Roles of Cytosolic Nucleic Acid Sensors in Cancer and Infection

Pattern recognition receptors are innate immune sensors that recognize pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPs) with crucial roles in host defense against microbial infection, autoimmune diseases and cancer. Cytosolic nucleic acids including DNA and RNA originate from pathogens or self-cells, which form major groups of PAMPs and DAMPs. A range of nucleic acid sensors have evolved to sense various types of nucleic acids. How different DNA-sensing pathways regulate microbial infection and cancer is the focus of this dissertation. Stimulator of IFN genes (STING) is a cytosolic innate immune sensor for cyclic dinucleotides that also serves a dual role as an adaptor molecule for a number of intracellular DNA receptors. A physiological role for STING in cancer was previously unknown. We showed that STING-deficient mice were highly susceptible to colitis-associated colorectal cancer. Colons of STING-deficient mice exhibited significant intestinal damage and overt proliferation with increased levels of pro-inflammatory cytokines during early stages of tumorigenesis, uncovering an unexpected and important role for STING in mediating protection against colorectal tumorigenesis. Absent in melanoma 2 (AIM2) forms an inflammasome with ASC and caspase-1 upon recognition of double-stranded DNA (dsDNA) in the cytosol leading to caspase-1 activation and caspase-1-dependent pyroptosis and release of cytokines IL-1 and IL-18. Mutations in AIM2 are frequently identified in patients with colorectal cancer, but how AIM2 modulates colonic tumorigenesis is unknown. We found that AIM2-deficient mice were hypersusceptible to colonic tumor development. While production of inflammasome-associated cytokines and other inflammatory mediators was largely intact in AIM2-deficient mice, intestinal stem cells lacking AIM2 were prone to uncontrolled proliferation. Aberrant Wnt signaling expanded a population of tumor-initiating stem cells in the absence of AIM2 driving the tumor development in AIM2-deficient mice. In addition to its role in cancer, AIM2 recognizes bacteria including Francisella tularensis subspecies novicida (F. novicida) and induces inflammasome responses. Type I interferon (IFN) signaling drives activation of AIM2 inflammasome in F. novicida-infected macrophages; however, the relative contribution of IFNs and inflammasome responses in host defense against F. novicida infection is less understood. We found intact AIM2 inflammasome responses in mice lacking type I IFN signaling during infection with F. novicida. Lack of type I IFN signaling conferred protection to F. novicida infection in contrast to the increased susceptibility in AIM2-deficient mice. Interestingly, mice lacking both AIM2 and IFNAR2 were protected against the infection indicating a dominant role for type I IFNs in mediating detrimental responses despite the protective AIM2 inflammasome responses. Gasdermin D (GSDMD) is activated by caspase-1 to generate pores on the plasma membrane to induce pyroptosis downstream of the AIM2 inflammasome. We also demonstrated that mice lacking GSDMD were highly susceptible to F. novicida infection. Interestingly, GSDMD is required for optimal caspase-1 activation during F. novicida infection, providing protection to the host during the infection. In addition, we identified differential mechanisms regulating expression of inflammasome-associated cytokines IL-1β and IL-18. IL-1β is only induced in response to inflammatory stimuli and its expression is not sustained during chronic treatment, while IL-18 is constitutively expressed and further induced after the stimulation in a type I IFN signaling-dependent manner. Overall, this dissertation addresses protective roles for cytosolic nucleic acid-sensing molecules, STING and AIM2, in colon cancer, uncovers an interplay between the AIM2 inflammasome and type IFN signaling during F. novicida infection, and demonstrates a novel function for GSDMD in regulating AIM2 inflammasome. The dissertation finally describes distinctive mechanisms governing inflammasome-associated cytokines IL-1β and IL-18

Specification and epigenetic resetting of the pig germline exhibit conservation with the human lineage

Primordial germ cells (PGCs) are the founder cells of germline which follow a specific programme of development characterized by a unique transcriptional network and the resetting of epigenome. Studies in human PGCs (hPGCs) are limited to late migratory and gonadal stages as earlier embryos are almost not accessible. Previous study showed that pig PGC (pPGC) share similar developmental programme to human germ cells in vitro. Therefore, pig may serve as an alternative model to provide insight on transcriptional network and epigenetic reprogramming applicable to hPGC. Using single-cell RNA-seq and whole-genome bisulfite-seq with post-bisulfite adaptor tagging (PBAT-seq), here I show that extensive epigenetic reprogramming, including active DNA demethylation, depletion of macroH2A1, global enrichment of H3K27me3 and X chromosome reactivation (XCR), starts in pre- and early migratory pPGC. Concomitantly, there is dampening of glycolytic gene expression and re-expression of some pluripotency genes like those in preimplantation embryos. Evolutionarily young transposable elements (TEs) and gene coding regions resistant to DNA demethylation, i.e. escapees, have also been identified in extremely hypomethylated gonadal pPGCs. Some of those aforementioned events show conservation with hPGCs but not mPGCs, suggesting that the pig is a relevant model for studies on non-rodent PGC specification and transgenerational epigenetic inheritance. Detailed insights into the pig germline will likely contribute to advances in human germline biology, including in vitro gametogenesi

Advances in Atomic Time Scale imaging with a Fine Intrinsic Spatial Resolution

Atomic time scale imaging, opening a new era for studying dynamics in microcosmos, is presently attracting immense research interesting on the global level due to its powerful ability. On the atom level, physics, chemistry, and biology are identical for researching atom motion and atomic state change. The light possesses twoness, the information carrier and the research resource. The most fundamental principle of this imaging is that light records the event modulated light field by itself, so called all optical imaging. This paper can answer what is the essential standard to develop and evaluate atomic time scale imaging, what is the optimal imaging system, and what are the typical techniques to implement this imaging, up to now. At present, the best record in the experiment, made by multistage optical parametric amplification (MOPA), is realizing 50 fs resolved optical imaging with a spatial resolution of ~83 lp/mm at an effective framing rate of 10^13 fps for recording an ultrafast optical lattice with its rotating speed up to 10^13 rad/s

Rethinking Incentives in Recommender Systems: Are Monotone Rewards Always Beneficial?

