Biology subjects

Hua, D.

Publications and source records attributed to Hua, D..

11 recordsLinked to original sources

bioRxiv2025

Mutations in SOD1 induce ALS-related phenotypes in 3D iPSC-derived motor neuron (MN) spheroids

A significant challenge in ALS research is the heterogeneity of the disease. Even mutations within the same gene can lead to different disease prognosis. For instance, in silico protein modeling predicts distinct properties for distinct SOD1 mutations. With this in mind, in this study, we generated and characterized 3D iPSC-derived MN spheroids carrying homozygous knock-in SOD1 mutations (D90A and G93A), as well as a double mutation (D90A/G93A), to evaluate potential synergistic effects. An isogenic control line with the same genetic background was used for phenotypic comparisons with the knock-in variants. Mutant SOD1 MN spheroids exhibited multiple ALS-related phenotypes including altered SOD1 expression, reduced cell viability, downregulation of neurofilament (NF) subunit expression, hypoactivity, and altered burst activity. Our results highlight the advantages of using 3D MN spheroids as a disease model and stress the importance of considering phenotype variability at the genetic level in ALS.

neuroscience↗

bioRxiv2025

Flaviviruses Hijack HuR to Suppress CNPY3: A Novel Pathway for Immune Evasion and Therapeutic Intervention

Flaviviruses represent a serious global health threat, infecting millions annually with high rates of cross-infection among different flaviviruses, yet no broad-spectrum antiviral therapy currently targets these pathogens. Through biological big data analysis, we observed a significant downregulation of Canopy FGF Signaling Regulator 3 (CNPY3), a positive regulator of defense responses, in flavivirus-infected patients, with the level of downregulation correlating with infection severity. This observation was validated in cellular and animal models. Mechanistically, we demonstrate that flaviviruses hijack the RNA-binding protein Human antigen R (HuR) to destabilize CNPY3 mRNA via adenine-uridine-rich elements (AREs), thus downregulating CNPY3 expression and promoting viral replication. Our findings identify CNPY3 as a novel antiviral mediator essential for the TLR-mediated type I interferon (IFN-I) pathway in defense against flaviviruses. In vitro, CNPY3 overexpression reduced DENV and ZIKV replication, confirming its antiviral role. To explore therapeutic potential, we developed lipid nanoparticles (LNPs) encapsulating CNPY3 mRNA (LNP-CNPY3), and early administration in flavivirus-infected mice improved survival, reduced viral loads, and attenuated neuroinflammation by enhancing antiviral and interferon responses. Together, these findings establish CNPY3 as a critical antiviral target and support LNP-CNPY3 as a promising therapeutic approach against flavivirus infections.

microbiology↗

bioRxiv2024

Genomic diversity and underlying metabolic variations of the human gut microbiome between populations at single nucleotide resolution

BackgroundA comprehensive and representative reference database is crucial for accurate taxonomic and functional profiling of the human gut microbiome in population-level studies. However, with 70% of current microbial reference data derived from Europeans and the Americans, East Asia, especially China, remain underrepresented. MethodsWe constructed the human Gut Microbiome Reference (GMR), comprising 478,588 high-quality microbial genomes from Chinese (247,134) and non-Chinese (231,454) populations. Species-level clustering and protein annotations were performed to characterize microbial diversity and function. We further integrated novel genomes into taxonomic profiling database and validated the improvements using independent cohort data. ResultsThe GMR dataset spans 6,664 species, including 26.4% newly classified species, and encodes over 20 million unique proteins, with 47% lacking known functional annotations. Notably, we observed that 35.35% and 32.46% of species unique to Chinese and non-Chinese populations, respectively. For 2,145 species shared between populations, 74% of 304 species with balanced prevalence between populations exhibited population-specific phylogenetic stratification, involving health relevant functionalities such as antibiotic resistance. Integration of novel genomes into taxonomic improved population-level species profiling by up to 23% and uncovered replicable associations between novel species and host physiological traits. ConclusionsOur study largely expands the compositional and functional landscape of the human gut microbiome, providing a crucial resource for studying the role of gut microbiome for regional health disparities.

genomics↗

bioRxiv2023

Gut microbial genomes with paired isolates from China signify probiotic and cardiometabolic effects

