Biology subjects

Hu, D.

Publications and source records attributed to Hu, D..

At least 73 records · Page 4Linked to original sources

bioRxiv2023

Metabolic reprogramming of cancer cells by JMJD6-mediated pre-mRNA splicing is associated with therapeutic response to splicing inhibitor

Dysregulated pre-mRNA splicing and metabolism are two hallmarks of MYC-driven cancers. Pharmacological inhibition of both processes has been extensively investigated as potential therapeutic avenues in preclinical and clinical studies. However, how pre-mRNA splicing and metabolism are orchestrated in response to oncogenic stress and therapies is poorly understood. Here, we demonstrate that Jumonji Domain Containing 6, Arginine Demethylase and Lysine Hydroxylase, JMJD6, acts as a hub connecting splicing and metabolism in MYC-driven neuroblastoma. JMJD6 cooperates with MYC in cellular transformation by physically interacting with RNA binding proteins involved in pre-mRNA splicing and protein homeostasis. Notably, JMJD6 controls the alternative splicing of two isoforms of glutaminase (GLS), namely kidney-type glutaminase (KGA) and glutaminase C (GAC), which are rate-limiting enzymes of glutaminolysis in the central carbon metabolism in neuroblastoma. Further, we show that JMJD6 is correlated with the anti-cancer activity of indisulam, a "molecular glue" that degrades splicing factor RBM39, which complexes with JMJD6. The indisulam-mediated cancer cell killing is at least partly dependent on the glutamine-related metabolic pathway mediated by JMJD6. Our findings reveal a cancer-promoting metabolic program is associated with alternative pre-mRNA splicing through JMJD6, providing a rationale to target JMJD6 as a therapeutic avenue for treating MYC-driven cancers.

cancer biology↗

bioRxiv2023

Genomic epidemiology and multilevel genome typing of Bordetella pertussis

Bordetella pertussis is responsible for the respiratory infectious disease pertussis (or whooping cough), which causes one of the most severe diseases in infants, although it can be prevented by whole cell and acellular vaccines. The recent resurgence of pertussis is partially due to pathogen adaptation to vaccines as well as resistance to antimicrobials. Surveillance of current circulating and emerging strains is therefore vital to understand the risks they pose to public health. Although there is increased genomics based typing, a genomic nomenclature for this pathogen has not been well established. Here, we implemented the Multilevel Genome Typing (MGT) system for B. pertussis with five levels of resolution, which provide targeted typing of relevant lineages as well as discrimination of closely related strains at the finest scale. The low resolution levels can describe the distribution of alleles of major vaccine antigen genes such as ptxP, fim3, fhaB and prn as well as temporal and spatial trends within the B. pertussis global population. Mid-resolution levels enables typing of antibiotic resistant lineages and Prn deficient lineages within the ptxP3 clade. High resolution levels can capture small-scale epidemiology such as local transmission events and has comparable resolution to existing genomic methods of strain relatedness assessment. The scheme offers stable MGT type assignments aiding harmonisation of typing and communication between laboratories. The scheme is available at www.mgtdb.unsw.edu.au/pertussis/ is regularly updated from global data repositories and accepts public data submissions. The MGT scheme provides a comprehensive, robust, and scalable system for global surveillance of B. pertussis.

microbiology↗

bioRxiv2023

Emergence of rhythmic chunking in complex stepping of mice

Motor chunking is important for motor execution, allowing atomization and efficiency of movement sequences. However, it remains unclear why and how chunks contribute to motor execution. To analyze the structure of naturally occurring chunks, we trained mice to run in a complex series of steps and identified the formation of chunks. We found that intervals (cycle) and the positional relationship between the left and right limbs (phase) of steps inside the chunks, unlike those outside the chunks, were consistent across occurrences. Further, licking by the mice was also more periodic and linked to the specific phases of limb movements within the chunk. Based on these findings, we propose the rhythm chunking hypothesis, whereby within chunks, the repetitive movements of many body parts are linked by the rhythm parameters: cycle and phase. The computational complexity of movement may thereby be reduced by adjusting movements as the combination of rhythms.

