Biology subjects

Tian, D.

Publications and source records attributed to Tian, D..

At least 37 records · Page 2Linked to original sources

bioRxiv2024

Topoisomerase I is an Evolutionarily Conserved Key Regulator for Satellite DNA Transcription

Repetitive satellite DNAs, divergent in nucleic-acid sequence and size across eukaryotes, provide a physical site for centromere assembly to orchestrate chromosome segregation during the cell cycle. These non-coding DNAs are transcribed by RNA polymerase (RNAP) II and the transcription has been shown to play a role in chromosome segregation, but a little is known about the regulation of centromeric transcription, especially in higher organisms with tandemly-repeated-DNA-sequence centromeres. Using RNA interference knockdown, chemical inhibition and AID/IAA degradation, we show that Topoisomerase I (TopI), not TopII, promotes the transcription of -satellite DNAs, the main type of satellite on centromeres in human cells. Mechanistically, TopI localizes to centromeres, binds RNAP II and facilitates RNAP II elongation on centromeres. Interestingly, in response to DNA double-stranded breaks (DSBs) induced by chemotherapy drugs or CRSPR/Cas9, -satellite transcription is dramatically stimulated in a DNA damage checkpoint-independent but TopI-dependent manner. These DSB-induced -satellite RNAs were predominantly derived from the -satellite high-order repeats of human centromeres and forms into strong speckles in the nucleus. Remarkably, TopI-dependent satellite transcription also exists in mouse 3T3 and Drosophila S2 cells and in Drosophila larval imaginal wing discs and tumor tissues. Altogether, our findings herein reveal an evolutionally conserved mechanism with TopI as a key player for the regulation of satellite transcription at both cellular and animal levels.

cell biology↗

bioRxiv2024

The first discovery of SFTSV in the Centre of Metropolitan Beijing, China

Severe fever with thrombocytopenia virus (SFTSV), an emerging tick-borne bandavirus, poses a significant public health threat in rural China. Since 2021, an increase in local cases has been noted in the rural-urban fringe surrounding Beijing. This study aimed to assess the formation of natural foci in urban areas by conducting a field survey of ticks and hedgehogs from Beijings second to fifth ring roads. Our survey revealed a diverse tick population in city parks, including the major SFTSV vector, H. longicornis. Parthenogenetic H. longicornis, known for its role in rapid SFTSV spread, was identified in key locations like Beihai Park and Taoranting Park, near the Forbidden City. Notably, high SFTSV seroprevalence and RNA prevalence were found in hedgehogs and parasitic ticks in the center of Beijing. These findings highlight the circulation of SFTSV in central Beijing, underscoring the need for urgent attention and enhanced surveillance measures.

microbiology↗

bioRxiv2023

Circadian photoreceptor CRYPTOCHROME promotes wakefulness under short winter-like days via a GABAergic circuitry

A cardinal symptom of seasonal affective disorder (SAD, also known as winter depression) is hypersomnolence, while the cause of this "winter sleepiness" is not known. Here we found that lack of the circadian photoreceptor cryptochrome (cry) leads to increased sleep under short winter-like days in fruit flies, reminiscent of the hypersomnolence in SAD. CRY functions in neurons that synthesize the major inhibitory neurotransmitter GABA, including the small ventral lateral neurons which are known to be circadian pacemakers, and down-regulates the GABAergic tone. This in turn leads to increased neural activity of the wake-promoting large ventral lateral neurons, a subset of circadian neurons that are inhibited by GABA-A receptor. CRY protein is known to be degraded by light, thus rendering CRY to be functional within this GABAergic circuitry to enhance wakefulness only under short day length. Taken together, we demonstrate a mechanism that specifically regulates wakefulness under short winter-like days, which may provide insights regarding the winter sleepiness in SAD.

neuroscience↗

bioRxiv2023

A Plant Flavonol Rescues a Pathogenic Mutation Associated with Kinesin in Neurons

