Jiang J et al. (2014) Worm "Pluripotent cells will not dosage compensate."

Jiang J, Csankovszki G, Lau AC

[Worm, 2014]

Dosage compensation is the mechanism that balances gene expression levels between males and females as well as between the X chromosome and autosomes. In mammals, loss of pluripotency and differentiation are closely linked with the onset of dosage compensation. Pluripotency factors negatively regulate Xist (the non-coding RNA that triggers X chromosome inactivation) and positively regulate Tsix, a repressor of Xist, to inhibit dosage compensation. In addition, X chromosome dose also regulates exit from the pluripotent state. A double dose of X chromosomes in undifferentiated female cells inhibits the MAPK and Gsk3 signaling pathways and activates the Akt pathway, thereby blocking differentiation. Here we review our recent report, which showed that the onset of dosage compensation is also linked to the loss of pluripotency in C. elegans. We discuss these findings in light of what is known about pluripotency and differentiation in this organism.

Jiang J et al. (2019) Nat Commun "Irrelevance of linear controllability to nonlinear dynamical networks."

Lai YC, Jiang J

[Nat Commun, 2019]

There has been tremendous development in linear controllability of complex networks. Real-world systems are fundamentally nonlinear. Is linear controllability relevant to nonlinear dynamical networks? We identify a common trait underlying both types of control: the nodal "importance". For nonlinear and linear control, the importance is determined, respectively, by physical/biological considerations and the probability for a node to be in the minimum driver set. We study empirical mutualistic networks and a gene regulatory network, for which the nonlinear nodal importance can be quantified by the ability of individual nodes to restore the system from the aftermath of a tipping-point transition. We find that the nodal importance ranking for nonlinear and linear control exhibits opposite trends: for the former large-degree nodes are more important but for the latter, the importance scale is tilted towards the small-degree nodes, suggesting stronglythe irrelevance of linear controllability to these systems. The recent claim of successful application of linear controllability to Caenorhabditis elegans connectome is examined and discussed.

Jiang J et al. (2023) Sci Rep "Segmentation, tracking, and sub-cellular feature extraction in 3D time-lapse images."

Szymanski DB, Shailja S, Khan A, Manjunath BS, Goebel M, Jiang J, Belteton SA

[Sci Rep, 2023]

This paper presents a method for time-lapse 3D cell analysis. Specifically, we consider the problem of accurately localizing and quantitatively analyzing sub-cellular features, and for tracking individual cells from time-lapse 3D confocal cell image stacks. The heterogeneity of cells and the volume of multi-dimensional images presents a major challenge for fully automated analysis of morphogenesis and development of cells. This paper is motivated by the pavement cell growth process, and building a quantitative morphogenesis model. We propose a deep feature based segmentation method to accurately detect and label each cell region. An adjacency graph based method is used to extract sub-cellular features of the segmented cells. Finally, the robust graph based tracking algorithm using multiple cell features is proposed for associating cells at different time instances. We also demonstrate the generality of our tracking method on C. elegans fluorescent nuclei imagery. Extensive experiment results are provided and demonstrate the robustness of the proposed method. The code is available on GitHub and the method is available as a service through the BisQue portal.

Jiang J et al. (2016) Vaccine "Enhanced humoral response to influenza vaccine in aged mice with a novel adjuvant, rOv-ASP-1."

Murasko DM, Fisher EM, Concannon M, Shen H, Jiang J, Lustigman S

[Vaccine, 2016]

Immunization is the best way to prevent seasonal epidemics and pandemics of influenza. There are two kinds of influenza vaccines available in the United States: an inactivated vaccine (TIV) and an attenuated vaccine; however, only TIV is approved for immunization of the elderly population. While the aged population has the highest rate of influenza vaccination, the protective efficacy is low as evidenced by elderly individuals having the highest mortality associated with influenza. Recently, we reported that an adjuvant derived from the helminth parasite Onchocerca volvulus, named O. volvulus activation-associated secreted protein-1 (Ov-ASP-1), can significantly enhance the protective efficacy of an inactivated vaccine (TIV) in young adult mice. In the current study, we examined whether this recombinant Ov-ASP-1 (rOv-ASP-1) can enhance the efficacy of TIV in aged mice as well. While primary immunization with TIV alone produced only a low level of influenza-specific antibodies (total IgG, IgG1, and IgG2c) in aged mice, the antibody levels were significantly increased after immunization with TIV+rOv-ASP-1. More importantly, the level of the total IgG in aged mice administered TIV+rOv-ASP-1 was comparable to that of young adult mice immunized with TIV alone. Co-administration of rOv-ASP-1 induced a low level of cross-reactive antibody and enhanced the protective efficacy of TIV in aged mice, reflected by significantly increased survival after challenge with a heterologous influenza virus. rOv-ASP-1 was also superior to the conventional adjuvant alum in inducing specific IgG after TIV immunization in aged mice, and in conferring protection after challenge. These results demonstrate that rOv-ASP-1 may serve as a potential adjuvant for influenza vaccine to improve the efficacy of protection in the elderly.

