Role of TNF in Heterologous Immunity between Lymphocytic Choriomeningitis Virus and Vaccinia Virus: A Dissertation

Prior immunity to a related or unrelated pathogen greatly influences the host’s immune response to a subsequent infection and can cause a dramatic difference in disease course, a phenomenon known as heterologous immunity. Heterologous immunity can influence protective immunity, immunopathology and/or immune deviation of cytokine-producing T cell subsets. Examples of heterologous immunity have been well documented in mouse models, as well as during human infections. For example, prior immunity to lymphocytic choriomeningitis virus (LCMV) provides partial protection against vaccinia virus (VV), as LCMV-immune mice show reduced VV titers and increased survival upon lethal dose VV infection. Heterologous protection against VV challenge, as a result of LCMV immunity, is mediated by LCMV-specific CD4 and CD8 T cells, as transfer of LCMV-specific memory T cells can mediate this protective effect in naïve mice. The recognition of a single TCR with more than one MHC-peptide complex is referred to as T cell cross-reactivity. A VV Kb-restricted epitope a11r198 was identified to be able to induce cross-reactive responses from LCMV-specific CD8 T cells. During VV infection, LCMV-specific memory T cells that are cross-reactive to VV epitopes produce IFN-γ early in VV infection. IFN-γ is essential for mediating the protection against VV in LCMV-immune mice, as this heterologous protection is absent in IFN-γR-/-and IFN-γ blocking antibody-treated LCMV-immune mice. In addition to protective immunity, cross-reactive LCMV-specific memory T cells and IFN-γ also induce an altered immunopathology during heterologous VV challenge. LCMV-immune mice show moderate to severe levels of inflammation of the fat tissue, known as panniculitis, in the visceral fat pads upon VV challenge. In humans, panniculitis is a painful condition, most commonly presenting as erythema nodosum. Erythema nodosum is a disease of unknown etiology with no known treatment. It may occur following intracellular bacterial and viral infections, and occasionally happens after vaccination with VV for smallpox. During infections there can be a delicate balance between the ability of immune responses to provide protective immunity, and the tendency to induce immunopathology. By using the mouse model of heterologous immunity between LCMV and VV, we tried to understand how the immunity to LCMV biased the balance between the protective immunity and immunopathology, and what effector molecules were responsible for the pathogenesis of panniculitis in this system. TNF is a pleiotropic cytokine, which is required for normal innate and adaptive immune responses. Its functions range from inducing proliferative responses including cell survival, to destructive responses such as promoting apoptosis and programmed necrosis. In response to inflammatory stimuli, activated macrophages/ monocytes produce large amounts of TNF, and upon activation, T cells, B cells and NK cells also produce TNF. In vitro and in vivo studies have shown that TNF in synergy with IFN-γ plays an important role in mediating host defense against pathogens, such as Listeria monocytogenesand poxviruses in mice and hepatitis B virus and human immunodeficiency virus in humans. However, inappropriate expression of TNF often results in tissue damage. Considering the important role TNF plays in both host defense and mediating autoimmune diseases, we hypothesized that TNF was required for mediating both protective and pathogenic effects in the heterologous immunity between LCMV and VV. We first examined whether TNF was involved in mediating protective heterologous immunity. LCMV-immune mice, that were TNF-deficient as a consequence of genetic deletion (TNF-/-) or receptor blockade by treatment with etanercept (TNFR2: Fc fusion protein), were challenged with VV. These TNF-deficient mice showed normal recruitment and selective expansion of cross-reactive LCMV-specific memory CD8 T cells. They also exhibited efficient clearance of VV similar to LCMV-immune mice with normal TNF function. Thus, we concluded that neither TNF nor lymphotoxin (LT), which uses the same receptors as TNF, was required in mediating protective heterologous immunity against VV. Indeed, prior immunity to LCMV could completely compensate for the role of TNF in protection of naïve mice against VV infection, even under conditions of lethal dose inoculum. Thus, heterologous immunity may help explain why treatment of humans with etanercept is reasonably well tolerated with relatively few infectious complications. One of the histological characteristics of panniculitis is necrosis of adipose tissue. It is known that three members in the TNF superfamily, i.e. TNF/LT, FasL and TRAIL are able to induce necrosis of a target cell. It is also known that TNF is able to induce VV-infected cells to go through necrosis, when apoptosis is blocked in these cells by VV protein. Furthermore, TNF and FasL have already been shown to be associated with some skin and fat pathology. Thus, we hypothesized that TNF, FasL and TRAIL were involved in the pathogenesis of panniculitis in VV infected LCMV-immune mice. By using blocking antibodies or genetically deficient mice, we demonstrated that both TNF/LT and FasL were crucial for inducing panniculitis. Although TNFR1 has been reported to induce programmed necrosis, our data indicated that TNFR2, not TNFR1, was involved in mediating tissue damage in the fat pads of LCMV-immune mice infected with VV. We also found that TNF signaled through TNFR2 to up-regulate the expression of Fas on adipocytes. Thus, the engagement of Fas on the adipocytes with FasL expressed on activated VV-specific and cross-reactive LCMV-specific CD8 T cells in the fat pads could lead to panniculitis. Thus, our data may identify a potential mechanism in the pathogenesis of human panniculitis, and may suggest a possible treatment for this painful disease. Recent reports suggest that heterologous immunity may contribute to the tremendous variation in symptoms between individuals, from subclinical to death, upon viral infection. Even in genetically identical mice, variations in immunopathology from none to life-threatening levels of pathology are observed in LCMV-immune mice during VV infection. By adoptive transfer of splenocytes from a single LCMV-immune donor into two recipients, we showed that similar levels of pathology were generated in mice receiving the same splenocytes. However, the level of pathology varied among recipients receiving splenocytes from different LCMV-immune donors. The difference in levels of VV-induced pathology observed in individual LCMV-immune mice was a reflection of the private specificity of the T cell repertoire, which is a unique characteristic of each individual immune host. The goal of this doctoral thesis is to understand how heterologous immunity contributes to the pathogenesis of panniculitis. Our data demonstrate that TNF/LT and FasL directly contribute to development of panniculitis in LCMV-immune mice during VV infection, and suggest that anti-TNF treatment might be a useful treatment for diseases, such as erythema nodosum and lupus-induced acute fatty necrosis in humans