animal behavior and cognition↗

bioRxiv2023

Social Isolation Causes Cortical and Trabecular Bone Loss in Adult Male, but not Female, C57BL/6J Mice

Social isolation is a potent form of psychosocial stress and is a growing public health concern, particularly among older adults. Even prior to the onset of the COVID-19 pandemic, which has significantly increased the prevalence of isolation and loneliness, researchers have been concerned about a rising "epidemic" of loneliness. Isolation is associated with an increased risk for many physical and mental health disorders and increased overall mortality risk. In addition to social isolation, older adults are also at greater risk for osteoporosis and related fractures. While researchers have investigated the negative effects of other forms of psychosocial stress on bone, including depression and PTSD, the effects of social isolation on bone have not been thoroughly investigated. The aim of this study was to test the hypothesis that social isolation would lead to bone loss in male and female C57BL/6J mice. 16-week-old mice were randomized into social isolation (1 mouse/cage) or grouped housing (4 mice/cage) for four weeks (N=16/group). Social isolation significantly decreased trabecular (BV/TV, BMD, Tb. N., Tb. Th.) and cortical bone (Ct.Th., Ct.Ar., Ct.Ar./Tt.Ar., pMOI, Ct.Por.) parameters in male, but not female mice. Isolated male mice had signs of reduced bone remodeling represented by reduced osteoblast numbers, osteoblast-related gene expression and osteoclast-related gene expression. However, isolated females had increased bone resorption-related gene expression, without any change in bone mass. Overall, our data suggest that social isolation has negative effects on bone in males, but not females, although females showed suggestive effects on bone resorption. These results provide critical insight into the effects of isolation on bone and have key clinical implications as we grapple with the long-term health impacts of the rise in social isolation related to the COVID-19 pandemic.

physiology↗

bioRxiv2023

Hetnet connectivity search provides rapid insights into how two biomedical entities are related

Hetnets, short for "heterogeneous networks", contain multiple node and relationship types and offer a way to encode biomedical knowledge. One such example, Hetionet connects 11 types of nodes -- including genes, diseases, drugs, pathways, and anatomical structures -- with over 2 million edges of 24 types. Previous work has demonstrated that supervised machine learning methods applied to such networks can identify drug repurposing opportunities. However, a training set of known relationships does not exist for many types of node pairs, even when it would be useful to examine how nodes of those types are meaningfully connected. For example, users may be curious not only how metformin is related to breast cancer, but also how the GJA1 gene might be involved in insomnia. We developed a new procedure, termed hetnet connectivity search, that proposes important paths between any two nodes without requiring a supervised gold standard. The algorithm behind connectivity search identifies types of paths that occur more frequently than would be expected by chance (based on node degree alone). We find that predictions are broadly similar to those from previously described supervised approaches for certain node type pairs. Scoring of individual paths is based on the most specific paths of a given type. Several optimizations were required to precompute significant instances of node connectivity at the scale of large knowledge graphs. We implemented the method on Hetionet and provide an online interface at https://het.io/search. We provide an open source implementation of these methods in our new Python package named hetmatpy.

bioinformatics↗

bioRxiv2022

Kinetic model derivation for design, building and operation of solid waste treatment unit based on system dynamics and computer simulation

Solid waste disposal is significantly important to maintain normal operation of both natural and artificial ecosystems. In this study, a kinetic model of solid waste treatment unit (SWTU) was upfront developed based on microbial ecology, system dynamics, cybernetics and digital simulation, which accurately described the relationships and interactions between solid waste decomposition (SWD) processes and biotic/abiotic factors. Then a specific SWTU prototype was designed and built from this kinetic model. A 370-day experiment demonstrated that SWTU maintained normal operation with robust stability and desired dynamic behaviors, and effectively disposed the solid waste. Therefore, this kinetic model was highly valid due to its high structural and behavioral similarity with the prototype. This research could lay a strong theoretical foundation for further closed-loop control and optimization of SWTU, and provide scientific guidance to environmental management and sustainable development.