The gut microbiome displays significant genetic differences between populations while systematic characterization of the genomic landscape of the gut microbiome in Asia populations remains limited. Here, we present the Chinese gut microbial reference (CGMR) set, comprising 101,060 high quality metagenomic assembled genomes (MAGs) of 3,707 non-redundant species paired with 1,376 live isolates from a national wide collection of 3,234 fecal samples across China. This improved reference set contains 987 novel species compared with existing resources worldwide. By associating MAGs with geographic and phenotypic characteristics, we observed regional-specific coexisting MAGs and MAGs with probiotic and cardiometabolic functionalities. We further conducted mice experiments to confirm the probiotic effects of two Faecalibacterium intestinalis isolates in alleviating constipation, the cardiometabolic influences of three Bacteroides fragilis_A isolates in obesity, and the functional potential of isolates from the two new species belonging to the genera Parabacteroides and Lactobacillus in host lipids metabolism. Our study not only expands the current microbial genomes with paired isolates but also demonstrates their probiotic and cardiometabolic effects on hosts, contributing to the mechanistic understanding of host-microbe interactions and the translation of microbiome-based personalized therapies.

microbiology↗

bioRxiv2023

Temporal colonization of the gut microbiome in neonatal Bos taurus at single nucleotide resolution

BackgroundThe rumen of neonatal calves is underdeveloped and exhibits limited functionality during early life. Thus, the acquisition and colonization of microbes in the gut are key to establishing a healthy host-microbiome symbiosis for neonatal calves. Microbiome-linked health outcomes appear to be the consequences of individual strains of specific microbes. However, the temporal colonization of pioneering microbial strains and their linkages to the health and growth of neonatal calves are poorly understood. ResultsTo address this, we longitudinally profiled the gut microbiome of 36 neonatal calves from birth up to 2 months postpartum and carried out microbial transplantation (MT) to reshape their gut microbiome. Genomic reconstruction of deeply sequenced fecal samples resulted in a total of 3,931 metagenomic assembled genomes (MAGs), of which 397 were identified as new species when compared with existing databases of Bos taurus. Single nucleotide level metagenomic profiling shows a rapid influx of microbes after birth, followed by strong selection during the first few weeks of life. MT was found to reshape the genetic makeup of 33 MAGs (FDR<0.05), mainly from Prevotella and Bacteroides species. We further linked over 20 million microbial single nucleotide variations (SNVs) to 736 plasma metabolites, which enabled us to characterize 24 study-wide significant associations (P < 4.4x10-9) that identify the potential microbial genetic regulation of host immune and neuro-related metabolites, including glutathione and L-dopa. Our integration analyses further revealed that microbial genetic variations may influence the health status and growth performance of neonatal calves by modulating metabolites via structural regulation of their encoded proteins. For instance, we found that the albumin levels and total antioxidant capacity in neonatal calves were correlated with L-dopa, which was determined by SNVs via structural regulations of metabolic enzymes. ConclusionsThe current results indicate that the temporal colonization of microbial strains and MT-induced strain replacement are integral in the development of the gut microbiome of neonatal calves and may help to develop strategies that can improve the health status and growth performance of neonatal calves.

microbiology↗

bioRxiv2022

DiffDomain enables identification of structurally reorganized topologically associating domains

Topologically associating domains (TADs) are critical structural units in three-dimensional genome organization of mammalian genome. Dynamic reorganizations of TADs between health and disease states are associated with transcription and other essential genome functions. However, computational methods that can identify reorganized TADs are still in the early stages of development. Here, we present DiffDomain, an algorithm leveraging high-dimensional random matrix theory to identify structurally reorganized TADs using chromatin contact maps. Method comparison using multiple real Hi-C datasets reveals that DiffDomain outperforms alternative methods for FPRs, TPRs, and identifying a new subtype of reorganized TADs. The robustness of DiffDomain and its biological applications are demonstrated by applying on Hi-C data from different cell types and disease states. Identified reorganized TADs are associated with structural variations and changes in CTCF binding sites and other epigenomic changes. By applying to a single-cell Hi-C data from mouse neuronal development, DiffDomain can identify reorganized TADs between cell types with reasonable reproducibility using pseudo-bulk Hi-C data from as few as 100 cells per condition. Moreover, DiffDomain reveals that TADs have differential cell-to-population variability and heterogeneous cell-to-cell variability. Therefore, DiffDomain is a statistically sound method for better comparative analysis of TADs using both Hi-C and single-cell Hi-C data.

