LINE-1 repression in Epstein-Barr virus-associated gastric cancer through viral-host genome interaction.

Long INterspersed Element 1 (LINE-1 or L1) acts as a major remodeling force in genome regulation and evolution. Accumulating evidence shows that virus infection impacts L1 expression, potentially impacting host antiviral response and diseases. The underlying regulation mechanism is unclear. Epstein-Barr virus (EBV), a double-stranded DNA virus linked to B-cell and epithelial malignancies, is known to have viral-host genome interaction, resulting in transcriptional rewiring in EBV-associated gastric cancer (EBVaGC). By analyzing publicly available datasets from the Gene Expression Omnibus (GEO), we found that EBVaGC has L1 transcriptional repression compared with EBV-negative gastric cancer (EBVnGC). More specifically, retrotransposition-associated young and full-length L1s (FL-L1s) were among the most repressed L1s. Epigenetic alterations, especially increased H3K9me3, were observed on FL-L1s. H3K9me3 deposition was potentially attributed to increased TASOR expression, a key component of the human silencing hub (HUSH) complex for H3K9 trimethylation. The 4C- and HiC-seq data indicated that the viral DNA interacted in the proximity of the TASOR enhancer, strengthening the loop formation between the TASOR enhancer and its promoter. These results indicated that EBV infection is associated with increased H3K9me3 deposition, leading to L1 repression. This study uncovers a regulation mechanism of L1 expression by chromatin topology remodeling associated with viral-host genome interaction in EBVaGC.

Repurposing Axl Kinase Inhibitors for the Treatment of Respiratory Syncytial Virus Infection.

Respiratory syncytial virus (RSV) infection persists as a common pathogen of pulmonary infection in infants and in the elderly with high morbidity and mortality. However, no specific therapeutics are available. Axl, a member of the TAM (Tyro3, Axl, and Mertk) family receptor kinases, is a pleiotropic inhibitor of the innate immune response and functions as a negative regulator of interferon pathway activation. In this report, we investigated Axl inhibitors for their effects against RSV infection. Axl inhibition with kinase inhibitors, including BMS-777607, R428, and TP-0903, or Axl ablation resulted in a significant reduction of RSV infection in cell-based assays. In an animal model of pulmonary RSV infection, treatment with BMS-777607, R428, or TP-0903 ameliorated pulmonary pathology with a significant reduction of RSV titers in the lung tissues and, consequently, decreased the expression of proinflammatory genes. The host promotes ISG expression for the antiviral response and for viral clearance. We found that Axl inhibition led to more robust IFN-ß expression and antiviral gene induction. Thus, the results of this study imply that Axl kinase inhibitors may possess a broad spectrum of antiviral effects by promoting ISG expression.

Axl Mediates Resistance to Respiratory Syncytial Virus Infection Independent of Cell Attachment.

Respiratory syncytial virus (RSV) is a leading cause of severe lower respiratory tract infections in infants and young children. Axl, a TAM family receptor tyrosine kinase, has been demonstrated to be a receptor mediating enveloped virus infection. Here we show that Axl functions as a suppressor of antiviral response during RSV infection. Knockdown of Axl expression in human cells resulted in cell resistance to RSV infection, although the treatment did not significantly affect RSV binding or cell entry. Mice deficient in Axl showed resistance to RSV infection, including reduction in viral load and in pulmonary injury. Although T lymphocyte and macrophage infiltration was reduced, more IFN-γ-producing cells were present in BAL fluid in Axl-/- mice. Fewer alternatively activated alveolar macrophages were found in the lungs of Axl-/- mice. Axl-/- mouse embryonic fibroblasts and siRNA-treated human cells had more robust IFN-ß and IFN-stimulated gene induction of antiviral genes. Furthermore, reexpression of Axl using adenovirus-mediated Axl delivery repressed IFN-stimulated gene induction in Axl-null mouse embryonic fibroblasts by RSV infection. The results suggest that Axl, independent of being a virus entry receptor of RSV infection, negatively regulates IFN signaling to modulate host antiviral response against RSV infection.

Inflammation in the pathogenesis of ischemic stroke.

Ischemic stroke is a common cause of permanent disability in adults worldwide. Inflammation plays a significant role in the pathogenesis of ischemic stroke and its mechanism is complex. Both pro-inflammatory and anti-inflammatory mediators are involved in the pathogenesis of ischemic stroke, an imbalance of which leads to inflammation. Inflammatory cells from both the innate and acquired immune systems are involved in ischemic stroke-related inflammation; processes that are linked by the action of interleukin-17A (IL-17A). Although most inflammatory cells promote inflammation, T regulatory cells (Tregs) may have a protective function at the early stages of an ischemic injury, but a negative role during later stages. However, the precise mechanism of inflammation in ischemic stroke remains elusive; further understanding of it may provide new ideas for the prevention and treatment of ischemic stroke. In this review, we discuss the role of pro-inflammatory and anti-inflammatory mediators and related immune cells in the pathogenesis of ischemic stroke.

[Acupuncture treatment programs for post-stroke motor rehabilitation in community hospitals: study protocol of a multicenter, randomized, controlled trial].

BACKGROUND: Stroke is responsible for increasingly high rates of mortality and disability worldwide. Approximately two million people suffer from stroke for the first time in China each year. The high incidence (50%) of post-stroke disability brings a heavy burden to patients and their caregivers. Acupuncture has been widely used in the communities for post-stroke rehabilitation in China. The objective of this trial is to apply our acupuncture research achievement to treatment and evaluation of post-stroke hemiplegic patients in community. METHODS AND DESIGN: A multicenter, randomized, controlled trial will be performed in Longhua Hospital and a number of community health service centers in Shanghai. A total of 124 patients (estimated sample size) with post-stroke hemiplegia will be randomly divided into an acupuncture group and a control group. The patients undergoing randomization should be stratified according to National Institutes of Health Stroke Scale score at baseline. Within the acupuncture group, different acupuncture protocols are administered to patients with flaccid paralysis or spastic paralysis based on the Ashworth Scale. Patients in the acupuncture group will also be treated with comprehensive rehabilitation therapy. The control group will be treated with comprehensive rehabilitation therapy only. The primary outcome measures are the Simplified Fugl-Meyer Motor Scale, the Modified Barthel Index, and the Burden of Stroke Scale. Secondary outcome measures are the modified Rankin Scale, the modified Ashworth Scale and the Stroke Scale of Traditional Chinese Medicine. Outcome measures will be performed after 4 and 8 weeks of treatment. The patients will be followed up after 6 months. DISCUSSION: The results of this study are expected to demonstrate that our standardized acupuncture protocol for treating and evaluating post-stroke hemiplegic patients will improve motor function and lessen the burden of post-stroke patients within the communities. This will provide the evidence to support successful translation of acupuncture therapy for post-stroke hemiplegic patients in community hospital use. TRIAL REGISTRATION: This trial was registered in Chinese Clinical Trial Registry with the registration number ChiCTR-TRC-11001347.