Nano-and micro-based systems for immunotolerance induction in multiple sclerosis

It is estimated that more than 2.5 million individuals worldwide have multiple sclerosis (MS). MS is an autoimmune neurodegenerative disease resulting from the destruction of the myelin sheath that enwraps axons driven by an immune cell attack to the central nervous system. Current therapeutic programs for MS focus in immunosuppression and more recently in the use of immunomodulatory molecules. These therapeutic approaches provide significant improvements in the management of the disease, but are frequently associated with an increased susceptibility of opportunistic infection. In this commentary, we highlight the application of nano and micro-technologies as emerging and innovative solutions for MS therapy with the potential to restore immune homeostasis via antigen-specific interactions. Furthermore, we propose and discuss the usage of a minimally invasive approach, namely microneedle patches, as a new therapeutic route. Microneedle patches for the delivery of specific antigens to restore immunotolerance in the context of multiple sclerosis.This project has received funding from the European Union's Seventh Framework Program for research, technological development and demonstration under grant agreement no 600375. Joao Cerqueira received a grant from 2CA - Braga to the project "The impact of modafinil in cognition in multiple sclerosis."info:eu-repo/semantics/publishedVersio

Freeform 3D printing using a continuous viscoelastic supporting matrix

Embedded bio-printing has fostered significant advances toward the fabrication of soft complex tissue-like constructs, by providing a physical support that allows the freeform shape maintenance within the prescribed spatial arrangement, even under gravity force. Current supporting materials still present major drawbacks for up-scaling embedded 3D bio-printing technology towards tissue-like constructs with clinically relevant dimensions. Herein, we report a a cost-effective and widely available supporting material for embedded bio-printing consisting on a continuous pseudo-plastic matrix of xanthan-gum (XG). This natural polisaccharide exhibits peculiar rheological properties that have enabled the rapid generation of complex volumetric 3D constructs with out of plane features. The freedom of design within the three orthogonal axes through the independent and controlled bio-printing process opens new opportunities to produce on demand large arbitrary shapes for personalized medicine. Additionally, we have demonstrated the versatile functionality of XG as a photocurable gel reservoir to engineer perfused cell-laden hydrogel constructs, addressing other practical biomedical applications such as in vitro models and organ-on-chip platforms.publishe

Rubus ulmifolius Schott fruits: A detailed study of its nutritional, chemical and bioactive properties

The authors are grateful to the Foundation for Science and Technology (FCT, Portugal) and FEDER under Program PT2020 for financial support to CIMO (UID/AGR/00690/2013), L. Barros and R. Calhelha contracts. The authors are also grateful to the Interreg España- Portugal for financial support through the project 0377_Iberphenol_6_E). This work is also funded by the European Structural and Investment Funds (FEEI) through the Regional Operational Program North 2020, within the scope of Project NORTE- 01-0145-FEDER-023289: DeCodE and project Mobilizador Norte-01- 0247-FEDER-024479: ValorNatural®. The authors also thank Professor of Botany Carlos Aguiar for the help given for the plant material collection and botanical identification.info:eu-repo/semantics/publishedVersio

It takes two to remyelinate: A bioengineered platform to study astrocyte-oligodendrocyte crosstalk and potential therapeutic targets in remyelination