A Large Sample of Extremely Metal-poor Galaxies at z<1z<1 Identified from the DESI Early Data

Extremely metal-poor galaxies (XMPGs) at relatively low redshift are excellent laboratories for studying galaxy formation and evolution in the early universe. Much effort has been spent on identifying them from large-scale spectroscopic surveys or spectroscopic follow-up observations. Previous work has identified a few hundred XMPGs. In this work, we obtain a large sample of 223 XMPGs at $z<1$ from the early data of the Dark Energy Spectroscopic Instrument (DESI). The oxygen abundance is determined using the direct $T_{\rm e}$ method based on the detection of the [O III]$\lambda$4363 line. The sample includes 95 confirmed XMPGs based on the oxygen abundance uncertainty; remaining 128 galaxies are regarded as XMPG candidates. These XMPGs are only 0.01% of the total DESI observed galaxies. Their coordinates and other proprieties are provided in the paper. The most XMPG has an oxygen abundance of $\sim 1/34 Z_{\odot}$, stellar mass of about $1.5\times10^7 M_{\odot}$ and star formation rate of 0.22 $M_{\odot}$ yr$^{-1}$. The two most XMPGs present distinct morphologies suggesting different formation mechanisms. The local environmental investigation shows that XMPGs preferentially reside in relatively low-density regions. Many of them fall below the stellar mass-metallicity relations (MZRs) of normal star-forming galaxies. From a comparison of the MZR with theoretical simulations, it appears that XMPGs are good analogs to high-redshift star-forming galaxies. The nature of these XMPG populations will be further investigated in detail with larger and more complete samples from the on-going DESI survey.Comment: accepted for publication in Ap

GTC Follow-up Observations of Very Metal-Poor Star Candidates from DESI

The observations from the Dark Energy Spectroscopic Instrument (DESI) will significantly increase the numbers of known extremely metal-poor stars by a factor of ~ 10, improving the sample statistics to study the early chemical evolution of the Milky Way and the nature of the first stars. In this paper we report high signal-to-noise follow-up observations of 9 metal-poor stars identified during the DESI commissioning with the Optical System for Imaging and low-Intermediate-Resolution Integrated Spectroscopy (OSIRIS) instrument on the 10.4m Gran Telescopio Canarias (GTC). The analysis of the data using a well-vetted methodology confirms the quality of the DESI spectra and the performance of the pipelines developed for the data reduction and analysis of DESI data.Comment: 13 pages, 4 figures, to be submitted to ApJ, data available from https://doi.org/10.5281/zenodo.802084

GTC follow-up observations of very metal-poor star candidates from DESI

The observations from the Dark Energy Spectroscopic Instrument (DESI) will significantly increase the numbers of known extremely metal-poor stars by a factor of ∼10, improving the sample statistics to study the early chemical evolution of the Milky Way and the nature of the first stars. In this paper we report follow-up observations with high signal-to-noise ratio of nine metal-poor stars identified during the DESI commissioning with the Optical System for Imaging and Low-Resolution Integrated Spectroscopy (OSIRIS) instrument on the 10.4 m Gran Telescopio Canarias. The analysis of the data using a well-vetted methodology confirms the quality of the DESI spectra and the performance of the pipelines developed for the data reduction and analysis of DESI data

