Biology subjects

Xin, D.

Publications and source records attributed to Xin, D..

16 recordsLinked to original sources

bioRxiv2025

Single-cell and Spatial Omics Reveals Region-Specific Plasticity and Therapeutic Vulnerabilities in Metastatic High-Risk Neuroblastoma

Neuroblastoma, a deadly pediatric cancer derived from sympathetic ganglia of the peripheral nervous system, frequently metastasizes, driving poor outcomes. Primary neuroblastomas are well-characterized, but the mechanisms underlying metastasis remain poorly understood. Here, by applying single-cell and spatial multi-omics analyses to primary and metastatic tumors, we found that lymph-node metastases in high-risk neuroblastomas display distinctive cellular heterogeneity and plasticity, marked by mesenchymal-like and stem-like states and heightened epithelial-to-mesenchymal transition activity compared to primary adrenal tumors. Additionally, compared to primary adrenal masses, the metastatic niche display increased immunosuppressive myeloid programs, heightened immune checkpoint signaling, and lymphocyte exhaustion, which are indicative of immune evasion and dysfunction. Notably, metastatic neuroblastomas show elevated eIF4F translation machinery and XPO1 levels. Dual inhibition of eIF4A and XPO1 synergistically halted tumor growth and prolonged survival in xenograft models. Together, our multi-omics studies reveal the molecular and cellular plasticity that contributes to therapy resistance and highlight exploitable therapeutic vulnerabilities in high-risk metastatic neuroblastomas.

cancer biology↗

bioRxiv2025

A Tonic Signaling Code Predicts CAR-T Cell Efficacy in Diffuse Midline Glioma

Diffuse midline glioma (DIPG/DMG) is a uniformly fatal pediatric brain tumor with no effective cure. Although CAR T-cell therapy shows promise, clinical outcomes remain inconsistent due to limited persistence and premature exhaustion. Reliable predictive biomarkers are lacking, and proposed exhaustion or stemness markers provide limited utility. Here, we systematically compare multiple CAR-T constructs targeting clinically-relevant antigen B7-H3 and identify antigen-independent CAR activation, or tonic signaling, as a key determinant of therapeutic performance. We find that B7-H3 CAR-T cells with restrained tonic signaling display superior tumor killing, persistence, and resistance to exhaustion, along with reduced CAR membrane clustering, in patient-derived DIPG models. Integrated multi-omics and single-cell profiling further reveal a CAR-T tonic signaling-associated gene signature that outperforms conventional exhaustion or stemness markers in predicting therapeutic efficacy across multiple clinical trials, including DIPG and other tumor types. Together, these findings define a mechanistic and predictive framework to guide CAR design and improve clinical outcomes.

cancer biology↗

bioRxiv2025

Multimodal Validation of the Existence of Transitional Cerebellar Progenitors in the Human Fetal Cerebellum

The developing human cerebellum comprises a series of transient progenitor states that are essential for generating diverse neural subtypes, yet the identity and validation of intermediate cell populations bridging stem-like and lineage-committed neuronal precursors remain limited. In our previous single-cell transcriptomic study, we identified a distinct transitional cerebellar progenitor (TCP) population enriched in specific progenitor zones such as the rhombic lip during human fetal cerebellar development. To address the concerns raised in the Matters Arising regarding the existence of the TCP cells, we provide additional multimodal validations of this population. Rigorous reanalysis of our single-cell transcriptomic data, applying stringent quality control measures, validated the quality of TCP cells and their classification as a transcriptionally distinct population. Multiple orthogonal validations of TCP signature genes (SOX11 and HNRNPH1) using RNAscope in situ hybridization, Xenium-based spatial transcriptomics, and immunohistochemistry on additional fetal cerebellar samples across different stages demonstrated the consistent presence of TCPs in the rhombic lip, transitioning from PRTG+ stem-like zones in the ventricular zone at early developmental stages to the subventricular zone overlapping with EOMES+ unipolar brush cell precursors at later stages. TCP-like populations were also independently identified in two fetal cerebellar single-nucleus transcriptomic atlases, and their gene signature was enriched in a cell population associated with aggressive medulloblastomas. Collectively, these multimodal validations confirm the existence of a transitional progenitor population in the human fetal cerebellum, with implications for cerebellar lineage progression and medulloblastoma origin.

