In this study, we tested our hypothesis regarding mechanistic cross-talk between gastrointestinal inflammation and memory loss in a mouse model. Intrarectal injection of the colitis inducer ...2,4,6-trinitrobenzenesulfonic acid (TNBS) in mice caused colitis via activation of nuclear factor (NF)-κB and increase in membrane permeability. TNBS treatment increased fecal and blood levels of lipopolysaccharide (LPS) and the number of Enterobacteriaceae, particularly Escherichia coli (EC), in the gut microbiota composition, but significantly reduced the number of Lactobacillus johnsonii (LJ). Indeed, we observed that the mice treated with TNBS displayed impaired memory, as assessed using the Y-maze and passive avoidance tasks. Furthermore, treatment with EC, which was isolated from the feces of mice with TNBS-induced colitis, caused memory impairment and colitis, and increased the absorption of orally administered LPS into the blood. Treatment with TNBS or EC induced NF-κB activation and tumor necrosis factor-α expression in the hippocampus of mice, as well as suppressed brain-derived neurotrophic factor expression. However, treatment with LJ restored the disturbed gut microbiota composition, lowered gut microbiota, and blood LPS levels, and attenuated both TNBS- and EC-induced memory impairment and colitis. These results suggest that the gut microbiota disturbance by extrinsic stresses can cause gastrointestinal inflammation, resulting in memory impairment.
Wood-burning aerosol produced under smoldering conditions was photochemically aged with different relative humidity (RH) and NOx conditions using a 104 m3 dual outdoor chamber under natural sunlight. ...Light absorption of organic carbon (OC) was measured over the course of photooxidation using a UV-visible spectrometer connected to an integrating sphere. At high RH, the color decayed rapidly. NOx slightly prolonged the color of wood smoke, suggesting that NOx promotes the formation of chromophores via secondary processes. Overall, the mass absorption cross section (integrated between 280 and 600 nm) of OC increased by 11-54% (except high RH) in the morning and then gradually decreased by 19-68% in the afternoon. This dynamic change in light absorption of wood-burning OC can be explained by two mechanisms: chromophore formation and sunlight bleaching. To investigate the effect of chemical transformation on light absorption, wood smoke particles were characterized using various spectrometers. The intensity of fluorescence, which is mainly related to polycyclic aromatic hydrocarbons (PAHs), rapidly decreased with time, indicating the potential bleaching of PAHs. A decline of levoglucosan concentrations evinced the change of primary organic aerosol with time. The aerosol water content measured by Fourier transform infrared spectroscopy showed that wood-burning aerosol became less hygroscopic as photooxidation proceeded. A similar trend in light absorption changes has been observed in ambient smoke aerosol originating from the 2012 County Line wildfire in Florida. We conclude that the biomass-burning OC becomes less light absorbing after 8-9 h sunlight exposure compared to fresh wood-burning OC.
This paper presents a funnel dynamic surface control combined with fuzzy echo state networks (FESNs) for the prescribed tracking performance of a strict feedback multi-input-multi-output (MIMO) ...nonlinear dynamic system. A new funnel variable is defined so that the funnel virtual control forces the tracking error to fall within funnel boundary, and adaptive FESN method is also proposed to improve the approximation performance in conventional neural network algorithms. A strict feedback controller and adaptive laws for estimating the uncertainties were derived using the recursive steps of dynamic surface control based on the Lyapunov stability theory. Lyapunov stability analysis confirmed the boundedness and convergence of the closed-loop system. The performance of the proposed control scheme was validated by simulations and experimental applications to the tracking control of a MIMO nonlinear system and a robot manipulator.
Tumour-infiltrating lymphocytes (TILs) are known to be associated with response to primary systemic therapy (PST) in breast cancer. This study was conducted to assess the association of TIL subsets ...with pathological complete response (pCR) after PST in breast cancer in relation to breast cancer subtype, breast cancer stem cell (BCSC) phenotype and epithelial-mesenchymal transition (EMT).
The pre-chemotherapeutic biopsy specimens of 153 breast cancer patients who underwent surgical resection after anthracycline- or anthracycline/taxane-based PST were analysed. TIL subsets (CD4+, CD8+, and FOXP3+ TILs), BCSC phenotype, and the expression of EMT markers were evaluated by immunohistochemistry and were correlated with pCR after PST.
