Induction of innate immunity by Aspergillus fumigatus cell wall polysaccharides is enhanced by the composite presentation of chitin and beta-glucan

Chitin and β-glucan are conserved throughout evolution in the fungal cell wall and are the most common polysaccharides in fungal species. Together, these two polysaccharides form a structural scaffold that is essential for the survival of the fungus. In the present study, we demonstrated that Aspergillus fumigatus alkali-insoluble cell wall fragments (AIF), composed of chitin linked covalently to β-glucan, induced enhanced immune responses when compared with individual cell wall polysaccharides. Intranasal administration of AIF induced eosinophil and neutrophil recruitment, chitinase activity, TNF-α and TSLP production in mice lungs. Selective destruction of chitin or β-glucan from AIF significantly reduced eosinophil and neutrophil recruitment as well as chitinase activity and cytokine expression by macrophages, indicating the synergistic effect of the cell wall polysaccharides when presented together as a composite PAMP. We also showed that these cell wall polysaccharides induced chitin-specific IgM in mouse serum. Our in vivo and in vitro data indicate that chitin and β-glucan play important roles in activating innate immunity when presented as composite cell wall PAMPs.     

Systemic immunogenicity of para-Phenylenediamine and Diphenylcyclopropenone: two potent contact allergy-inducing haptens

p-Phenylenediamine (PPD) and Diphenylcyclopropenone (DPCP) are two potent haptens. Both haptens are known to cause delayed-type hypersensitivity, involving a cytokine response and local infiltration of T-cell subpopulations, resulting in contact dermatitis. We investigated the systemic immune effects of PPD and DPCP, two relatively unexplored skin allergens. The dorsal sides of the ears of BALB/c mice were exposed to PPD or DPCP (0.1 % w/v or 0.01 % w/v), or vehicle alone. Mice were treated once daily for 3 days (induction period) and subsequently twice per week for 8 weeks. Local and systemic immune responses in the auricular and pancreatic lymph nodes, spleen, liver, serum, and ears were analyzed with cytokine profiling MSD, flow cytometry, and qPCR. Ear swelling increased significantly in mice treated with 1 % PPD, 0.01 % DPCP or 0.1 % DPCP, compared with vehicle treatment, indicating that the mice were sensitized and that there was a local inflammation. Auricular lymph nodes, pancreatic lymph nodes, spleen, and liver showed changes in regulatory T-cell, B-cell, and NKT-cell frequencies, and increased activation of CD8⁺ T cells and B cells. Intracellular cytokine profiling revealed an increase in the IFN-γ- and IL-4-positive NKT cells present in the liver following treatment with both haptens. Moreover, we saw a tendency toward a systemic increase in IL-17A. We observed systemic immunological effects of PPD and DPCP. Furthermore, concentrations too low to increase ear thickness and cause clinical symptoms may still prime the immune system. These systemic immunological effects may potentially predispose individuals to certain diseases.     

Structure–property relations in linear viscoelasticity of supramolecular hydrogels

Extraordinary mechanical properties of supramolecular gels (fracture toughness, fatigue resistance, injectability and self-healing ability) are strongly affected by their viscoelastic response driven by rearrangement (association and dissociation) of physical bonds. The kinetics of rearrangement is traditionally studied in small-amplitude shear oscillatory tests by analyzing the effect of the frequency of oscillations ω on the storage G′ and loss G′′ moduli. Conventional Maxwell-type models describe observations rather poorly when the gels reveal a pronounced flattening of the graphs G′′(ω) at high frequencies. A simple model is derived in linear viscoelasticity of supramolecular gels. Its advantage is that the model reproduces experimental data correctly, on the one hand, and involves only four material constants, on the other. Based on the analysis of experimental data on gels cross-linked by coiled-coil complexes, covalent and ionic bonds, phenylboronic acid-diol complexes and metal–ligand coordination bonds, the model is applied to develop structure–property relations that describe the influence of chemical structure of supramolecular gels (concentration of polymer chains and type and molar fraction of temporary bonds) and environmental conditions (temperature, pH and ionic strength of buffer solutions) on their viscoelastic response.

A model is developed for the linear viscoelastic response of supramolecular gels and applied to the analysis of structure–property relations in gels with various supramolecular motifs.     