developmental biology↗

bioRxiv2024

Rhizobial effector NopM ubiquitinates Nod factor receptor NFR5 and promotes rhizobial infection in Lotus japonicus

Bacterial pathogens and nitrogen-fixing rhizobia employ type III protein secretion system (T3SS) effectors as potent tools to manipulate plant signaling pathways, thereby facilitating infection and host colonization. However, the molecular mechanisms by which rhizobial effectors affect legume infection remain largely elusive. In this study, we investigated the symbiotic role of T3SS effectors in the interaction between Sinorhizobium fredii NGR234 and Lotus japonicus. Mutants deficient in the T3SS genes Tts1 or NopA showed enhanced rhizobial infection of L. japonicus roots. Further mutant analysis showed that the NopT effector negatively affects infection, while the NopM effector in the absence of NopT promotes infection. Notably, NopM interacts with the Nod factor receptors LjNFR1 and LjNFR5. NopM ubiquitinates LjNFR5 on ten lysine residues as identified using mass spectrometry. Expression of NopM in L. japonicus resulted in an approximately twofold increase in LjNFR5 protein levels and enhanced rhizobial infection. Our findings indicate that NopM directly interferes with the symbiotic signaling pathway through interaction and ubiquitination of Nod factor receptors, which likely benefits rhizobial infection of L. japonicus. Our research contributes to the intricate interplay between the Nod factor signaling pathway and rhizobial T3SS effectors delivered into host cells. Significance StatementThis study unravels intricate mechanisms underlying the symbiotic interaction between Sinorhizobium fredii NGR234 and Lotus japonicus. By focusing on the role of the rhizobial effector NopM, this research sheds light on how bacteria manipulate host symbiotic signaling to promote infection and colonization. NopM interacts with NFRs and ubiquitinates LjNFR5, suggesting a novel strategy employed by rhizobia to enhance symbiotic signaling.

microbiology↗

bioRxiv2024

Whole-Genome Analysis of Stress Resistance-Related Genes in Listeria monocytogenes

Listeria monocytogenes is a crucial foodborne pathogen with significant public health implications. This study analyzed whole-genome sequences (WGS) of L. monocytogenes strains from public databases, examining associations between resistance genes, lineage, strain type, isolation source, and geography. Results revealed that after eliminating duplicates and strains with incomplete WGS, a total of 316 strains were deemed suitable for subsequent analyses. Within these strains, lineages I and II were extensively distributed, predominantly isolated from clinical and food sources. 56.65% of these strains fell into seven major Clonal Complexes (CC), identified by Multilocus Sequence Typing (MLST), correlating significantly with isolation information. Analysis of 46 resistance-related genes showed a high consistency of resistance genes in the same type of strains, hinting at a potential causal chain of habits-foods-environments evolutions. Moreover, the standard strains exhibit similar gene carriage rates as the sample strains, with multiple variations observed in acid-resistance genes. In conclusion, through a comprehensive analysis of the L. monocytogenes genome sequences, this study deepens our understanding of the differences and associations between its lineage, strain typing, isolation sources, geographical distribution, and resistance genes. It has also explored the potential impact of environmental noise on the expression of these genes, offering a scientific foundation for devising more effective prevention and control strategies against L. monocytogenes. Future endeavors should further dissect the functions of stress resistance genes and the variations in their expression, with the aim of gaining a deeper insight into the risks posed by L. monocytogenes to public health safety.

bioinformatics↗

bioRxiv2023

Overexpression of the violaxanthin de-epoxidase confers faster NPQ and photosynthesis induction in rice

Plants in the field experience fluctuations in light conditions. Plants with swift responses to dynamic light conditions usually gain competitive advantage in the field. The dynamic photosynthesis can be reflected in dynamic changes in almost all processes in photosynthesis, with dominant factors being dynamic changes in non-photochemical quenching, Rubisco activation and stomatal dynamics. Each of these dynamic responses is controlled by defined mechanisms. In this study, we showed that overexpression of VDE, an enzyme involved in the xanthophyll cycle and non-photochemical quenching, in rice resulted in faster NPQ induction, less photoinhibition, and faster photosynthesis induction, which together caused increased biomass production by about 11[~]16%. This study, demonstrating a previously unnoticed role of VDE in altering the dynamics of photosynthesis induction besides decreasing photoinhibition, offers a potential strategy to improve canopy photosynthesis through capitalizing the ability of plants to use dynamic light. HighlightThe overexpression of VDE in rice resulted in faster NPQ induction, less photoinhibition, and faster photosynthesis induction, which together caused increased biomass in field.

