A nonlinear two-dimensional (2D) continuum with a latent internal structure is introduced as a coarse model of a plane network of beams which, in turn, is assumed as a model of a pantographic ...structure made up by two families of equispaced beams, superimposed and connected by pivots. The deformation measures of the beams of the network and that of the 2D body are introduced and the former are expressed in terms of the latter by making some kinematical assumptions. The expressions for the strain and kinetic energy densities of the network are then introduced and given in terms of the kinematic quantities of the 2D continuum. To account for the modelling abilities of the 2D continuum in the linear range, the eigenmode and eigenfrequencies of a given specimen are determined. The buckling and post-buckling behaviour of the same specimen, subjected to two different loading conditions are analysed as tests in the nonlinear range. The problems have been solved numerically by means of the COMSOL Multiphysics finite element software.
ABSTRACT
Blazar S5 0716+714 is well-known for its short-term variability, down to intraday time-scales. We here present the 2-min cadence optical light curve obtained by the TESS space telescope in ...2019 December–2020 January and analyse the object fast variability with unprecedented sampling. Supporting observations by the Whole Earth Blazar Telescope Collaboration in B, V, R, and I bands allow us to investigate the spectral variability during the TESS pointing. The spectral analysis is further extended in frequency to the UV and X-ray bands with data from the Neil Gehrels Swift Observatory. We develop a new method to unveil the shortest optical variability time-scales. This is based on progressive de-trending of the TESS light curve by means of cubic spline interpolations through the binned fluxes, with decreasing time bins. The de-trended light curves are then analysed with classical tools for time-series analysis (periodogram, autocorrelation, and structure functions). The results show that below 3 d there are significant characteristic variability time-scales of about 1.7, 0.5, and 0.2 d. Variability on time-scales $\lesssim 0.2$ d is strongly chromatic and must be ascribed to intrinsic energetic processes involving emitting regions, likely jet substructures, with dimension less than about 10−3 pc. In contrast, flux changes on time-scales $\gtrsim 0.5$ d are quasi-achromatic and are probably due to Doppler factor changes of geometric origin.
Extracellular vesicles (EVs), are naturally occurring cargo delivery tools with the potential to be used as drug vehicles of single agents or combination therapies. We previously demonstrated that ...human lung cancer cell-derived EVs could be used for the systemic delivery of oncolytic virus (OVs) and chemotherapy drugs such as paclitaxel (PTX), leading to enhanced anti-tumor effects in nude mice. In the current work, we evaluated the biodistribution of EVs by using bioluminescence and fluorescence imaging technologies, thus proving the ability of these EVs-formulations to specifically target the neoplasia, while leaving other body tissues unaffected. Moreover, in vivo imaging of NFκB activation in an immunocompetent reporter mouse model allowed to demonstrate the selective ability of EVs to induce tumor-associated inflammatory reactions, which are characterized by immunogenic cell death and CD3+/CD4+/CD8+ T-cell infiltration. While EVs have the potential to induce a systemic immune reaction by pro-inflammatory cytokines, our study provides compelling evidences of a localized inflammatory effect in the peritumoral area. Collectively, our findings strongly support the systemic administration of EVs formulations with OVs alone or in combination with chemotherapy agents as a novel strategy aimed at treating primary and metastatic cancers.
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Background
Psoriasis is an immune‐mediated inflammatory disease in which the Th17 pathway is mainly involved. Systemic interventions with biologics that specifically block the Th17 pathway are ...effective to treat severe psoriasis. However, for efficient topical treatment, small molecules are more suitable than antibodies to penetrate and target epidermal keratinocytes, the key players in psoriasis. Celastrol, a well‐described triterpene, is present in low amounts in Tripterygium wilfordii roots. By using plant cell culture (PCC), we were able to boost Celastrol production in bioreactors. Here, we evaluated immune modulator effect of Celastrol enriched extract (CEE) in Th17/Th22 psoriasis induced in 2D and 3D human models in vitro in view of its dermatological usage.