Jiang J et al. (2022) Nat Commun "C. elegans enteric motor neurons fire synchronized action potentials underlying the defecation motor program."

Tao L, Liu Q, Zhang R, Jiang J, Li H, Su Y

[Nat Commun, 2022]

C. elegans neurons were thought to be non-spiking until our recent discovery of action potentials in the sensory neuron AWA; however, the extent to which the C. elegans nervous system relies on analog or digital coding is unclear. Here we show that the enteric motor neurons AVL and DVB fire synchronous all-or-none calcium-mediated action potentials following the intestinal pacemaker during the rhythmic C. elegans defecation behavior. AVL fires unusual compound action potentials with each depolarizing calcium spike mediated by UNC-2 followed by a hyperpolarizing potassium spike mediated by a repolarization-activated potassium channel EXP-2. Simultaneous behavior tracking and imaging in free-moving animals suggest that action potentials initiated in AVL propagate along its axon to activate precisely timed DVB action potentials through the INX-1 gap junction. This work identifies a novel circuit of spiking neurons in C. elegans that uses digital coding for long-distance communication and temporal synchronization underlying reliable behavioral rhythm.

Jiang H et al. (2014) J Virol "Engineering recombinant Orsay virus directly in the metazoan host Caenorhabditis elegans."

Jiang H, Wang D, Franz CJ

[J Virol, 2014]

The recent identification of Orsay virus, the first virus that is capable of naturally infecting Caenorhabditis elegans, provides a unique opportunity to explore host-virus interaction studies in this invaluable model organism. A key feature of this system is the robust genetic tractability of the host, C. elegans, which would ideally be complemented by the ability to genetically manipulate Orsay virus in parallel. To this end, we developed a plasmid-based reverse genetics system for Orsay virus by creating transgenic C. elegans strains harboring Orsay virus cDNAs. Both wild-type and mutant Orsay viruses, including a FLAG epitope-tagged recombinant Orsay virus, were generated by use of the reverse genetics system. This is the first plasmid-based virus reverse genetics system in the metazoan C. elegans. The Orsay virus reverse genetics we established will serve as a fundamental tool in host-virus interaction studies in the model organism C. elegans. Importance: To date, Orsay virus is the first and the only identified virus capable of naturally infecting Caenorhabditis elegans. C. elegans is a simple multicellular model organism that mimics many fundamental features of human biology and has been used to define many biological properties conserved through evolution. Thus, the Orsay virus-C. elegans infection system provides a unique opportunity to study host-virus interactions. In order to take maximal advantage of this system, the ability to genetically engineer mutant forms of Orsay virus would be highly desirable. Most efforts to engineer viruses have been done with cultured cells. Here we describe the creation of mutant viruses directly in the multicellular organism C. elegans without the use of cell culture. We engineered a virus expressing a genetically tagged protein that could be detected in C. elegans. This provides proof of concept for modifying Orsay virus, which will greatly facilitate studies in this experimental system.

Jiang N et al. (2003) J Biol Chem "Human CLK2 links cell cycle progression, apoptosis, and telomere length regulation."

Hekimi S, Kebir H, Jiang N, Shoubridge EA, Benard CY

[J Biol Chem, 2003]

Mutations in the clk-2 gene of the nematode Caenorhabditis elegans affect organismal features such as development, behavior, reproduction and aging, as well as cellular features such as the cell cycle, apoptosis, the DNA replication checkpoint and telomere length. clk-2 encodes a novel protein (CLK-2) with a unique homologue in each of the sequenced eukaryotic genomes. We have studied hCLK2, the human homologue of CLK-2, to determine whether it affects the same set of cellular features as CLK-2. We find that overexpression of hCLK2 decreases cell cycle length and that inhibition of hCLK2 expression arrests the cell cycle reversibly. Overexpression of hCLK2, however, renders the cell hypersensitive to apoptosis triggered by oxidative stress or DNA replication block, and gradually increases telomere length. The evolutionary conservation of the pattern of cellular functions affected by CLK-2 suggests that the function of hCLK2 in humans might also affect the same organismal features as in worms, including life span. Surprisingly, we find that hCLK2 is found in all cellular compartments and exists as a membrane-associated as well as a soluble form.