ecology↗

bioRxiv2022

Transgressive and parental dominant gene expression and cytosine methylation during seed development in Brassica napus hybrids

The enhanced performance of hybrids though heterosis remains a key aspect in plant breeding, however the underlying mechanisms are still not fully elucidated. To investigate the potential role of transcriptomic and epigenomic patterns in early expression of hybrid vigour, we investigated gene expression, small RNA abundance and genome-wide methylation in hybrids from two distant Brassica napus ecotypes during seed and seedling developmental stages using next-generation sequencing technologies. A total of 71217, 773, 79518 and 31825 differentially expressed genes, microRNAs, small interfering RNAs and differentially methylated regions were identified, respectively. Approximately 70% of the differential expression and methylation patterns observed could be explained due to parental dominance levels. Via gene ontology enrichment and microRNA-target association analyses during seed development we found copies of reproductive, developmental and meiotic genes with transgressive and paternal dominance patterns. Interestingly, maternal dominance was more prominent in hypermethylated and downregulated features during seed formation. This contrasts to the general maternal gamete demethylation reported during gametogenesis in most plant species. Associations between methylation and gene expression allowed identification of putative epialleles with diverse pivotal biological functions during seed formation. Furthermore, most differentially methylated regions, differentially expressed siRNAs and transposable elements were found in regions flanking genes that had no differential expression. This suggests that differential expression and methylation of epigenomic features may help maintain expression of pivotal genes in a hybrid context. Differential expression and methylation patterns during seed formation in an F1 hybrid provide novel insight into genes and mechanisms with a potential role in early heterosis. Key messageTranscriptomic and epigenomic profiling of gene expression and small RNAs during seed and seedling development reveals expression and methylation dominance levels with implications on early stage heterosis in oilseed rape.

plant biology↗

bioRxiv2022

Profile of the somatic mutational landscape in breast tumors from Hispanic/Latina women

Breast cancer causes the most cancer deaths among Hispanic/Latinas (H/L). However, limited tumor-sequencing data from H/L are available to guide treatment. To address this gap, we performed whole-exome sequencing of DNA from 140 HL germline and 146 matched breast tumors and RNA-seq for the tumors. We generated somatic-mutation profiles, identified copy-number alterations (CNAs), and compared results to non-Hispanic White (White) women in The Cancer Genome Atlas. Similar to Whites, PIK3CA and TP53 were the most commonly mutated genes in breast tumors from H/L. We found 4 common COSMIC mutation signatures (1, 2, 3, 13) and signature 16 not previously reported in other breast-cancer datasets. We observed recurrent amplifications in breast-cancer drivers including MYC, FGFR1, CCND1, and ERBB2, and a recurrent amplification on 17q11.2 associated with high KIAA0100 gene expression, implicated in breast-cancer aggressiveness. Expanded research is required to determine how these characteristics of H/L tumors impact treatment response and survival.

cancer biology↗

bioRxiv2022

A peculiar evolutionary feature of monkeypox virus

From 1 Jan 2022 to 15 June 2022, more than 2,100 cases of monkeypox have been reported in 42 countries. This unusual outbreak of monkeypox has raised new concerns in academia and the public. To keep abreast of the trend of the monkeypox epidemic, it is extremely urgent and important to surveille the accumulated genomic mutations and the change of the transmission ability of the pathogen, monkeypox virus (MPXV). We report a non-canonical RNA secondary structure, G-quadruplex (RG4), that surprisingly evolved stepwise with various variants. The RG4 motif is located in the coding sequence region of MPXV C9L gene that is functional in inhibiting host innate immune response. The evolution decreases the stability of this RG4 and promotes C9L protein level in living cells. Importantly, all the reported MPXV genomes in 2022 contain the most unstable RG4 variant, which may be the reason of the increasing spread of MPXV. These findings recommend that health authorities and researchers pay attention to the genomic evolution of MPXV.

genetics↗

bioRxiv2022

Redefining and subtyping of major depression based on brain functional connectivity signatures with high generalization: an ensemble hybrid framework