Methods
Human CD4+ T cells (hCD4), Normal Human Epidermal Keratinocytes (NHEK), micro‐epidermis and reconstructed human epidermis (RHE) were preincubated with CEE and reference controls. Then, hCD4 were stimulated by anti‐CD3/CD28 while others were stimulated by Th17/22 cytokines cocktails. Psoriasis biomarkers were assessed by ELISA (hCD4 and RHE), by RT‐qPCR (NHEK) or by ICH/ELISA (micro‐epidermis).
Results
In 2D stimulated models (hCD4 and NHEK), CEE dose dependently inhibited, respectively, the expression of Th17 cytokines and psoriasis induced biomarkers. In 3D models (RHE and micro‐epidermis), IL‐8 expression was significantly reduced (RHE) and native phenotype was restored by CEE (micro‐epidermis).
Conclusion
These results clearly showed that Th17/Th22 cytokines, main inflammatory parameters, and psoriasis associated key biomarkers were inhibited by CEE in both 2D and 3D human in vitro models. Therefore, skin homeostasis could be restored by these modulator effects. Moreover, this high added value CEE was obtained by an ecofriendly bioprocess in contrast to traditional roots extracts. This is the first time that a well‐defined CEE immune modulator has been proposed for psoriasis adjuvant care to reduce inflammation.
In an effort to locate the sites of emission at different frequencies and physical processes causing variability in blazar jets, we have obtained high time-resolution observations of BL Lacertae over ...a wide wavelength range: with the Transiting Exoplanet Survey Satellite (TESS) at 6000-10000 with 2 minute cadence; with the Neil Gehrels Swift satellite at optical, UV, and X-ray bands; with the Nuclear Spectroscopic Telescope Array at hard X-ray bands; with the Fermi Large Area Telescope at γ-ray energies; and with the Whole Earth Blazar Telescope for measurement of the optical flux density and polarization. All light curves are correlated, with similar structure on timescales from hours to days. The shortest timescale of variability at optical frequencies observed with TESS is ∼0.5 hr. The most common timescale is 13 1 hr, comparable with the minimum timescale of X-ray variability, 14.5 hr. The multiwavelength variability properties cannot be explained by a change solely in the Doppler factor of the emitting plasma. The polarization behavior implies that there are both ordered and turbulent components to the magnetic field in the jet. Correlation analysis indicates that the X-ray variations lag behind the γ-ray and optical light curves by up to ∼0.4 day. The timescales of variability, cross-frequency lags, and polarization properties can be explained by turbulent plasma that is energized by a shock in the jet and subsequently loses energy to synchrotron and inverse Compton radiation in a magnetic field of strength ∼3 G.
In this paper a one-dimensional continuum endowed with polynomial nonlinear hyperelastic constitutive functions is used in order to capture the necking and the kinking arising in carbon nanotubes. In ...view of some preceding works by Antman and Podio-Guidugli these phenomena are seen as cases of bifurcation from a trivial nonlinear equilibrium path. The bifurcation analysis is performed by means of the asymptotic method. For a sample case, the bifurcation point and the eigenmode are determined by solving a standard eigenvalue problem. The slopes of the trivial and the bifurcated equilibrium curves at the critical point are also determined and shown.
Background
Inflammatory skin disorders, including atopic dermatitis (AD), associated pruritus and sensitive skin, have a complex multifactorial pathogenesis including neurogenic inflammation ...involving the release in blood and skin of neurotransmitters such as substance P (SP).
Aims and Methods
In vitro models evaluated the effect of the original biological extract of Aquaphilus dolomiae extract‐G3 (ADE‐G3) on cutaneous neurogenic inflammation.
Results
ADE‐G3 significantly inhibited SP‐stimulated release of IL‐1β and TNF‐α from normal human epidermal keratinocytes; significantly and dose‐dependently inhibited SP‐stimulated activation of human mast cells; significantly inhibited veratridine‐stimulated release of SP from human sensory neurons; modulated expression of genes involved in lipid synthesis, innate immunity, corneocyte scaffolding and epidermal differentiation in a histamine‐sensitized reconstructed human epidermis model; and, when applied topically to ex vivo human explants, inhibited IL‐8 and histamine release.