KIF1A, a microtubule-based motor protein responsible for axonal transport, is linked to a group of neurological disorders known as KIF1A-associated neurological disorder (KAND). Current therapeutic options for KAND are limited. Here, we introduced the clinically relevant KIF1A(R11Q) variant into the C. elegans homolog UNC-104, resulting in uncoordinated animal behaviors. Through genetic suppressor screens, we identified intragenic mutations in UNC-104s motor domain that rescued synaptic vesicle localization and coordinated movement. We showed that two suppressor mutations partially recovered motor activity in vitro by counteracting the structural defect caused by R11Q at KIF1As nucleotide-binding pocket. We found that supplementation with fisetin, a plant flavonol, improved KIF1A(R11Q) worms movement and morphology. Notably, our biochemical and single-molecule assays revealed that fisetin directly restored the ATPase activity and processive movement of human KIF1A(R11Q) without affecting wild-type KIF1A. These findings suggest fisetin as a potential intervention for enhancing KIF1A(R11Q) activity and alleviating associated defects in KAND.

cell biology↗

bioRxiv2023

Chemogenetic approaches reveal dual functions of microglia in epilepsy

Microglia are key players in maintaining brain homeostasis and exhibit phenotypic alterations in response to epileptic stimuli. However, it is still relatively unknown if these alterations are pro- or anti-epileptic. To unravel this dilemma, we employed chemogenetic manipulation of microglia via of the artificial Gi-Dreadd receptor within a kainic acid (KA) induced murine seizure model. Our results indicate that Gi-Dreadd activation can reduce seizure severity. Additionally, we observed increased interaction between microglia and neuronal soma, which correlated with reduced neuronal hyperactivity. Interestingly, prolonged activation of microglial Gi-Dreadds by repeated doses over 3 days, arrested microglia in a less active, homeostatic-like state, which associated with increased neuronal loss after KA induced seizures. RNAseq analysis revealed that prolonged activation of Gi-Dreadd interferes with interferon {beta} signaling and microglia proliferation. Thus, our findings highlight the importance of microglial activation not only during status epilepticus (SE) but also within later seizure induced pathology.

neuroscience↗

bioRxiv2023

SoyOmics: A deeply integrated database on soybean multi omics

As one of the most important crops to supply majority plant oil and protein for the whole world, soybean is facing an increasing global demand. Up to now, vast multi-omics data of soybean were generated, thereby providing valuable resources for functional study and molecular breeding. Nevertheless, it is tremendously challenging for researchers to deal with these big multi-omics data, particularly considering the unprecedented rate of data growth. Therefore, we collect the reported high-quality omics, including assembly genomes, graph pan-genome, resequencing and phenotypic data of representative germplasms, transcriptomic and epigenomic data from different tissues, organs and accessions, and construct an integrated soybean multi-omics database, named SoyOmics (https://ngdc.cncb.ac.cn/soyomics). By equipping with multiple analysis modules and toolkits, SoyOmics is of great utility to facilitate the global scientific community to fully use these big omics datasets for a wide range of soybean studies from fundamental functional investigation to molecular breeding.

bioinformatics↗

bioRxiv2023

Bacterial muropeptides promote OXPHOS and suppress mitochondrial stress in normal and human mitochondrial disease models