Peri-ictal heart rate variability parameters as surrogate markers of seizure severity

This study aims at defining objective parameters reflecting the severity of peri-ictal autonomic changes and their relation to post-ictal generalized electroencephalography (EEG) suppression (PGES), with the view that such changes could be detected by wearable seizure detection systems and prove useful to assess the risk of sudden unexpected death in epilepsy (SUDEP). To this purpose, we assessed peri-ictal changes in heart rate variability (HRV) and correlated them with seizure duration, intensity of electromyography-based ictal muscle activity, and presence and duration of post-ictal generalized EEG suppression (PGES). We evaluated 75 motor seizures from 40 patients, including 61 generalized tonic-clonic seizures (GTCS) and 14 other major motor seizure types. For all major motor seizures, HRV measurements demonstrated a significantly decreased parasympathetic activity and increased sympathetic activity in the post-ictal period. The post-ictal increased sympathetic activity was significantly higher for GTCS as compared with non-GTCS. The degree of peri-ictal decreased parasympathetic activity and increased sympathetic activity was associated with longer PGES (>20 s), longer seizure duration, and greater intensity of ictal muscle activity. Mean post-ictal heart rate (HR) was an independent predictor of PGES duration, seizure duration, and intensity of ictal muscle contraction. Our results indicate that peri-ictal changes in HRV are potential biomarkers of major motor seizure severity.     

Colon and rectal cancer risk after bariatric surgery in a multicountry Nordic cohort study

Obesity is a risk factor for colorectal cancer. Yet, some research indicates that weight-reducing bariatric surgery also increases colorectal cancer risk. Our study was undertaken because current evidence examining bariatric surgery and risk of colorectal cancer is limited and inconsistent. This population-based cohort study included adults with a documented obesity diagnosis in Denmark, Finland, Iceland, Norway or Sweden in 1980–2015. The incidence of colorectal cancer in participants with obesity who had and had not undergone bariatric surgery was compared to the incidence in the corresponding background population by calculating standardized incidence ratios (SIR) with 95% confidence intervals (CI). Additionally, operated and nonoperated participants with obesity were compared using multivariable Cox regression, providing hazard ratios (HR) with 95% CIs adjusted for confounders. Among 502,772 cohort participants with an obesity diagnosis, 49,931(9.9%) underwent bariatric surgery. The overall SIR of colon cancer was increased after bariatric surgery (SIR 1.56; 95% CI 1.28–1.88), with higher SIRs ≥10 years postsurgery. The overall HR of colon cancer in operated compared to nonoperated participants was 1.13 (95% CI 0.92–1.39) and 1.55 (95% CI 1.04–2.31) 10–14 years after bariatric surgery. Bariatric surgery did not significantly increase the risk of rectal cancer (SIR 1.14, 95% CI 0.83–1.52; HR 1.08, 95% CI 0.79–1.49), but the risk estimates increased with longer follow-up periods. Our study suggests that bariatric surgery is associated with an increased risk of colon cancer, while the support for an increased risk of rectal cancer was weaker.     

Anti‐fibrotic mechanisms of angiotensin AT2‐receptor stimulation

The angiotensin AT₂‐receptor is a main receptor of the protective arm of the renin‐angiotensin system. Understanding of this unconventional G‐protein coupled receptor has significantly advanced during the past decade, largely because of the availability of a selective non‐peptide AT₂‐receptor agonist, which allowed the conduct of a multitude of studies in animal disease models. This article reviews such preclinical studies that in their entirety provide strong evidence for an anti‐fibrotic effect mediated by activation of the AT₂‐receptor. Prevention of the development of fibrosis by AT₂‐receptor stimulation has been demonstrated in lungs, heart, blood vessels, kidney, pancreas and skin. In lungs, AT₂‐receptor stimulation was even able to reverse existing fibrosis. The article further discusses intracellular signalling mechanisms mediating the AT₂‐receptor‐coupled anti‐fibrotic effect, including activation of phosphatases and subsequent interference with pro‐fibrotic signalling pathways, induction of matrix‐metalloproteinases and hetero‐dimerization with the AT₁‐receptor, the TGF‐βRII‐receptor or the RXFP1‐receptor for relaxin. Knowledge of the anti‐fibrotic effects of the AT₂‐receptor is of particular relevance because drugs targeting this receptor have entered clinical development for indications involving fibrotic diseases.