Current clinical diagnosis of major depression is solely based on subjective symptoms and signs rather than the underlying biological mechanisms, which has hindered the improvement in treatment effectiveness and outcomes. Redefining and subtyping major depressive disorder (MDD) based on neural circuits has been an emerging consensus. Here, we proposed a novel ensemble hybrid deep-learning framework based on graph neural network for redefining and subtyping of MDD with the brains "fingerprinting", i.e. nuanced functional connectivity profiles. A graph neural network (GNN) based supervised model was first employed to discriminate MDD patients from healthy controls. The graph embedding features obtained from the supervised classifier was then employed for subtyping of MDD with an unsupervised clustering by fast search and find of density peaks (CFDP) approach. The generalization accuracy and reproducibility of the proposed framework were further validated with one of the largest resting-state fMRI data set for MDD which included 2428 participants recruited from 25 independent sites. Our classifier showed a high generalization of 75% for leave-one-site-out cross validation. In addition, we obtained three biologically homogenous MDD subtypes characterized by impairments in subcortical-limbic, DMN-FPN, VN-SMN circuits, respectively. Notably, we demonstrated that subtyping of MDD according to graph embedding features showed high robustness and reproducibility across different sites. The proposed framework is not only essential for redefining and subtyping of MDD, but also paves the way towards precision medicine of mental disorders.

neuroscience↗

bioRxiv2022

MorphoGNN: Morphological Embedding for Single Neuron with Graph Neural Networks

With the development of optical imaging systems, neuroscientists can now obtain large datasets of morphological structure at a single neuron scale positioned across the whole mouse brain. However, the enormous amount of morphological data challenges the classic approach of neuron classification, indexing and other analysis tasks. In this paper, we propose MorphoGNN, a single neuron morphological embedding based on the graph neural networks (GNN). This method learns the spatial structure information between the nodes of reconstructed neuron fibers by its nearest neighbors on each layer and captures the lower-dimensional representation of a single neuron through an end-to-end model. This model is composed of densely connected edge convolution (EdgeConv) layers and a double pooling operator, regularized with joint cross-entropy loss and triplet loss. An increasing population of the neighbor nodes meets the need of learning more information with features expanding at the deep layer. We tested the proposed embeddings on the neuron classification and retrieval tasks. Our method achieves competitive performance both on the general point cloud dataset and the neuron morphology dataset.

neuroscience↗

bioRxiv2022

CUT&Tag recovers up to half of ENCODE ChIP-seq peaks

Techniques for genome-wide epigenetic profiling have been undergoing accelerated development toward recovery of high-quality data from bulk and single cell samples. DNA-protein interactions have traditionally been profiled via chromatin immunoprecipitation followed by next generation sequencing (ChIP-seq), which has become the gold standard for studying histone modifications or transcription factor binding. Cleavage Under Targets & Tagmentation (CUT&Tag) is a rapidly expanding new technique that enables profiling of such interactions in situ at high sensitivity and is adaptable to single cell applications. However, thorough evaluation and benchmarking against established ChIP-seq datasets are lacking. Here, we comprehensively benchmarked CUT&Tag for H3K27ac and H3K27me3 against published ChIP-seq profiles from ENCODE in K562 cells. Combining multiple new and published CUT&Tag datasets, there was an average recall of 54% known ENCODE peaks for both histone modifications. To optimize data analysis steps, we tested peak callers MACS2 and SEACR and identified optimal peak calling parameters. Considering both precision and recall of known ENCODE peaks, the peak callers were comparable in their performance, although peaks produced by MACS2 match ENCODE peak width distributions more closely. We found that reducing PCR cycles during library preparation lowered duplication rates at the expense of ENCODE peak recovery. Despite the moderate ENCODE peak recovery, peaks identified by CUT&Tag represent the strongest ENCODE peaks and show the same functional and biological enrichments as ChIP-seq peaks identified by ENCODE. Our workflow systematically evaluates the merits of methodological adjustments, providing a benchmarking framework for the experimental design and analysis of CUT&Tag studies, and will facilitate future efforts to apply CUT&Tag in human tissues and single cells.