Mitochondrial dysfunction critically contributes to many major human diseases but effective therapeutic methods to combat mitochondrial dysfunction are lacking1,2. Mitochondria of animal cells are sites of interaction between gut microbial metabolites and host factors, and many such interactions may be beneficial to mitochondrial health and host physiology3, albeit that specific beneficial interactions and the underlying mechanisms remain to be uncovered. Here we report the role of muropeptides derived from bacterial cell wall peptidoglycan (PG) in promoting mitochondrial functions in mammalian models. We found that muropeptides directly bind to ATP synthase, which stabilizes the complex and promotes its activity. The benefit is seen in increased oxidative respiration and mitochondrial membrane potential, as well as decreased oxidative stress in human intestinal epithelial cells (IECs). Strikingly, we also found that muropeptide treatment can recover mitochondrial structure and functions, as well as inhibit several pathological phenotypes of mutant fibroblast cells derived from mitochondrial disease patients. In mice, we show muropeptides accumulate in mitochondria of IECs and promote small intestinal homeostasis and nutrient absorption by modulating energy metabolism. This study identifies ATP synthase as a muropeptide receptor and the corresponding physiological function in mammals, and points to a potential treatment for human mitochondrial dysfunction diseases. HighlightsO_LIBacterial muropeptides bind and stabilize ATP synthase complex and enhance its activity C_LIO_LIMuropeptides enhance mitochondrial OXPHOS in human IECs C_LIO_LIMuropeptides recover mitochondrial structure and functions in mitochondrial disease cells C_LIO_LIMuropeptides promote small intestinal epithelial homeostasis and nutrient uptake in mice C_LI

cell biology↗

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

Global terrestrial nitrogen uptake and nitrogen use efficiency

Plant biomass production (BP), nitrogen uptake (Nup) and their ratio, nitrogen use efficiency (NUE), must be quantified to understand how nitrogen (N) cycling constrains terrestrial carbon (C) uptake. But the controls of key plant processes determining Nup and NUE, including BP, C and N allocation, tissue C:N ratios and N resorption efficiency (NRE), remain poorly known. We compiled measurements from 804 forest and grassland sites and derived regression models for each of these processes with growth temperature, vapour pressure deficit, stand age, soil C:N ratio, fAPAR (remotely sensed fraction of photosynthetically active radiation absorbed by green vegetation) and growing-season average daily incident photosynthetic photon flux density (gPPFD) (effectively the seasonal concentration of light availability, which increases polewards) as predictors. An empirical model for leaf N was based on optimal photosynthetic capacity (a function of gPPFD and climate) and observed leaf mass-per-area. The models were used to produce global maps of Nup and NUE. Global BP was estimated as 72 Pg C/yr; Nup as 950 Tg N/yr; and NUE as 76 gC/gN. Forest BP was found to increase with growth temperature and fAPAR and to decrease with stand age, soil C:N ratio and gPPFD. Forest NUE is controlled primarily by climate through its effect on C allocation - especially to leaves, being richer in N than other tissues. NUE is greater in colder climates, where N is less readily available, because belowground allocation is increased. NUE is also greater in drier climates because leaf allocation is reduced. NRE is enhanced (further promoting NUE) in both cold and dry climates. These findings can provide observationally based benchmarks for model representations of C-N cycle coupling. State-of-the-art vegetation models in the TRENDY ensemble showed variable performance against these benchmarks, and models including coupled C-N cycling produced relatively poor simulations of Nup and NUE.

ecology↗

bioRxiv2022

McAN: an ultrafast haplotype network construction algorithm

SummaryHaplotype network is becoming popular due to its increasing use in analyzing genealogical relationships of closely related genomes. We newly proposed McAN, a minimum-cost arborescence based haplotype network construction algorithm, by considering mutation spectrum history (mutations in ancestry haplotype should be contained in descendant haplotype), node size (corresponding to sample count for a given node) and sampling time. McAN is two orders of magnitude faster than the state-of-the-art algorithms, making it suitable for analyzation of massive sequences. AvailabilitySource code is written in C/C++ and available at https://github.com/Theory-Lun/McAN and https://ngdc.cncb.ac.cn/biocode/tools/BT007301 under the MIT license. The online web service of McAN is available at https://ngdc.cncb.ac.cn/ncov/online/tool/haplotype. SARS-CoV-2 dataset are available at https://ngdc.cncb.ac.cn/ncov/.

bioinformatics↗

bioRxiv2022

Nucleome Browser: An integrative and multimodal data navigation platform for 4D Nucleome

