Multiple genetic loci contribute to the development of systemic lupus erythematosus (SLE). In murine models for SLE, various genes on chromosome four have been implicated. IL-14 is a cytokine originally identified as a B cell growth factor. The il14 gene is located on chromosome 4. IL-14α is a cytokine encoded by the plus strand of the IL-14 gene using exons 3–10. The expression of IL-14α is increased in (NZB × NZW)F1 mice. In this study, we produced IL-14α-transgenic mice to study the role of IL-14α in the development of autoimmunity. At age 3–9 mo, IL-14α-transgenic mice demonstrate increased numbers of B1 cells in the peritoneum, increased serum IgM, IgG, and IgG 2a and show enhanced responses to T-dependent and T-independent Ags compared with littermate controls. At age 9–17 mo, IL-14α-transgenic mice develop autoantibodies, sialadenitis, as in Sjögren’s syndrome, and immune complex-mediated nephritis, as in World Health Organization class II SLE nephritis. Between the ages 14–18 mo, 95% of IL-14α-transgenic mice developed CD5+ B cell lymphomas, consistent with the lymphomas seen in elderly patients with Sjögren’s syndrome and SLE. These data support a role for IL-14α in the development of both autoimmunity and lymphomagenesis. These studies may provide a genetic link between these often related disorders.

The etiology of salivary gland injury in primary Sjögren’s disease is not well understood. We have previously described a mouse model of Sjögren’s disease, IL-14α transgenic (IL14αTG) mice, which reproduces many of the features of the human disease. We now demonstrate a critical role for lymphotoxin α (LTA) in the pathogenesis of Sjögren’s disease in IL14αTG mice. IL14αTG mice express LTA mRNA in their salivary glands and spleen and produce soluble LTA protein in their salivary secretions. When IL14αTG mice were crossed with LTA−/− mice, the IL14αTG.LTA−/− mice retained normal salivary gland secretions and did not develop either lymphocytic infiltration of their salivary glands or secondary lymphomas. However, both IL14αTG and IL14αTG.LTA−/− mice produced similar amounts of IFN-α and had similar deposition of autoantibodies in their salivary glands. Both IL14α and IL14α/LTA−/− mice had similar B cell responses to T-dependent and T-independent Ags, L-selectin expression, and expression of RelA, RelB, and NF-κB2 in their spleens. These studies suggest that LTA plays a critical role in the local rather than systemic inflammatory process of Sjögren’s disease. Furthermore, local production of soluble LTA in the salivary glands of IL14αTG mice is necessary for the development of overt Sjögren’s disease. Autoantibody deposition alone is not sufficient to produce salivary gland dysfunction. We also demonstrate that LTA is increased in the salivary gland secretions and sera of patients with Sjögren’s disease, further strengthening the biological relevance of the IL14αTG model to understanding the pathogenesis of human disease.

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We explore value-based multi-agent reinforcement learning (MARL) in the popular paradigm of centralized training with decentralized execution (CTDE). CTDE requires the consistency of the optimal joint action selection with optimal individual action selections, which is called the IGM (Individual-Global-Max) principle. However, in order to achieve scalability, existing MARL methods either limit representation expressiveness of their value function classes or relax the IGM consistency, which may lead to poor policies or even divergence. This paper presents a novel MARL approach, called duPLEX dueling multi-agent Q-learning (QPLEX), that takes a duplex dueling network architecture to factorize the joint value function. This duplex dueling architecture transforms the IGM principle to easily realized constraints on advantage functions and thus enables efficient value function learning. Theoretical analysis shows that QPLEX solves a rich class of tasks. Empirical experiments on StarCraft II unit micromanagement tasks demonstrate that QPLEX significantly outperforms state-of-the-art baselines in both online and offline task settings, and also reveal that QPLEX achieves high sample efficiency and can benefit from offline datasets without additional exploration. * Equal contribution.Preprint. Under review.

Genetic factors are known to be important in the development of gastric cancer (GC). Prostate stem cell antigen (PSCA) has been shown to be expressed in diffuse-type GC, and PSCA variation is associated with susceptibility to diffuse-type GC in Japanese and Korean populations. The aim of this study was to investigate the association between PSCA gene polymorphisms and GC in a Tibetan population. We analyzed single-nucleotide polymorphisms of the PSCA gene in 196 patients with GC and 246 controls in a Tibetan population, using a polymerase chain reaction/ligase detection reaction test. The rs2294008 C/T polymorphism of the PSCA gene was significantly associated with the susceptibility to GC. The CT genotype was associated with a significantly higher risk of GC when compared with the CC genotype (odds ratio [OR] = 1.50; 95% confidence interval [CI], 1.01-2.23). Patients carrying the T allele had a significantly higher risk for developing GC compared with individuals carrying the C allele (OR = 1.34; 95% CI, 1.00-1.79). Haplotype analyses showed that CA haplotype was associated with a significantly decreased risk of GC when compared with the CG haplotype (OR = 0.47; 95% CI, 0.24-0.93). Our data indicate that PSCA gene polymorphisms may be associated with GC in Tibetans.

Background: Osteopontin (OPN) is highly expressed in colorectal cancer (CRC) and is associated with disease progression in vivo. High levels of OPN have been demonstrated to predict low survival rates in CRC. Autophagy is a process of self-digestion, which is thought to play a significant role in carcinogenesis. However, the mechanisms of OPN's effects on CRC cell autophagy have not been elucidated. Therefore, we aimed to investigate possible mechanisms of OPN's effects on CRC autophagy. Methods: HCT116 cell proliferation, apoptosis, and migration and invasion ability were identified by cell counting k¡t-8 assay, flow cytometry, wound healing assay, and transwell chamber invasion assay, respectively. The ratios of proteins LC3-II/LC3-I, P62, and Atg7 were analyzed by Western-blot. Expressions of Beclin-1, Atg4b, Bnip3, and Vps34, both in transcriptional and translational levels, were analyzed and compared by RT-PCR and Western blot. Immunofluorescence and co-focusing experiments were used to investigate the formation of autophagosomes. Results: The results showed that OPN can promote cell proliferation, migration, and invasion, as well as inhibit cell apoptosis. It was also demonstrated that OPN could inhibit cell autophagy. Further experiments revealed that the inhibitory effect of OPN on autophagy could be reversed by blocking the p38 MAPK pathway in HCT116 cells. Conclusion: OPN is involved in HCT116 cell progression and is capable of inhibiting cell autophagy possibly by activating the p38 MAPK signaling pathway, implying that OPN could be a potential novel molecular therapeutic biomarker in patients with CRC.

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PEGylation is effective in reducing the immunogenicity, immunotoxicity, and hepatotoxicity of α-MMC in vivo.