The loss of the myelin sheath insulating axons is the hallmark of demyelinating diseases. These pathologies often lead to irreversible neurological impairment and patient disability. No effective therapies are currently available to promote remyelination. Several elements contribute to the inadequacy of remyelination, thus understanding the intricacies of the cellular and signaling microenvironment of the remyelination niche might help us to devise better strategies to enhance remyelination. Here, using a new in vitro rapid myelinating artificial axon system based on engineered microfibres, we investigated how reactive astrocytes influence oligodendrocyte (OL) differentiation and myelination ability. This artificial axon culture system enables the effective uncoupling of molecular cues from the biophysical properties of the axons, allowing the detailed study of the astrocyte-OL crosstalk. Oligodendrocyte precursor cells (OPCs) were cultured on poly(trimethylene carbonate-co-ε-caprolactone) copolymer electrospun microfibres that served as surrogate axons. This platform was then combined with a previously established tissue engineered glial scar model of astrocytes embedded in 1 % (w/v) alginate matrices, in which astrocyte reactive phenotype was acquired using meningeal fibroblast conditioned medium. OPCs were shown to adhere to uncoated engineered microfibres and differentiate into myelinating OL. Reactive astrocytes were found to significantly impair OL differentiation ability, after six and eight days in a co-culture system. Differentiation impairment was seen to be correlated with astrocytic miRNA release through exosomes. We found significantly reduction on the expression of pro-myelinating miRNAs (miR-219 and miR-338) and an increase in anti-myelinating miRNA (miR-125a-3p) content between reactive and quiescent astrocytes. Additionally, we show that OPC differentiation inhibition could be reverted by rescuing the activated astrocytic phenotype with ibuprofen, a chemical inhibitor of the small rhoGTPase RhoA. Overall, these findings show that modulating astrocytic function might be an interesting therapeutic avenue for demyelinating diseases. The use of these engineered microfibres as an artificial axon culture system will enable the screening for potential therapeutic agents that promote OL differentiation and myelination while providing valuable insight on the myelination/remyelination processes

Alginate-lysozyme nanofibers hydrogels with improved rheological behavior, printability and biological properties for 3D bioprinting applications

In this study, alginate nanocomposite hydrogel bioinks reinforced with lysozyme nanofibers (LNFs) were developed. Alginate-LNF (A-LNF) suspensions with different LNF contents (1, 5 and 10 wt.%) were prepared and pre-crosslinked with 0.5% (w/v) CaCl2 to formulate A-LNF inks. These inks exhibit proper shear-thinning behavior and good recovery properties (~90%), with the pre-crosslinking step playing a crucial role. A-LNF fully crosslinked hydrogels (with 2% (w/v) CaCl2) that mimic 3D printing scaffolds were prepared, and it was observed that the addition of LNFs improved several properties of the hydrogels, such as the morphology, swelling and degradation profiles, and mechanical properties. All formulations are also noncytotoxic towards HaCaT cells. The printing parameters and 3D scaffold model were then optimized, with A-LNF inks showing improved printability. Selected A-LNF inks (A-LNF0 and A-LNF5) were loaded with HaCaT cells (cell density 2 × 106 cells mL-1), and the cell viability within the bioprinted scaffolds was evaluated for 1, 3 and 7 days, with scaffolds printed with the A-LNF5 bioink showing the highest values for 7 days (87.99 ± 1.28%). Hence, A-LNF bioinks exhibited improved rheological performance, printability and biological properties representing a good strategy to overcome the main limitations of alginate-based bioinks.publishe

Cardiorespiratory andmetabolic responses and reference equation validation to predict peak oxygen uptake for the incremental shuttle waking test in adolescent boys

Background Previous studies speculated that the Incremental Shuttle Walking Test (ISWT) is a maximal test in children and adolescents, however comparison between ISWT with cardiopulmonary exercise test has not yet performed. Furthermore, there is no regression equation available in the current literature to predict oxygen peak consumption (VO2 peak) in this population. This study aimed to assesses and correlate the cardiorespiratory responses of the ISWT with the cardiopulmonary exercise (CEPT) and to develop and validate a regression equation to predict VO2 peak in healthy sedentary adolescent boys. Methods Forty-one participants were included in the study. In the first stage, the VO2 peak, respiratory exchange ratio (R peak), heart rate max (HR max) and percentage of predicted HR max (% predicted HR max) were evaluated in CEPT and ISWT (n = 26). Second, an equation was developed (n = 29) to predict VO2 peak. In both phases, the VO2 peak, respiratory exchange ratio R and hearth rate (HR) were evaluated. In the third stage, the validation equation was performed by another 12 participants. Results Similar results in VO2 peak (P>0.05), R peak (P>0.05) and predicted maximum HR (P>0.05) were obtained between the ISWT and CEPT. Both tests showed moderate significant correlations of VO2 peak (r = 0.44, P = 0.002) e R peak (r = -0.53, P < 0.01), as well as the agreement of these measurements by Bland-Altman analysis (VO2 peak, bias = -0.13; R peak, bias = 0.0). Distance walked was the variable that explained 42.5% (R2 = 0.425, p = 0.0001) of the variance in VO2 peak. The equation was VO2 peak (predicted) = 20.94 + (0.02 x distance walked). The results obtained by the equation were not significantly different compared to the values obtained by the gas analyzer and the Bland-Altman analysis showed agreement (bias = 1.6). Conclusion The ISWT produced maximal cardiorespiratory responses comparable to the CEPT, and the developed equation showed viability for the prediction of VO2 peak in healthy sedentary adolescent boys.Conselho Nacional de Desenvolvimento Cient?fico e Tecnol?gico (CNPq)Coordena??o de Aperfei?oamento de Pessoal de N?vel Superior (CAPES)Funda??o de Amparo ? Pesquisa do estado de Minas Gerais (FAPEMIG

