Severe infection with influenza A (H1N1)pdm09 virus is characterized by acute lung injury. The limited efficacy of anti-viral drugs indicates an urgent need for additional therapies. We have ...previously reported that neutralization of gamma interferon (IFN-γ) could significantly rescue the thymic atrophy induced by severe influenza A (H1N1)pdm09 infection in BALB/c mice. A deeper investigation was conducted into the influence of neutralizing IFN-γ to the BALB/c mice weight, survival rate, and lung injury.
The BALB/c mice was infected with severe influenza A (H1N1)pdm09. Monoclonal antibodies against IFN-γ were injected into the abdominal cavities of the mice. After neutralization of IFN-γ occurred in mice infected by severe ∖ influenza A (H1N1)pdm09, observing the influence of neutralizing IFN-γ to the BALB/c mice weight, survival rate, lung injury.
Our results here showed that anti-IFN-γ therapy alleviated the acute lung injury in this mouse model. Neutralization of IFN-γ led to a significant reduction in the lung microvascular leak and the cellular infiltrate in the lung tissue, and also improved the outcome in mice mortality. Several pro-inflammatory cytokines, including interleukin (IL)-1α, tumor necrosis factor (TNF)-α and granulocyte-colony stimulating factor (G-CSF) in the bronchoalveolar lavage fluid (BALF), and the chemokines including G-CSF, monocyte chemoattractant protein-1 (MCP-1) in serum samples were found to be significantly reduced after anti-IFN-γ treatment.
These results suggested that IFN-γ plays an important role in acute lung injury induced by severe influenza A (H1N1)pdm09 infection, and monoclonal antibodies against IFN-γ could be useful as a potential therapeutic remedy for future influenza pandemics.
MAVS is a critical adaptor required for activating an innate antiviral immune response against viral infection. The activation of MAVS requires modification of the Lys63-linked ubiquitination and ...formation of prion-like aggregates. However, the molecular mechanisms regulating MAVS activity remain largely obscured. In this study, we identified a deubiquitinase YOD1, also known as a member of the ovarian tumor family, as a negative regulator of MAVS activation in both human and murine cells. YOD1 was recruited to mitochondria to interact with MAVS through its UBX and Znf domains after viral infection. Subsequently, YOD1 cleaved the K63-linked ubiquitination and abrogated the formation of prion-like aggregates of MAVS, which led to attenuation of IRF3, P65 activation, and IFN-β production. Knockdown of YOD1 potentiated IRF3 and P65 activation, IFN-β production, and antiviral innate immune response to RNA virus. Our findings thus provided, to our knowledge, novel insights into the regulatory cascade of the cellular antiviral response through YOD1-mediated K63-linked deubiquitination and aggregation of MAVS.
Background
The aim of this study is to add to the current knowledge regarding extracranial malignant rhabdoid tumor (MRT), a rare and highly aggressive tumor that occurs most commonly in infants and ...young children.
Patients and Methods
A retrospective medical record review was conducted on 53 patients with pathologically confirmed MRT in Beijing Children's Hospital between January 2007 and October 2017.
Results
Fifty‐three patients were diagnosed with MRT at a median age of 16 months, including 32 cases of malignant rhabdoid tumor of the kidney (MRTK) and 21 cases of extrarenal extracranial rhabdoid tumor (EERT). Fourteen (14/32, 43.75%) patients with MRTK and five (5/21, 23.81%) patients with EERT had metastases at diagnosis, and quite a few number of cases occurred tumor rupture (26.42%). Among the 53 patients, 40 (75.47%) patients died, 10 (18.87%) patients survived, and 3 patients (5.66%) were lost to follow‐up. Among the 40 dead patients, 38 patients died from rapid progression of the disease or tumor recurrence, and 2 patients died of severe postoperative complications. Most of the recurrent or relapsed cases (94.11%) occurred within 8 months, with a median time of 76 days after diagnosis. The overall survival rates of 3 years and 5 years for the entire cohort were 23.71% and 18.44%, respectively. After survival analysis, it was clear that a younger age at diagnosis and distant stage patients had relatively poor outcomes. The effect of treatment was the most difficult to analyze because patients were not treated uniformly. Statistically significant differences in survival were noted among patients treated with standard chemotherapy, total resection, and radiotherapy.
Conclusion
Extracranial MRT is still a highly aggressive tumor in children. Younger patients and those suffering from metastatic disease were most likely to have a poor outcome because of rapid progression or recurrence of the tumor.