Infiltration of CD4+ and CD8+ T lymphocytes was closely correlated with BCSC phenotype and EMT. High levels of CD4+, CD8+, and FOXP3+ TILs were associated with pCR, and CD8+ TILs were found to be an independent predictive factor for pCR. In addition, CD8+ TILs were associated with pCR irrespective of breast cancer subtype, CD44+/CD24- phenotype, EMT, and chemotherapeutic regimen in subgroup analyses.
These findings indicate that CD8+ cytotoxic T lymphocytes are a key component of TILs associated with chemo-response and can be used as a reliable predictor of response to anthracycline- or anthracycline/taxane-based PST in breast cancer.
Mapping host-pathogen interactions has proven instrumental for understanding how viruses manipulate host machinery and how numerous cellular processes are regulated. DNA viruses such as herpesviruses ...have relatively large coding capacity and thus can target an extensive network of cellular proteins. To identify the host proteins hijacked by this pathogen, we systematically affinity tagged and purified all 89 proteins of Kaposi’s sarcoma-associated herpesvirus (KSHV) from human cells. Mass spectrometry of this material identified over 500 virus-host interactions. KSHV causes AIDS-associated cancers, and its interaction network is enriched for proteins linked to cancer and overlaps with proteins that are also targeted by HIV-1. We found that the conserved KSHV protein ORF24 binds to RNA polymerase II and brings it to viral late promoters by mimicking and replacing cellular TATA-box-binding protein (TBP). This is required for herpesviral late gene expression, a complex and poorly understood phase of the viral lifecycle.
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•A herpesvirus-human protein interactome was systematically assembled in human cells•The KSHV interaction network is a tool for predicting viral protein functions•KSHV ORF24 recruits RNA polymerase II and replaces human TBP at late promoters
Kaposi’s sarcoma-associated herpesvirus (KSHV) is a major AIDS-associated pathogen. Davis et al. assemble a KSHV-host protein-protein interaction network that suggests herpesvirus-host evolutionary interplay. Using the network, they describe a hybrid KSHV-human transcription complex that activates viral late genes.
Mosquito-borne flaviviruses, including dengue virus (DENV) and Zika virus (ZIKV), are a growing public health concern. Systems-level analysis of how flaviviruses hijack cellular processes through ...virus-host protein-protein interactions (PPIs) provides information about their replication and pathogenic mechanisms. We used affinity purification-mass spectrometry (AP-MS) to compare flavivirus-host interactions for two viruses (DENV and ZIKV) in two hosts (human and mosquito). Conserved virus-host PPIs revealed that the flavivirus NS5 protein suppresses interferon stimulated genes by inhibiting recruitment of the transcription complex PAF1C and that chemical modulation of SEC61 inhibits DENV and ZIKV replication in human and mosquito cells. Finally, we identified a ZIKV-specific interaction between NS4A and ANKLE2, a gene linked to hereditary microcephaly, and showed that ZIKV NS4A causes microcephaly in Drosophila in an ANKLE2-dependent manner. Thus, comparative flavivirus-host PPI mapping provides biological insights and, when coupled with in vivo models, can be used to unravel pathogenic mechanisms.
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•Comparative AP-MS reveals shared and virus-specific interactions•NS5 suppresses interferon stimulated genes by inhibiting PAF1C recruitment•Pharmacological modulation of the SEC61 translocon inhibits virus replication•Zika virus NS4A inhibits brain development in vivo in an ANKLE2-dependent manner
Comparing protein-protein interactions across dengue and Zika viruses reveals both common mechanisms and functionally distinct pathways contributing to infection outcomes.
As an extension of the conventional output constraint problem, this paper proposes the use of nonlinear dynamic surface control (DSC) combined with adaptive fuzzy logic control to constrain the ...partial tracking errors of strict feedback nonlinear dynamic systems with uncertainties. Transformation of the tracking errors into new virtual error variables is used to recursively design a DSC controller, and a careful selection of the controller design parameters ensures that partial state tracking errors are confined at all times within the prescribed bounds. The stability and boundedness of all closed-loop signals were confirmed using the Lyapunov theorem. The simulation results highlight the efficacy and utility of the proposed control scheme.
Asymptomatic hemorrhagic transformation (HT) is not associated with immediate deterioration of patients with acute ischemic stroke. However, it is unclear whether it is clinically innocuous with ...respect to long-term outcome. The aim of this study was to determine the impact of asymptomatic HT on 3-month outcome.
