Natural variability of TRAIL, IP-10, and CRP in healthy adults - The "HERACLES" study.

A novel host-protein score (called MMBV) helps to distinguish bacterial from viral infection by combining the blood concentrations of three biomarkers: tumour necrosis factor related apoptosis inducing ligand (TRAIL), interferon gamma induced protein 10 (IP-10), and C-reactive protein (CRP). These host biomarkers are differentially expressed in response to bacterial versus viral acute infection. We conducted a prospective study, with a time series design, in healthy adult volunteers in the Netherlands. The aim was to determine the variability of TRAIL, IP-10, and CRP and the MMBV score in healthy adults across time. Up to six blood samples were taken from each healthy volunteer over a period of up to four weeks. In 77 healthy participants without recent or current symptoms, MMBV scores (maximal) were bacterial in 1.3 % and viral (or other non-infectious etiology) in 93.5 % of participants. There was little variation in the mean concentrations of TRAIL (74.5 pg/ml), IP-10 (113.6 pg/ml), and CRP (1.90 mg/L) as well as the MMBV score. The variability of biomarker measurement was comparable to the precision of the measurement platform for TRAIL, IP-10, and CRP. Our findings establish the mean values of these biomarkers and MMBV in healthy individuals and indicate little variability between and within individuals over time, supporting the potential utility of this novel diagnostic to detect infection-induced changes.

An immune-protein score combining TRAIL, IP-10 and CRP for predicting severe COVID-19 disease.

COVID-19 patients are oftentimes over- or under-treated due to a deficit in predictive management tools. This study reports derivation of an algorithm that integrates the host levels of TRAIL, IP-10, and CRP into a single numeric score that is an early indicator of severe outcome for COVID-19 patients and can identify patients at-risk to deteriorate. 394 COVID-19 patients were eligible; 29% meeting a severe outcome (intensive care unit admission/non-invasive or invasive ventilation/death). The score's area under the receiver operating characteristic curve (AUC) was 0.86, superior to IL-6 (AUC 0.77; p = 0.033) and CRP (AUC 0.78; p < 0.001). Likelihood of severe outcome increased significantly (p < 0.001) with higher scores. The score differentiated severe patients who further deteriorated from those who improved (p = 0.004) and projected 14-day survival probabilities (p < 0.001). The score accurately predicted COVID-19 patients at-risk for severe outcome, and therefore has potential to facilitate timely care escalation and de-escalation and appropriate resource allocation.

Observational cohort study of IP-10's potential as a biomarker to aid in inflammation regulation within a clinical decision support protocol for patients with severe COVID-19.

BACKGROUND: Treatment of severely ill COVID-19 patients requires simultaneous management of oxygenation and inflammation without compromising viral clearance. While multiple tools are available to aid oxygenation, data supporting immune biomarkers for monitoring the host-pathogen interaction across disease stages and for titrating immunomodulatory therapy is lacking. METHODS: In this single-center cohort study, we used an immunoassay platform that enables rapid and quantitative measurement of interferon γ-induced protein 10 (IP-10), a host protein involved in lung injury from virus-induced hyperinflammation. A dynamic clinical decision support protocol was followed to manage patients infected with severe acute respiratory syndrome coronavirus 2 and examine the potential utility of timely and serial measurements of IP-10 as tool in regulating inflammation. RESULTS: Overall, 502 IP-10 measurements were performed on 52 patients between 7 April and 10 May 2020, with 12 patients admitted to the intensive care unit. IP-10 levels correlated with COVID-19 severity scores and admission to the intensive care unit. Among patients in the intensive care unit, the number of days with IP-10 levels exceeding 1,000 pg/mL was associated with mortality. Administration of corticosteroid immunomodulatory therapy decreased IP-10 levels significantly. Only two patients presented with subsequent IP-10 flare-ups exceeding 1,000 pg/mL and died of COVID-19-related complications. CONCLUSIONS: Serial and readily available IP-10 measurements potentially represent an actionable aid in managing inflammation in COVID-19 patients and therapeutic decision-making. TRIAL REGISTRATION: Clinicaltrials.gov, NCT04389645, retrospectively registered on May 15, 2020.

Associations of Water-Soluble Macrocyclic Hosts with 4-Aminoazobenzene: Impact of pH.