Implications for Practice
This is the largest single‐institutional report that investigates the clinical characteristics and outcomes of extracranial malignant rhabdoid tumor (MRT) in China. Our study showed that gross hematuria and tumor rupture were typical characteristics of malignant rhabdoid tumor of the kidney. After survival analysis, it was found that the advanced stage of the tumor and an age ≤12 months at diagnosis were significantly associated with poorer survival. Although extracranial MRT is still a highly aggressive tumor in children, multimodal treatment approach, including chemotherapy, surgery, and radiotherapy, should be employed for this disease.
Extracranial malignant rhabdoid tumor (MRT) is a rare and aggressive tumor that occurs mainly in infants and young children. This review reports the clinical characteristics, treatment schedules, and outcomes of patients with MRT from a single institution in China.
► The IL-35 subunits were found to be expressed concurrently in human cancer cells. ► TNF-α and IFN-γ stimulation increased IL-35 expression in human cancer cells. ► IL-35 over-expression suppressed ...human cancer cell growth via cell cycle arrest. ► IL-35 over-expression increased the apoptosis sensitivity of human cancer cells. ► IL-35 regulated the expression of genes related to cell cycle and apoptosis.
Interleukin (IL)-35 is a novel heterodimeric cytokine in the IL-12 family and is composed of two subunits: Epstein-Barr virus-induced gene 3 (EBI3) and IL-12p35. IL-35 is expressed in T regulatory (Treg) cells and contributes to the immune suppression function of these cells. In contrast, we found that both IL-35 subunits were expressed concurrently in most human cancer cell lines compared to normal cell lines. In addition, we found that TNF-α and IFN-γ stimulation led to increased IL-35 expression in human cancer cells. Furthermore, over-expression of IL-35 in human cancer cells suppressed cell growth in vitro, induced cell cycle arrest at the G1 phase, and mediated robust apoptosis induced by serum starvation, TNF-α, and IFN-γ stimulation through the up-regulation of Fas and concurrent down-regulation of cyclinD1, survivin, and Bcl-2 expression. In conclusion, our results reveal a novel functional role for IL-35 in suppressing cancer activity, inhibiting cancer cell growth, and increasing the apoptosis sensitivity of human cancer cells through the regulation of genes related to the cell cycle and apoptosis. Thus, this research provides new insights into IL-35 function and presents a possible target for the development of novel cancer therapies.
We report the successful high-yield expression of
Candida utilis
uricase in
Escherichia coli
and the establishment of an efficient three-step protein purification protocol. The purity of the ...recombinant protein, which was confirmed to be
C. utilis
uricase by sodium dodecyl sulfate–polyacrylamide gel electrophoresis and matrix-assisted laser desorption/ionization time-of-flight mass spectrometer analysis, was >98% and the specific activity was 38.4 IU/mg. Crystals of
C. utilis
uricase were grown at 18°C using 25% polyethylene glycol 3350 as precipitant. Diffraction by the crystals extends to 1.93 Å resolution, and the crystals belong to the space group P2
1
2
1
2
1
with unit cell parameters
a
= 69.16 Å,
b
= 139.31 Å,
c
= 256.33 Å, and
α
=
β
=
γ
= 90°. The crystal structure of
C. utilis
uricase shares a high similarity with other reported structures of the homologous uricases from other species in protein database, demonstrating that the three-dimensional structure of the protein defines critically to the catalytic activities.
Cytokine-like 1 (CYTL1) was first identified in CD34+ cells derived from bone marrow and cord blood. The biological functions of CYTL1 remain largely unknown. Here, we reveal a relationship between ...CYTL1 expression and the biological characteristics of neuroblastoma (NB). The expression of CYTL1 was detected in 10 human tumor cell lines and human NB tissues by RT-PCR and real-time PCR. The inhibitory effect of CYTL1 knockdown on the proliferation, migration and invasion of SH-SY5Y human neuroblastoma cells was studied using the CCK-8 assay and Transwell chamber assays. Among the 10 human tumor cell lines that we examined, CYTL1 was expressed only in SH-SY5Y human neuroblastoma cells. Furthermore, we also observed high levels of CYTL1 expression in human NB tissues. When CYTL1 expression was blocked by siRNA, SH-SY5Y cells showed decreased proliferation, migration and invasion activities. Taken together, our results showed the first evidence of CYTL1 expression in SH-SY5Y neuroblastoma cells and human NB tissues, revealed a possible link between CYTL1 and NB development, and suggested CYTL1 as a potential therapeutic target and diagnosis biomarker for NB.