Conclusions
Topically applied ADE‐G3, once formulated, may improve neuro‐inflammation in patients with inflammatory skin disorders.
Aquaphilus dolomiae (AD) is a unique isolate from Avène Thermal Spring Water. I‐Modulia, the first biotech extract from culture of AD, was used as immune modulator in Th2 inflammatory models. In this ...short publication, firstly we describe generation of two AD de novo extracts specifically designed for repairing and for neuroinflammation modulation activities which will be described, respectively, in two other articles in this supplement. Finally, for I‐modulia, we describe new data on inhibition of human mast cell degranulation in vitro and its effect on substance P‐induced neurogenic inflammation on ex vivo human skin explants.
Background
Sensitive skin is a common condition of hyper‐reactivity to external stimuli, e.g. heat or abrasion. The symptoms are subjective but can be measured using validated emotional and technical ...methods. Avène water has several beneficial effects on the skin. In vitro studies indicated that the active component of this natural spring water, Aquaphilus dolomiae extract‐G3 (ADE‐G3), modulates cutaneous sensitivity via an anaesthetic‐like mechanism.
Objectives
To assess facial skin reactivity after repeated application of two formulations containing ADE‐G3.
Methods
In open‐label studies, healthy subjects with sensitive facial skin applied cream or balm twice daily for 84 days. The severity of skin sensitivity was measured using the Sensitive Scale (based on quantifying visible or subjective signs). Subjective responses associated with pain or uncomfortable feeling were assessed by measuring electrodermal response (EDR). This involves measuring variations in skin electrical resistance due to non‐conscious physiological changes in activity of the sympathetic nervous system. Subjects were also evaluated for beneficial effects according to a quantitative approach using semantic assessment of a question regarding their skin quality. Evaluations were performed before and after the first application, and after 29/30, 56 and 84 days of twice daily use.
Results
There was a significant decrease in the EDR after stimuli immediately after the application of both ADE‐G3 formulations, which continued to decrease over 84 days (40–50% decrease by D85). Likewise, all physical and functional signs of the Sensitive Scale were significantly decreased immediately after the first application and at all time points tested after treatment. Verbatim analysis revealed a semantic shift, from mainly negative terms on D1 to mainly positive terms at D85 for both tested products.
Conclusions
These results demonstrated that two formulations containing ADE‐G3 reduced skin sensitivity, indicating a decreased activation of the sympathetic nervous system associated with this condition.
ABSTRACT
Here we report on the results of the Whole Earth Blazar Telescope photo-polarimetric campaign targeting the blazar S5 0716+71, organized in 2014 March to monitor the source simultaneously in
...BVRI
and near-IR filters. The campaign resulted in an unprecedented data set spanning ∼110 hr of nearly continuous, multiband observations, including two sets of densely sampled polarimetric data mainly in the
R
filter. During the campaign, the source displayed pronounced variability with peak-to-peak variations of about 30% and “bluer-when-brighter” spectral evolution, consisting of a day-timescale modulation with superimposed hour-long microflares characterized by ∼0.1 mag flux changes. We performed an in-depth search for quasi-periodicities in the source light curve; hints for the presence of oscillations on timescales of ∼3 and ∼5 hr do not represent highly significant departures from a pure red-noise power spectrum. We observed that, at a certain configuration of the optical polarization angle (PA) relative to the PA of the innermost radio jet in the source, changes in the polarization degree (PD) led the total flux variability by about 2 hr; meanwhile, when the relative configuration of the polarization and jet angles altered, no such lag could be noted. The microflaring events, when analyzed as separate pulse emission components, were found to be characterized by a very high PD (>30%) and PAs that differed substantially from the PA of the underlying background component, or from the radio jet positional angle. We discuss the results in the general context of blazar emission and energy dissipation models.
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