We introduce Nucleome Browser (http://www.nucleome.org), an interactive, multimodal data visualization and exploration platform for 4D Nucleome research. Our tool effectively integrates heterogeneous datasets (e.g., genomics, imaging, 3D genome structure models, and single-cell data) and external data portals by a new adaptive communication mechanism. Nucleome Browser provides a scalable solution for integrating massive amounts of 4D Nucleome data to navigate multiscale nuclear structure and function in a wide range of biological contexts, enabling hypothesis generation and data sharing with the broad community.

bioinformatics↗

bioRxiv2021

Severe inbreeding and gene loss in the historical and extant population of the critically endangered Devils Hole pupfish

Small populations with limited geographic distributions are predicted to be threatened by inbreeding and lack of genetic diversity, both of which may negatively impact fitness and exacerbate population decline. One of the most extreme natural examples is the Devils Hole pupfish (Cyprinodon diabolis), an iconic and critically endangered species with the smallest known habitat range of any vertebrate. This imperiled species has experienced severe declines in population size over the last thirty years and suffered major, repeated bottlenecks in 2007 and 2013, when the population sunk to 38 and 35 individuals, respectively. Here we sequenced contemporary and historical genomes of Devils Hole and neighboring Death Valley and Ash Meadows desert pupfishes to examine the genomic consequences of small population size. We found extreme inbreeding (FROH = 0.71 - 0.82) and increased genetic load in the Devils Hole pupfish. We also document unique fixed loss-of-function (LOF) alleles and deletions in genes associated with sperm motility, stress, and hypoxia within the extant Devils Hole pupfish population that likely reduce fitness. Comparisons between contemporary samples (2008 - 2012) and a genome sequenced from a 1980 formalin-fixed museum specimen suggest that inbreeding has increased 6% as the population has declined, but that many putatively deleterious variants have been segregating in the population since at least 1980. This includes a fixed early stop codon in cfap43 (n = 8/8 samples), which is associated with sperm flagellum defects and causes infertility in humans and mice. Out of ninety-four unique deletions, fifteen were detected within 2 kb of annotated genes. Five have roles in physiological responses to hypoxia and mitochondrial activity, such as redd1 (n = 7/7 samples), suggesting impaired hypoxia tolerance in this species despite the low oxygen concentrations of Devils Hole. We thus document one of the most extreme inbreeding events in a natural population and a set of candidate deleterious variants to inform management and potential genetic rescue in this conservation icon.

evolutionary biology↗

bioRxiv2021

Tetratricopeptide repeat domain 36 protects renal tubular cells from cisplatin-induced apoptosis via maintaining mitochondrial homeostasis

The apoptosis of proximal tubule epithelial cells (PTECs) is a critical event of acute kidney injury (AKI). Tetratricopeptide repeat domain 36 (TTC36) with three tetratricopeptide repeats is evolutionarily conserved across mammals, which functions as a chaperone for heat shock protein 70. We have revealed that TTC36 is specifically expressed in PTECs in our previous work. There are few studies about the role TTC36 played in AKI. Therefore, in this study, we investigated the function of TTC36 in the apoptosis of HK2 cells, which are derived from the human proximal tubule. Firstly, we observed that TTC36 was obviously down-regulated and was negatively related to the kidney damage degree in a mouse model of acute kidney injury established by ischemia/reperfusion. In addition, TTC36 overexpression protected HK2 cells against cisplatin-induced apoptosis. Moreover, we discovered the mechanism that TTC36 mitigated cisplatin-triggered mitochondrial disorder via sustaining the membrane potential of mitochondria and mitochondrial autophagy-related gene expression. Collectively, these results suggested that TTC36 plays a protective role in the cisplatin-induced apoptosis of renal tubular cells through maintaining the mitochondrial potential and mitochondrial autophagy-related gene expression. These observations highlight the essential role of TTC36 in regulating PTEC apoptosis and imply TTC36/mitochondrial homeostasis axis as a potential target for the therapeutic intervention in AKI.

cell biology↗

bioRxiv2021

A recombinant receptor-binding domain in trimeric form generates completely protective immunity against SARS-CoV-2 infection in nonhuman primates