bioinformatics↗

bioRxiv2022

Genomic data support Betula halophila and Betula microphylla as one species and reveal unidirectional introgression from Betula pendula to Betula microphylla

Conservation of rare species faces challenges arising from uncertainties in species recognition, interspecific gene flow and global climate change. Betula microphylla and Betula halophila are endangered species in Xinjiang province, Northwest China, where they occur with the abundant Betula pendula. The species status of B. halophila remains dubious. The extent of gene flow between B. microphylla and B. pendula remain unexplored. Here, we first resolve the identity of B. halophila and then assess the extent of gene flow between B. microphylla and B. pendula using restriction-site associated DNA sequencing (RADseq). We sequenced 40 B. pendula individuals, 40 B. microphylla individuals, one B. halophila individual and seven B. tianshanica individuals. Our molecular analyses show that B. halophila and B. microphylla refer to the same species. STRUCTURE analyses show unidirectional genetic admixture from B. pendula to B. microphylla. The ABBA-BABA test indicates that the genetic admixture reflects introgression rather than incomplete lineage sorting. Furthermore, we identified 233 functional genes within the introgressed regions with eight genes related to salt-tolerance, suggesting the possibility of potential adaptive introgression. Our study shows an urgent need to conserve the genetically pure populations of B. microphylla and to shift conservation efforts from B. halophila to B. microphylla. In addition, ex-situ conservation of B. microphylla and conservation strategies to avoid genetic swamping by B. pendula and B. tianshanica should be implemented.

evolutionary biology↗

bioRxiv2022

Effective infection with dengue virus in experimental neonate and adult mice through intranasal route

As a member of the family Flaviviridae, the dengue virus is transmitted to humans through mosquito vectors. The virus causes dengue fever with flu-like symptoms, life-threatening dengue hemorrhagic fever, and dengue shock syndrome that affects four billion people in 128 countries. It can also be transmitted through atypical routes, such as needle stick injury, vertical transmission, and the receipt of contaminated blood or organs. Although sporadic cases cannot be classified as atypical transmission routes and raise respiratory exposure concerns, the risks remain unclear. Here, we analyzed the respiratory infectivity of the dengue virus in BALB/c suckling and A6 adult mice using the dengue virus serotype 2 and intranasal inoculation. The results showed that the clinical symptoms of intranasally infected mice included excitement, emaciation, malaise, and death, and histopathological changes and viremia dynamics were observed in multiple tissues, including the brain, liver, and spleen. Notably, the DENV serotype 2 showed clear brain tropism after intranasal infection, and viral loads peaked at seven days post-inoculation. Furthermore, the virus was isolated from mouse brains, and the sequence homology between the viral stock and dengue virus isolates was 99.99%. Similar results were observed in adult IFN-/{beta} receptor-deficient mice. Taken together, our results suggest that the DENV serotype 2 can infect suckling mice and adult immune-deficient mice via the nasal route. The results of our study broaden our perception of atypical dengue transmission routes and may help explain dengue virus infections that occur without the presence of mosquito vectors. ImportanceDengue is transmitted mainly via mosquito vectors. Flu-like dengue fever or life-threatening severe dengue threatens four billion people in 128 countries. Non-vector dengue cases have occurred occasionally since 1990. These cases cannot be classified as atypical transmission routes and are suspected to have arisen via sexual or respiratory transmission. Recently, the sexual transmission of dengue has been confirmed in humans. The respiratory infectivity of other members of the Flaviviridae family, such as Zika and Japanese encephalitis viruses, has been determined under experimental conditions. The potential for respiratory infection with the dengue virus has not yet been confirmed. In this study, we analyzed the respiratory infectivity of the dengue virus in suckling mice and adult immunodeficient mice via intranasal inoculation, thereby exploring the potential for respiratory transmission in cases with non-vector dengue infection, especially for patients who were exposed to dengue virus contaminants.

microbiology↗

bioRxiv2020

Bidirectional introgression between Betula tianshanica and Betula microphylla and its implications for conservation