The past decade has witnessed the flourishing of a new profession as media content creators, who rely on revenue streams from online content recommendation platforms. The reward mechanism employed by these platforms creates a competitive environment among creators which affect their production choices and, consequently, content distribution and system welfare. It is thus crucial to design the platform's reward mechanism in order to steer the creators' competition towards a desirable welfare outcome in the long run. This work makes two major contributions in this regard: first, we uncover a fundamental limit about a class of widely adopted mechanisms, coined Merit-based Monotone Mechanisms, by showing that they inevitably lead to a constant fraction loss of the optimal welfare. To circumvent this limitation, we introduce Backward Rewarding Mechanisms (BRMs) and show that the competition game resultant from BRMs possesses a potential game structure. BRMs thus naturally induce strategic creators' collective behaviors towards optimizing the potential function, which can be designed to match any given welfare metric. In addition, the BRM class can be parameterized to allow the platform to directly optimize welfare within the feasible mechanism space even when the welfare metric is not explicitly defined

A narrative review of diabetic bone disease: Characteristics, pathogenesis, and treatment

Recently, the increasing prevalence of diabetes mellitus has made it a major chronic illness which poses a substantial threat to human health. The prevalence of osteoporosis among patients with diabetes mellitus has grown considerably. Diabetic bone disease is a secondary osteoporosis induced by diabetes mellitus. Patients with diabetic bone disease exhibit variable degrees of bone loss, low bone mineral density, bone microarchitecture degradation, and increased bone fragility with continued diabetes mellitus, increasing their risk of fracture and impairing their ability to heal after fractures. At present, there is extensive research interest in diabetic bone disease and many significant outcomes have been reported. However, there are no comprehensive review is reported. This review elaborates on diabetic bone disease in the aspects of characteristics, pathogenesis, and treatment

Effective natural inhibitors targeting granzyme B in rheumatoid arthritis by computational study

BackgroundRheumatoid arthritis (RA) is an autoimmune disease characterized by erosive arthritis, and current treatments for RA fall short of the outcomes expected by clinicians and patients.ObjectivesThis study aimed to identify novel therapeutic and prognostic targets in RA at the genomic level and to screen desirable compounds with potential inhibitory effects on GZMB.MethodsWe performed differential gene analysis on GSE55235 and GSE55457 from Gene Expression Omnibus (GEO) and then obtained the intersection of the two differentially expressed genes (DEGs) lists by drawing Venn diagrams. Then we performed protein-protein interaction (PPI) network analysis, Gene Ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis on the DEGs of the intersection. Next, we downloaded the crystal structure of Granzyme B (GZMB). Molecular docking technology was used to screen potential inhibitors of GZMB in subsequent experiments, and we then analyzed the toxicity and water solubility of these potential inhibitors for future drug experiments. Finally, whether the docking of these small molecules with GZMB is stable is tested by molecular dynamics.ResultsA total of 352 mutual DEGs were identified. Twenty hub genes were obtained according to PPI network analysis, among which the GZMB gene attracted the attention of our research. Three potent natural compounds, ZINC000004557101, ZINC000012495776, and ZINC000038143593, bound to GZMB, show better binding affinity. Furthermore, they are predicted to own low Ames mutagenicity, developmental toxicity potential, rodent carcinogenicity, and high tolerance to cytochrome P4502D6. Molecular dynamics simulations show that ZINC000004557101 and GZMB have more advantageous potential energy and can exist stably in a natural environment. Moreover, we finally verified the inhibitory effect of ZINC000004557101 on granzyme B by 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and Western blotting experiment.ConclusionRA patients showed increased GZMB expression. ZINC000004557101 is a potential drug targeting GZMB for treating RA

Chemisorption Induced Formation of Biphenylene Dimer on Surfaces

We report an example that demonstrates the clear interdependence between surface-supported reactions and molecular adsorption configurations. Two biphenyl-based molecules with two and four bromine substituents, i.e. 2,2-dibromo-biphenyl (DBBP) and 2,2,6,6-tetrabromo-1,1-biphenyl (TBBP), show completely different reaction pathways on a Ag(111) surface, leading to the selective formation of dibenzo[e,l]pyrene and biphenylene dimer, respectively. By combining low-temperature scanning tunneling microscopy, synchrotron radiation photoemission spectroscopy, and density functional theory calculations, we unravel the underlying reaction mechanism. After debromination, a bi-radical biphenyl can be stabilized by surface Ag adatoms, while a four-radical biphenyl undergoes spontaneous intramolecular annulation due to its extreme instability on Ag(111). Such different chemisorption-induced precursor states between DBBP and TBBP consequently lead to different reaction pathways after further annealing. In addition, using bond-resolving scanning tunneling microscopy and scanning tunneling spectroscopy, we determine the bond length alternation of biphenylene dimer product with atomic precision, which contains four-, six-, and eight-membered rings. The four-membered ring units turn out to be radialene structures