genomics↗

bioRxiv2022

Genomic dissection of the microevolution of Australian epidemic Bordetella pertussis

Whooping cough (pertussis) is a highly contagious respiratory disease caused by the bacterium Bordetella pertussis. Despite high vaccine coverage, pertussis has re-emerged in many countries and caused two large epidemics in Australia since 2007. Here, we undertook a genomic and phylogeographic study of 385 Australian B. pertussis isolates collected from 2008 to 2017. The Australian B. pertussis population was found to be composed of mostly ptxP3 strains carrying different fim3 alleles, with ptxP3-fim3A genotype expanded far more than ptxP3-fim3B. Within the former, there were six co-circulating epidemic lineages (EL1 to EL6). The multiple ELs emerged, expanded, and then declined at different time points over the two epidemics, likely driven by immune selection from pertussis vaccination and natural infection in addition to local and global transmission events. Both hard and soft selective sweeps through vaccine selection pressures determined the current B. pertussis population dynamics. Relative risk analysis found that once a new B. pertussis lineage emerged, it was more likely to spread locally within the first 1.5 years. However, after 1.5 years, any new lineage was likely to expand to a wider region and became no longer spatially structured across the country. Phylogenetic analysis revealed the expansion of ptxP3 strains was also associated with replacement of the type III secretion system allele bscI1 with bscI3. This study advanced our understanding of the epidemic population structure and spatial and temporal dynamics of B. pertussis in a highly immunised population.

microbiology↗

bioRxiv2021

Digital restoration of the pectoral girdles of two Early Cretaceous birds, and implications for early flight evolution

Pectoral girdle morphology is a key determinant of flight capability, but in some respects is poorly known among stem birds. Here, we reconstruct the pectoral girdles of the Early Cretaceous birds Sapeornis and Piscivorenantiornis based on computed tomography and three-dimensional visualization, revealing key morphological details. Enantiornithines such as Piscivorenantiornis have a uniquely localized scapula-coracoid joint, with only one area of articulation. This single articulation contrasts with the double articulation widely present in non-enantiornithine pennaraptoran theropods, including Sapeornis and crown birds, which comprises main and subsidiary articular contacts. A partially closed triosseal canal occurs in non-euornithine birds, representing a transitional stage in flight apparatus evolution. Numerous modifications of the pectoral girdle along the line to crown birds, and lineage-specific pectoral girdle variations, produced diverse pectoral girdle morphologies among Mesozoic birds, which ensured that a commensurate range of capability levels and modes emerged during the early evolution of flight.

evolutionary biology↗

bioRxiv2021

Generation of Infant-dedicated Fine-grained Functional Parcellation Maps of Cerebral Cortex

Infancy is a dynamic and immensely important period in human brain development. Studies of infant functional development using resting-state fMRI rely on precisely defined cortical parcellation maps. However, available adult-based functional parcellation maps are not applicable for infants due to their substantial differences in functional organizations. Fine-grained infant-dedicated cortical parcellation maps are highly desired but remain scarce, due to difficulties ranging from acquiring to processing of infant brain MRIs. In this study, leveraging 1,064 high-resolution longitudinal rs-fMRIs from 197 infants from birth to 24 months and advanced infant-dedicated processing tools, we create the first set of infant-specific, fine-grained cortical functional parcellation maps. Besides the conventional folding-based cortical registration, we specifically establish the functional correspondences across individuals using functional gradient densities and generate both age-specific and age-common fine-grained parcellation maps. The first set of comprehensive brain functional developmental maps are accordingly derived, and reveals a complex, hitherto unseen multi-peak fluctuation development pattern in temporal variations of gradient density, network sizes, and local efficiency, with more dynamic changes during the first 9 months than other ages. Our proposed method is applicable in generating fine-grained parcellations for the whole lifespan, and our parcellation maps will be available online to advance the neuroimaging field.