plant biology↗

bioRxiv2023

Ensemble Processing and Synthetic Image Generation For Abnormally Shaped Nuclei Segmentation

Abnormalities in biological cell nuclei morphology are correlated with cell cycle stages, disease states, and various external stimuli. There have been many deep learning approaches that have described nuclei segmentation and analysis of nuclear morphology. One problem with many deep learning methods is acquiring large amounts of annotated nuclei data, which is generally expensive to obtain. In this paper, we propose a system to segment abnormally shaped nuclei with a limited amount of training data. We first generate specific shapes of synthetic nuclei groundtruth. We randomly sample these synthetic groundtruth images into training sets to train several Mask R-CNNs. We design an ensemble strategy to combine or fuse segmentation results from the Mask R-CNNs. We also design an oval nuclei removal by StarDist to reduce the false positives and improve the overall segmentation performance. Our experiments indicate that our method outperforms other methods in segmenting abnormally shaped nuclei.

cell biology↗

bioRxiv2023

Label-Free Mammalian Cell Tracking Enhanced by Precomputed Velocity Fields

Label-free cell imaging, where the cell is not "labeled" or modified by fluorescent chemicals, is an important research area in the field of biology. It avoids altering the cells properties which typically happens in the process of chemical labeling. However, without the contrast enhancement from the label, the analysis of label-free imaging is more challenging than label-based imaging. In addition, it provides few human interpretable features, and thus needs machine learning approaches to help with the identification and tracking of specific cells. We are interested in label-free phase contrast imaging to track cells flowing in a cell sorting device where images are acquired at 500 frames/s. Existing Multiple Object Tracking (MOT) methods face four major challenges when used for tracking cells in a microfluidic sorting device: (i) most of the cells have large displacements between frames without any overlap; (ii) it is difficult to distinguish between cells as they are visually similar to each other; (iii) the velocities of cells vary with the location in the device; (iv) the appearance of cells may change as they move in and out of the focal plane of the imaging sensor that observes the isolation process. In this paper, we introduce a method for tracking cells in a predefined flow in the sorting device via phase contrast microscopy. Our proposed method is based on DeepSORT and YOLOv4 and exploits prior knowledge of a cells velocity to assist tracking. We modify the Kalman filter in DeepSORT to accommodate a non-constant velocity motion model and integrate a representative velocity field obtained from fluid dynamics into the Kalman filter. The experimental results show that our proposed method outperforms several MOT methods for tracking cells in the sorting device.

cell biology↗

bioRxiv2022

Single-cell Atlas of Human Fetal Cerebellum Decoding Medulloblastoma Origin and Oncogenesis

Medulloblastoma (MB) is the most common malignant childhood brain tumor1,2, yet the origin of the most aggressive subgroup-3 form remains elusive, impeding development of effective targeted treatments. Previous analyses of mouse cerebella3,4 or human counterparts from frozen tissue nuclei5 have not fully defined the compositional heterogeneity of MBs. Here, we undertook an unprecedented single-cell profiling of freshly-isolated human fetal cerebella to establish a reference map delineating hierarchical cellular states in MBs. We identified a unique transitional cerebellar progenitor connecting neural stem cells to neuronal lineages in developing fetal cerebella. Intersectional analysis revealed that the transitional progenitors were enriched in aggressive MB subgroups, including group-3 and metastatic tumors. Single-cell multi-omics revealed underlying regulatory networks in the transitional progenitor populations, including transcriptional determinants HNRNPH1 and SOX11, which are correlated with clinical prognosis in group-3 MBs. Genomic and Hi-C profiling identified de novo long-range chromatin-loops juxtaposing HNRNPH1/SOX11-targeted super-enhancers to cis-regulatory elements of MYC, an oncogenic driver for group-3 MBs. Targeting the transitional progenitor regulators inhibited MYC expression and MYC-driven group-3 MB growth. Our integrated single-cell atlases of human fetal cerebella and MBs reveal potential cell populations predisposed to transformation and regulatory circuitries underlying tumor cell states and oncogenesis, highlighting hitherto unrecognized transitional progenitor intermediates predictive of disease prognosis and potential therapeutic vulnerabilities.