Safe and effective vaccination is critical to combatting the COVID-19 pandemic. Here, we developed a trimeric SARS-CoV-2 receptor-binding domain (RBD) subunit vaccine candidate that simulates the natural structure of the spike (S) trimer glycoprotein. Immunization with RBD-trimer induced robust humoral and cellular immune responses and a high level of neutralizing antibodies that were maintained for at least 4 months. Moreover, the antibodies that were produced in response to the vaccine effectively neutralized the SARS-CoV-2 501Y.V2 variant. Of note, when the titers of the antibodies dropped to a sufficiently low level, only one boost quickly activated the anamnestic immune response, resulting in complete protection against the SARS-CoV-2 challenge in rhesus macaques without typical histopathological changes or viral replication in the lungs and other respiratory tissues. Our results indicated that immunization with SARS-CoV-2 RBD-trimer could raise long-term and broad immunity protection in nonhuman primates, thereby offering an optimal vaccination strategy against COVID-19.

immunology↗

bioRxiv2021

A spatial and cellular distribution of neurotropic virus infection in the mouse brain revealed by fMOST and single cell RNA-seq

Neurotropic virus infection can cause serious damage to the central nervous system (CNS) in both human and animals. The complexity of the CNS poses unique challenges to investigate the infection of these viruses in the brain using traditional techniques. In this study, we explore the use of fluorescence micro-optical sectioning tomography (fMOST) and single cell RNA sequencing (scRNA-seq) to map the spatial and cellular distribution of a representative neurotropic virus, rabies virus (RABV), in the whole brain. Mice were inoculated with a lethal dose of recombinant RABV expressing enhanced green fluorescent protein (EGFP) under different infection routes, and a three-dimensional view of the distribution of RABV in the whole mouse brain was obtained using fMOST. Meanwhile, we pinpointed the cellular distribution of RABV by utilizing scRNA-seq. Our fMOST data provide the first evidence that RABV can infect multiple nuclei related to fear independent of different infection routes. More surprisingly, scRNA-seq data indicate that besides neurons RABV can infect macrophages and NK cells in vivo. Collectively, this study draws a comprehensively spatial and cellular map of RABV infection in the mouse brain, providing a novel and insightful strategy to investigate the pathogenesis of neurotropic viruses.

microbiology↗

bioRxiv2021

Killed whole genome-reduced bacteria surface-expressed coronavirus fusion peptide vaccines protect against disease in a porcine model

As the coronavirus disease 2019 (COVID-19) pandemic rages on, it is important to explore new evolution-resistant vaccine antigens and new vaccine platforms that can produce readily scalable, inexpensive vaccines with easier storage and transport. We report here a synthetic biology-based vaccine platform that employs an expression vector with an inducible Gram-negative autotransporter to express vaccine antigens on surface of genome-reduced bacteria to enhance interaction of vaccine antigen with immune system. As a proof of principle, we utilized genome-reduced E. coli to express SARS-CoV-2 and porcine epidemic diarrhea virus (PEDV) fusion peptide (FP) on the cell surface, and evaluated their use as a killed whole cell vaccine. The FP sequence is highly conserved across coronaviruses; the 6 FP core amino acid residues along with the 4 adjacent residues upstream and the 3 residues downstream the core are identical between SARS-CoV-2 and PEDV. We tested the efficacy of PEDV FP and SARS-CoV-2 FP vaccines in a PEDV challenge pig model. We demonstrated that both vaccines induced potent anamnestic responses upon virus challenge, potentiated IFN-{gamma} responses, reduced viral RNA loads in jejunum tissue, and provided significant protection against clinical disease. However, neither vaccines elicited sterilizing immunity. Since SARS-CoV-2 FP and PEDV FP vaccines provided similar clinical protection, the coronavirus FP could be a target for a broadly-protective vaccine using any platform. Importantly, the genome-reduced bacterial surface-expressed vaccine platform, when using a vaccine appropriate bacterial vector, has potential utility as an inexpensive, readily manufactured, and rapid vaccine platform for other pathogens. Significance StatementWe report a new vaccine platform to express vaccine antigens on surface of genome-reduced bacteria to enhance vaccine immunogenicity. We demonstrated the utility of this vaccine platform by expressing the highly conserved fusion peptide (FP) of SARS-CoV-2 and porcine epidemic diarrhea virus on the surface of E.coli to produce killed whole cell bacterial vaccines. The vaccine primes a potent anamnestic response, potentiates IFN-{gamma} responses, and provides significant protection in pigs against disease following virus challenge. The FP could be a target for a broadly-protective coronavirus vaccine since a Betacoronavirus SARS-CoV-2 FP vaccine provided cross-protection against Alphacoronavirus PEDV. When using a vaccine appropriate bacteria vector, this inexpensive new vaccine platform offers the potential for use in developing countries.

