Differential Requirement for c-Jun N-terminal Kinase 1 in Lung Inflammation and Host Defense

The c-Jun N-terminal kinase (JNK) - 1 pathway has been implicated in the cellular response to stress in many tissues and models. JNK1 is known to play a role in a variety of signaling cascades, including those involved in lung disease pathogenesis. Recently, a role for JNK1 signaling in immune cell function has emerged. The goal of the present study was to determine the role of JNK1 in host defense against both bacterial and viral pneumonia, as well as the impact of JNK1 signaling on IL-17 mediated immunity. Wild type (WT) and JNK1 −/− mice were challenged with Escherichia coli, Staphylococcus aureus, or Influenza A. In addition, WT and JNK1 −/− mice and epithelial cells were stimulated with IL-17A. The impact of JNK1 deletion on pathogen clearance, inflammation, and histopathology was assessed. JNK1 was required for clearance of E. coli, inflammatory cell recruitment, and cytokine production. Interestingly, JNK1 deletion had only a small impact on the host response to S. aureus. JNK1 −/− mice had decreased Influenza A burden in viral pneumonia, yet displayed worsened morbidity. Finally, JNK1 was required for IL-17A mediated induction of inflammatory cytokines and antimicrobial peptides both in epithelial cells and the lung. These data identify JNK1 as an important signaling molecule in host defense and demonstrate a pathogen specific role in disease. Manipulation of the JNK1 pathway may represent a novel therapeutic target in pneumonia

Lower Respiratory Tract Infection Induced by a Genetically Modified Picornavirus in Its Natural Murine Host

Infections with the picornavirus, human rhinovirus (HRV), are a major cause of wheezing illnesses and asthma exacerbations. In developing a murine model of picornaviral airway infection, we noted the absence of murine rhinoviruses and that mice are not natural hosts for HRV. The picornavirus, mengovirus, induces lethal systemic infections in its natural murine hosts, but small genetic differences can profoundly affect picornaviral tropism and virulence. We demonstrate that inhalation of a genetically attenuated mengovirus, vMC0, induces lower respiratory tract infections in mice. After intranasal vMC0 inoculation, lung viral titers increased, peaking at 24 h postinoculation with viral shedding persisting for 5 days, whereas HRV-A01a lung viral titers decreased and were undetectable 24 h after intranasal inoculation. Inhalation of vMC0, but not vehicle or UV-inactivated vMC0, induced an acute respiratory illness, with body weight loss and lower airway inflammation, characterized by increased numbers of airway neutrophils and lymphocytes and elevated pulmonary expression of neutrophil chemoattractant CXCR2 ligands (CXCL1, CXCL2, CXCL5) and interleukin-17A. Mice inoculated with vMC0, compared with those inoculated with vehicle or UV-inactivated vMC0, exhibited increased pulmonary expression of interferon (IFN-α, IFN-β, IFN-λ), viral RNA sensors [toll-like receptor (TLR)3, TLR7, nucleotide-binding oligomerization domain containing 2 (NOD2)], and chemokines associated with HRV infection in humans (CXCL10, CCL2). Inhalation of vMC0, but not vehicle or UV-inactivated vMC0, was accompanied by increased airway fluid myeloperoxidase levels, an indicator of neutrophil activation, increased MUC5B gene expression, and lung edema, a sign of infection-related lung injury. Consistent with experimental HRV inoculations of nonallergic, nonasthmatic human subjects, there were no effects on airway hyperresponsiveness after inhalation of vMC0 by healthy mice. This novel murine model of picornaviral airway infection and inflammation should be useful for defining mechanisms of HRV pathogenesis in humans

A Novel Inactivated Intranasal Respiratory Syncytial Virus Vaccine Promotes Viral Clearance without Th2 Associated Vaccine-Enhanced Disease

Respiratory syncytial virus (RSV) is a leading cause of bronchiolitis and pneumonia in young children worldwide, and no vaccine is currently available. Inactivated RSV vaccines tested in the 1960's led to vaccine-enhanced disease upon viral challenge, which has undermined RSV vaccine development. RSV infection is increasingly being recognized as an important pathogen in the elderly, as well as other individuals with compromised pulmonary immunity. A safe and effective inactivated RSV vaccine would be of tremendous therapeutic benefit to many of these populations.In these preclinical studies, a mouse model was utilized to assess the efficacy of a novel, nanoemulsion-adjuvanted, inactivated mucosal RSV vaccine. Our results demonstrate that NE-RSV immunization induced durable, RSV-specific humoral responses, both systemically and in the lungs. Vaccinated mice exhibited increased protection against subsequent live viral challenge, which was associated with an enhanced Th1/Th17 response. In these studies, NE-RSV vaccinated mice displayed no evidence of Th2 mediated immunopotentiation, as has been previously described for other inactivated RSV vaccines.These studies indicate that nanoemulsion-based inactivated RSV vaccination can augment viral-specific immunity, decrease mucus production and increase viral clearance, without evidence of Th2 immune mediated pathology

Attenuated Directed Exploration during Reinforcement Learning in Gambling Disorder

Gambling disorder (GD) is a behavioral addiction associated with impairments in value-based decision-making and behavioral flexibility and might be linked to changes in the dopamine system. Maximizing long-term rewards requires a flexible trade -off between the exploitation of known options and the exploration of novel options for information gain. This exploration-exploitation trade-off is thought to depend on dopamine neurotransmission. We hypothesized that human gamblers would show a reduction in directed (uncertainty-based) exploration, accompanied by changes in brain activity in a fronto-parietal exploration-related network. Twenty-three frequent, non-treatment seeking gamblers and twenty-three healthy matched con-trols (all male) performed a four-armed bandit task during functional magnetic resonance imaging (fMRI). Computational modeling using hierarchical Bayesian parameter estimation revealed signatures of directed exploration, random exploration, and perseveration in both groups. Gamblers showed a reduction in directed exploration, whereas random exploration and perseveration were similar between groups. Neuroimaging revealed no evidence for group differences in neural representa-tions of basic task variables (expected value, prediction errors). Our hypothesis of reduced frontal pole (FP) recruitment in gamblers was not supported. Exploratory analyses showed that during directed exploration, gamblers showed reduced parietal cortex and substantia-nigra/ventral-tegmental-area activity. Cross-validated classification analyses revealed that connectivity in an exploration-related network was predictive of group status, suggesting that connectivity patterns might be more predictive of problem gambling than univariate effects. Findings reveal specific reductions of strategic exploration in gamblers that might be linked to altered processing in a fronto-parietal network and/or changes in dopamine neurotransmission implicated in GD

Dynamic Circular Cellular Networks for Adaptive Smoothing of Multi-Dimensional Signals

In [10] a theoretical framework for locally-adaptive smoothing of multidimensional data was presented. Based on this framework we introduce a hardware efficient architecture suitable for mixed-mode VLSI implementation. Substantial shortcomings of analogue implementations are overcome by connecting all cells in a circular structure: i) influence of process parameter deviation ii) limited number of cells iii) input/output bottleneck. The connections between the analogue cells and the cells themselves are dynamically reconfigured. This results in a non-linear adaptive filter kernel which is shifted virtually over the signal vector of infinite length. A 1-d prototype with 32 cells has been fabricated using 0.8¯m CMOS-technology. The chip is fully functional with an overall error less than 1%; experimental results are presented in this paper