Jiang B et al. (2011) J Biol Inorg Chem "Sodium sulfite is a potential hypoxia inducer that mimics hypoxic stress in Caenorhabditis elegans."

Li Y, Jiang B, Zhang C, Liu H, Lu Y, Ren C, Wu Y, Gao Y, Li W, Ratcliffe PJ

[J Biol Inorg Chem, 2011]

Physical and chemical hypoxia have been widely used in the study of hypoxic injury; however, both of these hypoxia models have their own limitations. Physical hypoxia is usually difficult to control and maintain. Chemical hypoxia, which is usually induced by chemical hypoxia-mimicking agents, such as CoCl(2), may result in heavy metal toxicity or impose security threats. To develop a more suitable hypoxia model, we focused on sodium sulfite (Na(2)SO(3)) and evaluated its ability to remove dissolved oxygen in aqueous solutions. Our results showed that sodium sulfite successfully induced hypoxic conditions. The degree of hypoxia and the guarantee period of the sodium sulfite solution could be easily controlled by the concentration of soluble sodium sulfite. In addition, we used sodium sulfite to create a hypoxia model in Caenorhabditis elegans. Similar to physical hypoxia, the sodium sulfite solutions induced hypoxia-related death in the worms and led to morphologic cell defects and C. elegans hypoxia inducible factor 1 stabilization. Taken together, our data show that sodium sulfite is a potential hypoxia inducer that mimics hypoxic stress in C. elegans.

Jiang LL et al. (2013) J Biol Chem "Structural transformation of the amyloidogenic core region of TDP-43 protein initiates its aggregation and cytoplasmic inclusion."

He JH, Jiang LL, Hu HY, Zhao J, Xie MY, Che MX, Li HY, Zhou CJ

[J Biol Chem, 2013]

TDP-43 (TAR DNA-binding protein of 43 kDa) is a major deposited protein in amyotrophic lateral sclerosis and frontotemporal dementia with ubiquitin. A great number of genetic mutations identified in the flexible C-terminal region are associated with disease pathologies. We investigated the molecular determinants of TDP-43 aggregation and its underlying mechanisms. We identified a hydrophobic patch (residues 318-343) as the amyloidogenic core essential for TDP-43 aggregation. Biophysical studies demonstrated that the homologous peptide formed a helix-turn-helix structure in solution, whereas it underwent structural transformation from an -helix to a -sheet during aggregation. Mutation or deletion of this core region significantly reduced the aggregation and cytoplasmic inclusions of full-length TDP-43 (or TDP-35 fragment) in cells. Thus, structural transformation of the amyloidogenic core initiates the aggregation and cytoplasmic inclusion formation of TDP-43. This particular core region provides a potential therapeutic target to design small-molecule compounds for mitigating TDP-43 proteinopathies.

Jiang D et al. (2012) Int J Parasitol "Multiplex proteomics analysis of gender-associated proteins in Brugia malayi."

Weil G, Li B, Malone J, Jiang D, Townsend R

[Int J Parasitol, 2012]

Gender-associated (GA) genes are important for the development and reproduction of filarial nematodes. Identification and characterization of GA genes may provide insight into major pathways and processes involved in development and reproduction. The recent completion of the Brugia malayi genome has provided a good foundation for proteomics studies. Multiplex protein labelling and two-dimensional difference in-gel electrophoresis (2D-DIGE) combined with MALDI-TOF/TOF tandem MS were used to identify GA proteins. Thirty male and 32 female associated proteins were identified in this study. Many of these GA genes have homologues in Caenorhabditis elegans (83% male and 69% female), and most of the homologues have severe RNA interference (RNAi) phenotypes (72% male and 55% female) in C. elegans. Functional analysis showed that the male-associated genes are enriched for energy production, metabolic processes and cytoskeleton, while the female-associated genes are enriched for RNA modification and transcription. GA genes encode many excreted/secreted proteins. In situ localization studies showed that GA genes are mainly expressed in reproductive organs, and this is further evidence for their involvement in reproduction. Improved understanding of the basic biology of filarial nematodes may lead to improved tools for prevention and treatment of filarial infections. This study combined proteomics, in situ hybridization (ISH) and bioinformatics in a systems biology approach to improve understanding of gender differences and key proteins involved in reproduction in filarial worms. Advanced proteomics methods and bioinformatics led to the identification of 62 GA proteins for B. malayi. ISH revealed that most of those GA genes are expressed during embryogenesis or spermatogenesis. ISH results were consistent with RNAi data for C. elegans that linked the homologues of the B. malayi proteins to gamete production and embryogenesis.