cancer biology↗

bioRxiv2021

Regulation of osteoblast autophagy based on PI3K/AKT/mTOR signaling pathway study on the effect of β-ecdysterone on fracture healing

PurposeTo investigate the effects of {beta}-ecdysterone on fracture healing and the underlying mechanism. MethodsMTT assay was used to detect the cell viability and alkaline phosphatase (ALP) activity was measured using a commercial kit. AO/PI and flow cytometry assays were used to determine the state of apoptosis of osteoblasts. The expression level of RunX2, ATG7 and LC3 was evaluated by qRT-PCR and Western blot assays. X-ray and HE staining were conducted on the fractured femur to evaluate the pathological state. Immunohistochemical assay was used to detect the expression level of Beclin-1 and immunofluorescence assay was used to measure the expression level of LC3 in the fractured femurs. Western blot was utilized to determine the expression level of PI3K, p-AKT1, AKT1, p-mTOR, mTOR, p-p70S6K, and p70S6K. ResultsThe ALP activity and expression of RunX2 in fractured osteoblasts were significantly suppressed by 3-methyladenine and elevated by rapamycin, 60, and 80 M {beta}-ecdysterone. The apoptotic state of fractured osteoblasts was enhanced by 3-methyladenine and alleviated by rapamycin, 60, and 80 M {beta}-ecdysterone. The state of autophagy both in fractured osteoblasts and femurs was inhibited by 3-methyladenine and facilitated by rapamycin and {beta}-ecdysterone. Compared to control, Garrett score in 3-methyladenine group was significantly decreased and promoted in rapamycin and {beta}-ecdysterone groups, accompanied by ameliorated pathological state. Lastly, the PI3K/AKT/mTOR pathway both in fractured osteoblasts and femurs was activated by 3-methyladenine and inhibited by rapamycin and {beta}-ecdysterone. Conclusion{beta}-ecdysterone might facilitate fracture healing by activating autophagy through suppressing PI3K/AKT/mTOR signal pathway.

animal behavior and cognition↗

bioRxiv2019

Reconstructing species evolutionary trees using the numerical features of microRNA

Research has revealed that some microRNAs show obvious lineage or species specificity, but others show highly conserved properties among species. Based on these properties, we aimed to reconstruct a species evolution tree using a new technique that refers to the numerical features of microRNA. First, we selected 132 microRNA numerical features that included base content, secondary structure matching state frequency, free energy features and information entropy features, and 32 species that included 22 animals, 9 plants and a representative virus group. Second, we found several significantly different numerical features among lineages or species by statistical analysis and confirmed that differences in each numerical feature were not identical. Third, we designed a comprehensive feature and confirmed that it showed obvious lineage and species specificity. Last, species trees were built using the comprehensive feature. The results showed that the reconstructed species tree was almost in keeping with the actual chronological order of species evolution. This indicated that our analysis was effective. Our research strategy offers a new route for investigating species evolution.

bioinformatics↗

bioRxiv2019

Discovery Function Labels Based On Numerical Features Of MicroRNA Found In Plant

MicroRNAs(miRNAs),are a class of small endogenous non-coding RNAs that play Important post-transcriptional regulation role by degrading targeted mRNAs or repressing mRNA translation. We screened 84 miRNAs belonging to 21 conserved family from 4014 miRNAs in miRBase database which distributed in 47 plant species. Of the predicted 274 target genes,42 GO terms were found in the Gene Ontology. With the 135 numerical features which extracted by perl program, the difference significantly result of ANOVA (P<0.001) and multiple comparison show that the function labels G...,GC content and Helix in biological process, cellular component and biological function, respectively. Our result have suggested a potential connection between numerical features of miRNAs and the function of target genes of miRNAs.

bioinformatics↗

bioRxiv2019

A new strategy for selection of crop cultivated varieties based on yield factors driving and meteorological prediction