An investigation of the pH effect on the inclusion complexes of ß-cyclodextrins and calixarenesulfonates with 4-aminoazobenzene was conducted both by experiments and molecular simulations. The whole thermodynamic characterizations of the association between hosts and 4-aminoazobenzene ( K, Δr G0, Δr H0, and TΔr S0) were determined by UV-visible spectroscopy. ß-Cyclodextrin inclusion complexes are not affected by pH change unlike those obtained with calixarenes. All the studied systems were enthalpically favored. Nevertheless, the entropic behavior is different depending on the host. In order to interpret these experimental results, molecular simulations were used to calculate the number of atoms inserted into the cage-like host compounds and the number of water molecules expelled from the cavity.

Physico-chemical role of CdSe/ZnS quantum dots in the photo-polymerization process of acrylate composite materials.

The work presented in this paper is devoted to the physico-chemical role of quantum dots (QDs) in the photopolymerization of composite materials. We show first that the photoexcitation of CdSe/ZnS semiconductor quantum dots can initiate the polymerization of an acrylate monomer in association with a tertiary amine and in the absence of a photoinitiator. But by using a holographic technique, among the others, the gratings recorded in such composite materials are not stable and relax once the light interference pattern is switched off. This behaviour is attributed to a very low degree of conversion of monomers, which does not prevent the post-exposure diffusion of monomers and nanoparticles. The comparison with gratings obtained in the presence of a photosensitizer dye (higher hologram quality and stability) highlights the key importance of using such dye in the polymerization process. The gratings recorded in the complete syrup, containing the dye and QDs which differ by their size and UV-visible absorption spectra, exhibit an additional refractive index modulation. The latter results from the spatial distribution of QDs and the change in the kinetics of polymerization. We further focus on understanding the fall of the polymerization rate owing to the presence of QDs. This decrease may result from the trapping of the tertiary amine (co-initiator) at the surface of those QDs, which reduces the rate of decay of the dye and, consequently, the polymerization rate. Under such conditions, the diffusion of QDs and monomers is favoured and their spatial redistribution is enhanced. These features contribute to modify the physical properties of the gratings.

Chondrogenesis of hMSC in affinity-bound TGF-beta scaffolds.

Herein we describe a bio-inspired, affinity binding alginate-sulfate scaffold, designed for the presentation and sustained release of transforming growth factor beta 1 (TGF-ß1), and examine its effects on the chondrogenesis of human mesenchymal stem cells (hMSCs). When attached to matrix via affinity interactions with alginate sulfate, TGF-ß1 loading was significantly greater and its initial release from the scaffold was attenuated compared to its burst release (>90%) from scaffolds lacking alginate-sulfate. The sustained TGF-ß1 release was further supported by the prolonged activation (14 d) of Smad-dependent (Smad2) and Smad-independent (ERK1/2) signaling pathways in the seeded hMSCs. Such presentation of TGF-ß1 led to hMSC chondrogenic differentiation; differentiated chondrocytes with deposited collagen type II were seen within three weeks of in vitro hMSC seeding. By contrast, in scaffolds lacking alginate-sulfate, the effect of TGF-ß1 was short-term and hMSCs could not reach a similar differentiation degree. When hMSC constructs were subcutaneously implanted in nude mice, chondrocytes with deposited type II collagen and aggrecan typical of the articular cartilage were found in the TGF-ß1 affinity-bound constructs. Our results highlight the fundamental importance of appropriate factor presentation to its biological activity, namely - inducing efficient stem cell differentiation.

Free energy calculations in electroactive self-assembled monolayers (SAMs): impact of the chain length on the redox reaction.

The free energy approach is used to study the effect of the relative chain length of the two constituents of electroactive self-assembled monolayers (SAMs) on gold. In this study, the ferrocene groups are exposed to the electrolyte solution. This situation is achieved by using shorter diluent alkanethiol chains. To this end, the mixed monolayers formed by the self-assembly of 11-ferrocenylundecanethiol and butanethiol FcC(11)S/C(4)S and of 6-ferrocenylhexanethiol and butanethiol FcC(6)S/C(4)S onto a gold surface are studied. Calculation of enthalpy and entropy differences are also performed using molecular simulations. Additionally, the electrochemical signatures of these systems are determined to allow a direct comparison with our calculations. The thermodynamic properties are discussed in terms of enthalpy and entropy changes. Two effects account for the thermodynamic behavior. The first one involves the ion pairing between the ferrocenium group and the perchlorate anion. The second one concerns the desolvation of the first hydration shell of the anions. Finally, this work is also completed with a microscopic description associated with an energy characterization of these SAMs as a function of the surface coverage under conditions close to experiments.