O_LIMolecular markers can allow us to differentiate species that occupy a morphological continuum, and detect patterns of allele sharing that can help us understand the dynamics of geographic zones where they meet. Betula microphylla is a declining wetland species in NW China that forms a continuum of leaf morphology with its relative Betula tianshanica. C_LIO_LIWe use ecological niche models (ENM) to predict the distribution of B. microphylla, B. tianshanica and the more commonly occurring B. platyphylla. We use restriction-site associated DNA sequencing and SSRs to resolve their genetic structure and patterns of allele sharing. C_LIO_LIENM predicted an expansion of suitable range of B. tianshanica into B. microphylla since the Last Glacial Maximum and the contraction of B. microphyllas range in the future. We resolved the species identification of some intermediate morphotypes. We found signatures of bidirectional introgression between B. microphylla and B. tianshanica with SNPs showing more admixture than SSRs. Introgression from B. microphylla into B. tianshanica was greater in the Tianshan Mountains where the two species have occurred in proximity. Unexpectedly, introgression from B. tianshanica into B. microphylla was widespread in the Altay Mountains where there are no records of B. tianshanica occurrence. C_LIO_LIThis presence of B. tianshanica-derived alleles far beyond the species current range could be due to unexpectedly high pollen flow, undiscovered populations of B. tianshanica in the region, incomplete lineage sorting, or selection for adaptive introgression in B. microphylla. These different interpretations have contrasting implications for the conservation of B. microphylla. C_LI

evolutionary biology↗

bioRxiv2019

Broad-Spectrum Antifungal Activities and Mechanism of Drimane Sesquiterpenoids

Eight drimane sesquiterpenoids including (-)-drimenol and (+)-albicanol were synthesized from (+)-sclareolide and evaluated for their antifungal activities. Three compounds, (-)-drimenol, (+)-albicanol, and (1R,2R,4aS,8aS)-2-hydroxy-2,5,5,8a-tetramethyl-decahydronaphthalene-1-carbaldehyde (4) showed strong activity against C. albicans. (-)-Drimenol, the strongest inhibitor of the three, (at concentrations of 8 - 64 g/ml, causing 100% death of fungi), acts not only against C. albicans as a fungicidal manner, but also inhibits other fungi such as Aspergillus, Cryptococcus, Pneumocystis, Blastomyces, Fusarium, Rhizopus, Saksenaea and FLU resistant strains of C. albicans, C. glabrata, C. krusei, C. parapsilosis and C. auris. These observations suggest drimenol is a broad-spectrum antifungal agent. At high concentration (100 g/ml), drimenol caused a rupture of the fungal cell wall/membrane. In a nematode model of C. albicans infection, drimenol rescued the worms from C. albicans-mediated death, indicating drimenol is tolerable and bioactive in a metazoan. Genome-wide fitness profiling assays of both S. cerevisiae (nonessential homozygous and essential heterozygous) and C. albicans (Tn-insertion mutants) collections revealed putative genes and pathways affected by drimenol. Using a C. albicans mutants spot assay, the Crk1 kinase associated gene products, Ret2, Cdc37, and novel putative targets orf19.759, orf19.1672, and orf19.4382 were revealed to be the potential targets of drimenol. Further, computational modeling results suggest possible modification of the structure of drimenol including the A ring for improving antifungal activity.

microbiology↗

bioRxiv2019

Multifaceted diversity traits of crucial microbial groups in biological soil crusts promote soil multifunctionality

AbstractsMicrobial diversity is one of the most important drivers on ecosystem to maintain the simultaneous performance of functions (multifunctionality, MF) under climatic oscillation. However, existing studies typically consider taxonomic richness or Shannon index at the community level in which relations between diversity and functioning are not highly consistent. To disentangle the underlying linkages in real-world ecosystems, we conducted field investigation on biological soil crusts of Tibetan Plateau and evaluated multiple diversity facets (i.e., richness, evenness, and phylogeny-related trait dissimilarity) of carbon- and nitrogen-fixing functional groups (FGs). Seven crucial variables of soil functioning were also identified to calculate MF. We found that the integrated index, invoking multiple diversity components, was a stronger predictor on MF than richness. Moreover, the divergent performance of different diversity facets determined the idiosyncratic diversity effect of each FG on the MF. Namely, richness was the dominant factor for diazotrophs to maximize MF, whereas phylogenetic dissimilarity was the most important one for phototrophs. The heterogeneity among the focal FGs derived from the significant differentiation of the extent of multifunctional redundancy. Collectively, we speculated that the multifaceted diversity pattern depicts the response ability of crucial FGs by which biocrusts stabilize MF under environmental perturbation. Taken together, our results provided a perspective to bridge the gap between taxonomic and trait-based approaches for elucidating the biodiversity-ecosystem functioning relationship, and could ultimately help to boost the practices of dryland management against global change.

ecology↗