Meteorological conditions, as an uncontrollable factor, have a direct impact on the growth and yield of crops in the field. Its particularly important to choose the cultivated varieties suitable for environmental change. As for this problem, a new strategy for selection of crop cultivated varieties is proposed in this paper. The experiment selected Harbin pilot (Heilongjiang, China) and Changchun pilot (Jilin, China). In the experiment, the cultivated varieties suitable for forecasting meteorological conditions in 2015 could be provided according to the meteorological data of 2005-2014 years and the yield data of different soybean varieties in Harbin pilot. The same method was also taken in Changchun pilot. The results showed that the recommended varieties of Harbin pilot and Changchun pilot had 70% and 50% probability respectively for selection of soybean cultivated varieties when the yield evaluation trait was 100-seed-weight. As for seed weight per plant, the possibility of more than 60% of the recommended varieties in two pilots is to provide prejudgment. Therefore, this method can help to improve the current situation of the impact of uncontrollable meteorological conditions on crop yield and also can be applied to the selection of any other crops cultivated varieties under a certain environment.

plant biology↗

bioRxiv2019

Discovering Differences and Similarities among Species Based on Numeric Features of microRNAs

Numeric features of microRNA (miRNA) are different from the other RNAs and play a key role in the course of miRNA recognition. Are there significant differences about such numeric features between different species? Are there some species specific about it? In order to answer questions, we implemented the Kolmogorov-Smirnov test for 32 species based on 132 numeric features of miRNAs. Results demonstrate that almost all kinds of miRNA secondary structures matching frequencies show highly similar, and this means that such secondary structure tend to be specific to miRNAs. Length of pre-miRNA, minimal free energy (MFE), and number of stacks show bigger difference between different species, and this means that such features tend to be species-specific. In order to discover differences and similarities among species based on numeric features of miRNAs, we design two tools-species difference map and feature difference map. By species difference map, we find that numeric features of miRNAs can represent class attribute of species and the map basically describe relationship between different species. By feature difference map, we find that there are huge difference about difference of every numeric feature between different species, and this means that strength of such difference is not uniform. Meantime, it means that numeric feature of miRNAs can represent different attributes of corresponding species. Our study present relationship between different species by brand new style-numeric features of miRNAs.

bioinformatics↗

bioRxiv2018

Genetic And Epigenetic Fine Mapping Of Complex Trait Associated Loci In The Human Liver

Deciphering the impact of genetic variation on gene regulation is fundamental to understanding common, complex human diseases. Although histone modifications are important markers of gene regulatory regions of the genome, any specific histone modification has not been assayed in more than a few individuals in the human liver. As a result, the impacts of genetic variation that direct histone modification states in the liver are poorly understood. Here, we generate the most comprehensive genome-wide dataset of two epigenetic marks, H3K4me3 and H3K27ac, and annotate thousands of putative regulatory elements in the human liver. We integrate these findings with genome-wide gene expression data collected from the same human liver tissues and high-resolution promoter-focused chromatin interaction maps collected from human liver-derived HepG2 cells. We demonstrate widespread functional consequences of natural genetic variation on putative regulatory element activity and gene expression levels. Leveraging these extensive datasets, we fine-map a total of 77 GWAS loci that have been associated with at least one complex phenotype. Our results contribute to the repertoire of genes and regulatory mechanisms governing complex disease development and further the basic understanding of genetic and epigenetic regulation of gene expression in the human liver tissue.

genetics↗

bioRxiv2018

The reduced prevalence of macrolide resistance in Mycoplasma pneumoniae clinical isolates from pediatric patients in Beijing in 2016

Older children especially from seven to thirteen years old are more prone to develop Mycoplasma pneumoniae (MP) infection; in winter children are more susceptible to infect with MP. In Beijing, China in 2016 the rates of macrolide resistance of MP were 69.48% (in total children), 61.59% (in outpatients) and 79.28% (in hospitalized patients), respectively. All the macrolide resistant isolates harbored A2063G or A2064G mutation in the 23S rRNA gene. Seven isolates showed a mixed infection. Susceptibility results showed that 73 isolates with the A2063G mutation demonstrated different levels resistance to erythromycin (MIC=8 to>256g/ml), azithromycin (MIC=8 to>64g/ml) and josamycin (MIC=2 to 8g/ml). No cross-resistance was observed in the in the antibiotics of levofloxacin and tetracycline against MP.

microbiology↗