neuroscience↗

bioRxiv2021

Beneficial Effects of Celastrol on Immune Balance by Modulating Gut Microbiota in Dextran Sodium Sulfate-Induced Ulcerative Colitis

Ulcerative colitis (UC) is a chronic inflammatory bowel disease caused by multi-factors including colonic inflammation and microbiota dysbiosis. Previous studies have indicated that Celastrol (CSR) has strong anti-inflammatory and immune-inhibitory effects. Here, we investigated the effects of CSR on colonic inflammation and the mucosal immunity in an experimental colitis model, and addressed the mechanism by which CSR preforms the protective effect. We characterized the therapeutic effects and the potential mechanism of CSR in treating UC using histological staining, intestinal permeability assay, cytokine assay, flow cytometry, fecal microbiota transplantation (FMT), 16S rRNA sequencing, untargeted metabolomics, and cell differentiation approaches. CSR administration significantly ameliorated DSS-induced colitis, as evidenced by the recovery of body weight and colon length, decreased disease activity index (DAI) score, as well as decreased intestinal permeability. CSR down-regulated the secretion of proinflammatory cytokines, upregulated the anti-inflammatory mediators, and improved the balances of Treg/Th1 and Treg/Th17 to maintain colonic immune homeostasis. However, the protective effects of CSR disappeared when the antibiotic cocktail was applied to deplete the gut microbiota, and the gut microbiota-mediated effect was confirmed by FMT. Furthermore, CSR treatment increased the gut microbiota diversity and composition, and raised the metabolic productions of pyruvate and adenosine, which probably involve in gut microbiota mediated protective effect. In conclusion, CSR ameliorates colonic inflammation in a gut microbiota-dependent manner. The underlying protective mechanism is associated with the rectified Treg/Th1 and Treg/Th17 balance, and increased pyruvate and adenosine production. The study provided the solid evidence that CSR might be a promising therapeutic drug for UC.

microbiology↗

bioRxiv2021

Gene expression in African Americans and Latinos reveals ancestry-specific patterns of genetic architecture

We analyzed whole genome and RNA sequencing data from 2,733 African American and Hispanic/Latino children to explore ancestry- and heterozygosity-related differences in the genetic architecture of whole blood gene expression. We found that heritability of gene expression significantly increases with greater proportion of African genetic ancestry and decreases with higher levels of Indigenous American ancestry, consistent with a relationship between heterozygosity and genetic variance. Among heritable protein-coding genes, the prevalence of statistically significant ancestry-specific expression quantitative trait loci (anc-eQTLs) was 30% in African ancestry and 8% for Indigenous American ancestry segments. Most of the anc-eQTLs (89%) were driven by population differences in allele frequency, demonstrating the importance of measuring gene expression across multiple populations. Transcriptome-wide association analyses of multi-ancestry summary statistics for 28 traits identified 79% more gene-trait pairs using models trained in our admixed population than models trained in GTEx. Our study highlights the importance of large and ancestrally diverse genomic studies for enabling new discoveries of complex trait architecture and reducing disparities.

genetics↗

bioRxiv2021

Characterisation of the transcriptional dynamics underpinning the function, fate, and migration of the mouse Anterior Visceral Endoderm

During early post-implantation development of the mouse embryo, the Anterior Visceral Endoderm (AVE) differs from surrounding visceral endoderm (VE) in its migratory behaviour and ability to restrict primitive streak formation to the opposite side of the egg cylinder. In order to characterise the molecular basis for the unique properties of the AVE, we combined single-cell RNA-sequencing of the VE prior to and during AVE migration, with high-resolution imaging, short-term lineage labelling, phosphoproteomics and pharmacological intervention. This revealed the transient nature of the AVE, the emergence of heterogeneities in AVE transcriptional states relative to position of cells, and its prominence in establishing gene expression asymmetries within the spatial constraints of the embryo. We identified a previously unknown requirement of Ephrin- and Semaphorin-signalling for AVE migration. These findings point to a tight coupling of transcriptional state and position in the AVE and reveal molecular heterogeneities underpinning its migratory behaviour and function.

developmental biology↗