A consecutive series of 1,618 patients, hospitalized between January 2004 and August 2007 for ischemic stroke within 7 days from symptom onset were identified in a prospective stroke registry database. Those who had no evidence of acute cerebral ischemia on diffusion-weighted MRI, who did not undergo T2-weighted gradient echo MRI, whose modified Rankin Scale (mRS) score at 3 months after stroke onset was not available, or who had symptomatic HT were excluded. The odds ratio (OR) of asymptomatic HT was calculated for the full distribution of mRS score and adjusted for variables with p < 0.25 with respect to their associations with asymptomatic HT or functional outcome.
Of 1,412 patients eligible for the study, 100 (7.1%) had asymptomatic HT. Patients who experienced asymptomatic HT were more likely to have cardioembolic stroke, to receive thrombolytic therapy, to receive anticoagulation with heparin, and to have a higher initial NIH Stroke Scale score. The crude and adjusted ORs of asymptomatic HT for an increment of mRS score at 3 months were 2.94 (95% confidence interval 2.05-4.24) and 1.90 (1.27-2.82), respectively.
Our study shows that the odds of a worse outcome are increased by a factor of 2 in patients with asymptomatic HT compared with those without HT after acute ischemic stroke.
Eosinophils are multifunctional leukocytes that reside in the gastrointestinal (GI) lamina propria, where their basal function remains largely unexplored. In this study, by examining mice with a ...selective deficiency of systemic eosinophils (by lineage ablation) or GI eosinophils (eotaxin-1/2 double deficient or CC chemokine receptor 3 deficient), we show that eosinophils support immunoglobulin A (IgA) class switching, maintain intestinal mucus secretions, affect intestinal microbial composition, and promote the development of Peyer's patches. Eosinophil-deficient mice showed reduced expression of mediators of secretory IgA production, including intestinal interleukin 1β (IL-1β), inducible nitric oxide synthase, lymphotoxin (LT) α, and LT-β, and reduced levels of retinoic acid-related orphan receptor gamma t-positive (ROR-γt(+)) innate lymphoid cells (ILCs), while maintaining normal levels of APRIL (a proliferation-inducing ligand), BAFF (B cell-activating factor of the tumor necrosis factor family), and TGF-β (transforming growth factor β). GI eosinophils expressed a relatively high level of IL-1β, and IL-1β-deficient mice manifested the altered gene expression profiles observed in eosinophil-deficient mice and decreased levels of IgA(+) cells and ROR-γt(+) ILCs. On the basis of these collective data, we propose that eosinophils are required for homeostatic intestinal immune responses including IgA production and that their affect is mediated via IL-1β in the small intestine.
Background
Recent evidence indicates that Staphylococcus aureus, one of the most important human pathogens, secretes vesicles into the extracellular milieu.
Objective
To evaluate whether inhalation ...of S. aureus‐derived extracellular vesicles (EV) is causally related to the pathogenesis of inflammatory pulmonary diseases.
Methods
Staphylococcus aureus EV were prepared by sequential ultrafiltration and ultracentrifugation. The innate immune response was evaluated in vitro after the application of EV to airway epithelial cells and alveolar macrophages. In vivo innate and adaptive immune responses were evaluated after airway exposure to EV. Adjuvant effects of EV on the development of hypersensitivity to inhaled allergens were also evaluated after airway sensitization with S. aureus EV and ovalbumin (OVA).
Results
Staphylococcus aureus and S. aureus EV were detected in house dust. Alveolar macrophages produced both tumor necrosis α (TNF‐α) and interleukin 6 (IL‐6) after in vitro stimulation with S. aureus EV, whereas airway epithelial cells produced only IL‐6. Repeated airway exposure to S. aureus EV induced both Th1 and Th17 cell responses and neutrophilic pulmonary inflammation, mainly via a Toll‐like receptor 2 (TLR2)‐dependent mechanism. In terms of adjuvant effects, airway sensitization with S. aureus EV and OVA resulted in neutrophilic pulmonary inflammation after OVA challenge alone. This phenotype was partly reversed by the absence of interferon γ (IFN‐γ) or IL‐17.
Conclusion
Staphylococcus aureus EV can induce Th1 and Th17 neutrophilic pulmonary inflammation, mainly in a TLR2‐dependent manner. Additionally, S. aureus EV enhance the development of airway hypersensitivity to inhaled allergens.
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