Influence of CdSe/ZnS quantum dots in the polymerization process and in the grating recording in acrylate materials.

The initiation step of the polymerization of acrylate materials is first studied in detail by UV-visible spectroscopy, showing the involvement of each species of the three-component photosensitizer. Then, the implementation of a combined holographic and physicochemical investigation approach is used to determine the influence of photoluminescent CdSe/ZnS quantum dots (QDs) in the photopolymerization and grating recording process in composites containing those QD nanoparticles. The fluorescence microscopy evidences the dynamic distribution profile of QDs due to their diffusion from the irradiated zones to the interface between the bright and the dark zones and, finally, their accumulation in nonirradiated zones. At the same time, the infrared spectroscopy shows that the presence of QDs provides a noticeable decrease of the polymerization rate, which favors the diffusion of the monomer and QDs. These two phenomena contribute to the enhancement of the refractive index modulation depth.

Stromal cell-induced immune regulation in a transplantable lymphoid-like cell constructs.

Engineering of cell-based constructs for treating a variety of immune-related diseases by local transplantation of the cells in a pre-designed matrix is an emerging therapeutic approach, which can potentially reduce the side effects associated with systemic cell injection. Stromal cells have been shown to exert immunosuppressive properties and thus can be exploited for autoimmune regulation and cell transplantation. Here, we demonstrate the fabrication of a stromal cell-based construct, which serves as a lymphoid-like organ with immune regulatory characteristics. In the proposed system, stromal cells are co-seeded with dendritic cells (DC) in a macro-porous alginate scaffold containing the encephalitogenic myelin-derived peptide, proteolipid protein (PLP). We demonstrate that the presence of stromal cells attenuates DC maturation upon lipopolysaccharide stimulus. In vitro, we show that while the migration of pathogenic PLP-specific T cells to construct cultivated with or without stromal cells does not differ, their activation and proliferation are significantly suppressed in the presence of stromal cells. Upon in vivo transplantation, under the kidney capsule of mice, the pathogenic activation and proliferation of T cells which were drawn into the construct were suppressed in the co-seeded constructs. This system thus serves as a lymphoid-like organ with regulatory characteristics, which can be applied for local tolerance induction, for application in cell transplantations as well as autoimmune diseases.

Origin of the photo-cross-linking process in dichromated polyacrylamide under conventional and laser irradiation.

This work is devoted to determining the contribution of amide groups in the photoredox and cross-linking process of dichromated polyacrylamide based on the fate of the photoactive species and of the polymer under conventional and laser irradiation. It was shown that, in parallel to the reduction of chromium(VI) into chromium(V), the cross-linking of the matrix occurred through a complexation reaction around chromium(V) and through formation of covalent bonds between macromolecular chains. A comparison with dichromated poly(vinyl alcohol) was also reported to highlight the role of the chemical structure of the polymeric matrix in the mechanism of hologram formation. Moreover, for the first time it was demonstrated by in situ infrared spectroscopy that the physicochemical modifications undergone by the photosensitive materials were similar for the two modes of irradiation.

Direct evidence of photo-induced diffusion of quantum dots in a photopolymerizable matrix.

We present direct experimental evidence of photo-induced movement of photoluminescent quantum dots (QDs) dispersed in a photopolymerizable acrylate mixture. The resulting rearrangement of QDs into a spatially modulated pattern fixed in the polymer matrix is evidenced thanks to fluorescence microscopy.

Reorientational dynamics of p-sulfonatocalix[4]arene and of its La(III) complex in water.

The reorientational dynamics of p-sulfonatocalix[4]arene and of its La(III) complex in deuterated water were studied by 1H NMR longitudinal relaxation rates. It is shown that the relaxation is purely dipolar in the non-extreme narrowing regime. The distance between the geminal protons could be determined from the NMR data, giving good agreement with the values generally used in correlation time calculations. The correlation times show an Arrhenius behaviour in good agreement with previously reported data from 13C measurements for a similar uncomplexed calixarene. The Arrhenius energies of activation are identical for the uncomplexed and the complexed calixarenes, suggesting a reorientational motion strongly dependent on the structure of the water cage around the complex. This is also in agreement with a complexation of the La(III) cation in the second sphere of solvation of the sulfonate groups, as shown by molecular dynamics simulations.