HIV-1-specific CD8+ T cell responses and viral evolution in women and infants

CD8+ T lymphocyte responses play an important role in controlling HIV-1 replication but escape from CD8+ T cell surveillance may limit the effectiveness of these responses. Mother-to-child transmission of CD8+ T cell escape variants may particularly affect CD8+ T cell recognition of infant HIV-1 epitopes. In this study, amino acid sequence variation in HIV-1 gag and nef was examined in five untreated mother-infant pairs to evaluate the potential role of CD8+ T cell responses in the evolution of the viral quasispecies. Several CD8+ T cell escape variants were detected in maternal plasma. Evaluation of infant plasma viruses at 1-3 mo documented heterogeneity of gag and nef gene sequences and mother-to-child transmission of CD8+ T cell escape variants. Infant HLA haplotype and viral fitness appeared to determine the stability of the escape mutants in the infant over time. Changes in CD8+ T cell epitope sequences were detected in infants\u27 sequential plasma specimens, suggesting that infants are capable of generating virus-specific CD8+ T cell responses that exert selective pressures in vivo. Altogether, these studies document that HIV-1-specific CD8+ T cell responses contribute to the evolution of the viral quasispecies in HIV-1-infected women and their infants and may have important implications for vaccine design

Mechanical properties of seawater volcanic scoria aggregate concrete-filled circular GFRP and stainless steel tubes under axial compression

In this study, the properties of seawater volcanic scoria aggregate concrete (SVAC)-filled circular stainless steel (SFCST) and glass fibre-reinforced plastic (GFRP) tubes (SFCGT) were investigated. Ten groups were considered and 30 specimens were prepared, including four different parameters: the concrete type (SVAC and ordinary concrete [OC]), outer tube type (GFRP and stainless steel tubes), concrete strength (C30 and C40), and tube thickness (0, 3, and 4 mm). The typical influences of the SVAC and outer tube on the mechanical properties of specimens were then analysed. The research findings show that the strength and ductility of the SFCGT and SFCST are significantly higher than those of plain SVAC. The peak strain and strength enhancement factor of the SFCGT and SFCST increase with an increase in the tube thickness, and the concrete strength has a detrimental impact on the toughness of the specimen. Unlike in the confined OC specimens, a sudden decrease is observed in the stress–strain curves of the SFCGT and SFCST owing to the changes in the deformability of the SVAC. Generally, the strengths of the SFCGT and SFCST specimens are 10.3% lower and 4.1% higher than those of the confined OC specimens, respectively. Finally, analytical models of the strength and stress–strain curves considering the influences of the SVAC and passive confinement were established, and numerical simulations were performed to provide a basis for the practical application of the SFCGT and SFCST

Federated learning for personalized humor recognition

Computational understanding of humor is an important topic under creative language understanding and modeling. It can play a key role in complex human-AI interactions. The challenge here is that human perception of humorous content is highly subjective. The same joke may receive different funniness ratings from different readers. This makes it highly challenging for humor recognition models to achieve personalization in practical scenarios. Existing approaches are generally designed based on the assumption that users have a consensus on whether a given text is humorous or not. Thus, they cannot handle diverse humor preferences well. In this article, we propose the FedHumor approach for the recognition of humorous content in a personalized manner through Federated Learning (FL). Extending a pre-trained language model, FedHumor guides the fine-tuning process by considering diverse distributions of humor preferences from individuals. It incorporates a diversity adaptation strategy into the FL paradigm to train a personalized humor recognition model. To the best of our knowledge, FedHumor is the first text-based personalized humor recognition model through federated learning. Extensive experiments demonstrate the advantage of FedHumor in recognizing humorous texts compared to nine state-of-the-art humor recognition approaches with superior capability for handling the diversity in humor labels produced by users with diverse preferences.Nanyang Technological UniversityNational Research Foundation (NRF)This work is supported, in part, by Alibaba Group through the Alibaba Innovative Research (AIR) Program and the Alibaba-NTU Singapore Joint Research Institute (JRI), Nanyang Technological University, Singapore; the Nanyang Assistant/Associate Professorships (NAP); The RIE 2020 Advanced Manufacturing and Engineering Programmatic Fund (No. A20G8b0102), Singapore; NTU-SDU-CFAIR (NSC-2019-011); the National Natural Science Foundation of China under Grant NSFC 62106167; the National Research Foundation, Prime Minister’s Office, Singapore through the AI Singapore Programme (AISG2-RP-2020-019), NRF Investigatorship Programme (NRFI Award No. NRF-NRFI05-2019-0002) and NRF Fellowship (NRF-NRFF13-2021-0006)