microbiology↗

bioRxiv2020

The global landscape of SARS-CoV-2 genomes, variants, and haplotypes in 2019nCoVR

On 22 January 2020, the National Genomics Data Center (NGDC), part of the China National Center for Bioinformation (CNCB), created the 2019 Novel Coronavirus Resource (2019nCoVR), an open-access SARS-CoV-2 information resource. 2019nCoVR features a comprehensive integration of sequence and clinical information for all publicly available SARS-CoV-2 isolates, which are manually curated with value-added annotations and quality evaluated by our in-house automated pipeline. Of particular note, 2019nCoVR performs systematic analyses to generate a dynamic landscape of SARS-CoV-2 genomic variations at a global scale. It provides all identified variants and detailed statistics for each virus isolate, and congregates the quality score, functional annotation, and population frequency for each variant. It also generates visualization of the spatiotemporal change for each variant and yields historical viral haplotype network maps for the course of the outbreak from all complete and high-quality genomes. Moreover, 2019nCoVR provides a full collection of SARS-CoV-2 relevant literature on COVID-19 (Coronavirus Disease 2019), including published papers from PubMed as well as preprints from services such as bioRxiv and medRxiv through Europe PMC. Furthermore, by linking with relevant databases in CNCB-NGDC, 2019nCoVR offers data submission services for raw sequence reads and assembled genomes, and data sharing with National Center for Biotechnology Information. Collectively, all SARS-CoV-2 genome sequences, variants, haplotypes and literature are updated daily to provide timely information, making 2019nCoVR a valuable resource for the global research community. 2019nCoVR is accessible at https://bigd.big.ac.cn/ncov/.

genomics↗

bioRxiv2020

Development of a pan-neuronal genetic driver in Aedes aegypti mosquitoes

The mosquito Aedes aegypti is the primary worldwide vector of arboviruses that infect humans, including dengue, Zika, chikungunya, and yellow fever. Recent advances in transgenic technology have yielded important new insight into the biology of this disease vector. The early development of neurogenetic tools, in particular, is beginning to shed light on the neural basis of behaviors that allow Ae. aegypti to thrive in human environments and find and bite human hosts. Despite these advances, a pan-neuronal expression driver remains elusive. Pan-neuronal drivers give researchers genetic access to all neurons and thus provide a critical entry point for circuit dissection. Here, we describe our efforts to generate pan-neuronal drivers in Ae. aegypti via targeted knock-in of in-frame reporter constructs to the native coding sequence of broadly expressed neural genes with CRISPR/Cas9. Two of five attempts were successful, resulting in a Syt1:GCaMP6s strain that expresses synaptically-localized GCaMP in all neurons and a brp-T2A-QF2w driver strain that can be used to drive and amplify expression of any effector in all neurons via the Q binary system. We show that both manipulations broadly and uniformly label the nervous system and have only mild effects on behavior. We envision that these strains will facilitate neurobiological research in Ae. aegypti mosquitoes and provide documentation of both successful and failed manipulations as a roadmap for similar tool development in other non-model species.

neuroscience↗