, F, Cl and N3) at C14 position through hydrofunctionalization. Furthermore, the synthetic utility of this powerful chemoenzymatic methodology was demonstrated by performing a 7-step semisynthesis of periplogenin and the diversity-oriented synthesis of cardenolide (+)-digitoxigenin and its three diastereomers in a concise manner.

biochemistry↗

ChemPert: mapping between chemical perturbation and transcriptional response for non-cancer cells

Prior knowledge of perturbation data can significantly assist in inferring the relationship between chemical perturbations and their specific transcriptional response. However, current databases mostly contain cancer cell lines, which are unsuitable for the aforementioned inference in non-cancer cells. Here we present ChemPert (https://chempert.uni.lu/), a database consisting of 82270 transcriptional signatures across 167 non-cancer cell types, enabling more accurate predictions of perturbation responses and drugs compared to cancer databases in non-cancer cells. In particular, ChemPert correctly predicted drug effects for treating non-alcoholic steatohepatitis and novel drugs for osteoarthritis. Overall, ChemPert provides a valuable resource for drug discovery in non-cancer diseases.

bioinformatics↗