T cell phenotypes in COVID-19 - a living review

COVID-19 is characterized by profound lymphopenia in the peripheral blood, and the remaining T cells display altered phenotypes, characterized by a spectrum of activation and exhaustion. However, antigen-specific T cell responses are emerging as a crucial mechanism for both clearance of the virus and as the most likely route to long-lasting immune memory that would protect against re-infection. Therefore, T cell responses are also of considerable interest in vaccine development. Furthermore, persistent alterations in T cell subset composition and function post-infection have important implications for patients’ long-term immune function. In this review, we examine T cell phenotypes, including those of innate T cells, in both peripheral blood and lungs, and consider how key markers of activation and exhaustion correlate with, and may be able to predict, disease severity. We focus on SARS-CoV-2-specific T cells to elucidate markers that may indicate formation of antigen-specific T cell memory. We also examine peripheral T cell phenotypes in recovery and the likelihood of long-lasting immune disruption. Finally, we discuss T cell phenotypes in the lung as important drivers of both virus clearance and tissue damage. As our knowledge of the adaptive immune response to COVID-19 rapidly evolves, it has become clear that while some areas of the T cell response have been investigated in some detail, others, such as the T cell response in children remain largely unexplored. Therefore, this review will also highlight areas where T cell phenotypes require urgent characterisation

The role and uses of antibodies in COVID-19 infections: a living review

Coronavirus disease 2019 has generated a rapidly evolving field of research, with the global scientific community striving for solutions to the current pandemic. Characterizing humoral responses towards SARS-CoV-2, as well as closely related strains, will help determine whether antibodies are central to infection control, and aid the design of therapeutics and vaccine candidates. This review outlines the major aspects of SARS-CoV-2-specific antibody research to date, with a focus on the various prophylactic and therapeutic uses of antibodies to alleviate disease in addition to the potential of cross-reactive therapies and the implications of long-term immunity

Enantioselective cyclopropanation and aziridination catalyzed by copper(II) bis(oxazoline) anchored onto mesoporous materials

The preparation of multipurpose asymmetric heterogeneous catalysts based on the immobilization of expensive privileged chiral ligands onto porous supports is essential for their use in industry. The benchmark cyclopropanation of styrene has been performed using a copper(II) complex of a commercial chiral bis(oxazoline) anchored onto ordered mesoporous silica materials (including SBA-15) and their carbon replicas (including CMK-3), and for the first time, we also report on the asymmetric aziridination of styrene by anchored copper(II) bis(oxazoline). All the composites prepared were active and enantioselective in these two organic transformations. In the cyclopropanation of styrene, the best heterogeneous catalyst gave higher enantioselectivities and TON than in the corresponding homogeneous phase reactions. In the aziridination of styrene the enantioselectivities for the best heterogeneous catalysts were similar to the propylated bis(oxazoline). The mesoporous silica, prepared by a straightforward one-pot procedure, was always among the best supports for the functionalized bis(oxazoline) in all the asymmetric processes studied. However its carbon replica was not a good support for the outcome of these asymmetric transformations, always yielding the lowest enantioselectivities. Once again the mesoporous materials surface properties were an important factor for the uniform distribution of the homogeneous catalyst, as well as for the course of the asymmetric organic reactions, together with the pore size. The best results presented herein are comparable to the ones reported for copper(II) bis (oxazoline) (2) immobilized onto other types of porous supports. (C) 2014 Elsevier Ltd. All rights reserved