The influenza A (H1N1) pdm09 virus remains a critical global health concern and causes high levels of morbidity and mortality. Severe acute lung injury (ALI) and acute respiratory distress syndrome ...(ARDS) are the major outcomes among severely infected patients. Our previous study found that interleukin (IL)-17A production by humans or mice infected with influenza A (H1N1) pdm09 substantially contributes to ALI and subsequent morbidity and mortality. However, the cell types responsible for IL-17A production during the early stage of severe influenza A (H1N1) pdm09 infection remained unknown. In this study, a mouse model of severe influenza A (H1N1) pdm09 infection was established. Our results show that, in the lungs of infected mice, the percentage of γδT cells, but not the percentages of CD4
Th and CD8
Tc cells, gradually increased and peaked at 3 days post-infection (dpi). Further analysis revealed that the Vγ4
γδT subset, but not the Vγ1
γδT subset, was significantly increased among the γδT cells. At 3 dpi, the virus induced significant increases in IL-17A in the bronchoalveolar lavage fluid (BALF) and serum. IL-17A was predominantly secreted by γδT cells (especially the Vγ4
γδT subset), but not CD4
Th and CD8
Tc cells at the early stage of infection, and IL-1β and/or IL-23 were sufficient to induce IL-17A production by γδT cells. In addition to secreting IL-17A, γδT cells secreted interferon (IFN)-γ and expressed both an activation-associated molecule, natural killer group 2, member D (NKG2D), and an apoptosis-associated molecule, FasL. Depletion of γδT cells or the Vγ4
γδT subset significantly rescued the virus-induced weight loss and improved the survival rate by decreasing IL-17A secretion and reducing immunopathological injury. This study demonstrated that, by secreting IL-17A, lung Vγ4
γδT cells, at least, in part mediated influenza A (H1N1) pdm09-induced immunopathological injury. This mechanism might serve as a promising new target for the prevention and treatment of ALI induced by influenza A (H1N1) pdm09.
The decomposition network of ammonium perchlorate (AP) is essential for combustion performance and safety of solid propellants, while the detailed reaction pathway during thermolysis is far from ...clear due to the ultrafast and complex reactions involved. Herein, we present direct atomic simulations of AP thermal decomposition and propose a detailed decomposition network to fill the missing piece in the kinetic models by using a neural network model derived from ab initio calculations. The proton transfer is the dominant channel (NH4 + ClO4 → NH3 + HClO4), which is also observed in previous mass spectra experiments. In addition, gas products from decomposition play a critical role in promoting the decomposition of solid AP. For example, the H abstraction reaction by OH is found to be a critical pathway for AP decomposition. These simulations provide atomic insights into the complex reaction dynamics of AP and can be extended to investigate the reaction mechanism of novel energetic materials.
The RIG-I-like receptor (RLR) signaling pathway is pivotal for innate immunity against invading viruses, and dysregulation of this molecular cascade has been linked to various diseases. Here, we ...identified dimethylarginine dimethylaminohydrolase 2 (DDAH2) as a potent regulator of the RLR-mediated antiviral response in human and mouse. Overexpression of DDAH2 attenuated RLR signaling, whereas loss of DDAH2 function enhanced RLR signaling and suppressed viral replication ex vivo and in mice. Upon viral infection, DDAH2 relocated to mitochondria, where it induced the production of nitric oxide (NO) and the activation of dynamin-related protein 1 (Drp1), which promoted mitochondrial fission and blocked the activation of innate immune responses mediated by mitochondrial antiviral signaling (MAVS). TANK-binding kinase 1 (TBK1), a kinase downstream of MAVS, inhibited DDAH2 by phosphorylating DDAH2 at multiple sites. Our study thus identifies a reciprocal inhibitory loop between the DDAH2-NO cascade and the RLR signaling pathway that fine-tunes the antiviral immune response.
CL-20 is a high energy density material (HEDM) with superior energetic properties. The study of its decomposition mechanism is of great significance to its application in the defense and aerospace ...industries. Multiple kinetic models of CL-20 decomposition under four heating rates are derived from thermogravimetric (TG) experimental data. The derivation is conducted using the chemical reaction neural network (CRNN). The derived kinetic model can accurately predict the mass change during CL-20 decomposition by inferring the main reaction pathway and kinetic parameters. Two representative kinetic models, including a one-step and a multiple-step model with five substances, are presented to reveal their species evolution along with decomposition. In a further analysis, a potential reaction mechanism of CL-20 decomposition is constructed by combining the multiple-step kinetic model with five substances together with the constraints from experiments and previous works. The reaction mechanism includes three reaction classes: initial decomposition, autocatalytic acceleration, and secondary reactions among products. This work demonstrates that the kinetic models from the CRNN framework can capture the thermal decomposition of CL-20 well. It is expected that the CRNN framework will contribute to the kinetic modeling of other solid-phase energetic materials in the future.
•The chemical reaction neural network is first applied to the kinetic model of CL-20.•The one-step and multistep models are developed to reproduce the kinetics of CL-20.•The activation energy of the one-step model is close to the experimental value.•A skeleton reaction mechanism is proposed from the multistep model.
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