Rôles de deux corécepteurs impliqués dans le maintien des cellules T mémoires CD8+ et la maturation des cellules dendritiques

La reconnaissance d’un antigène présenté par les cellules présentatrices d’antigène induit la prolifération et la différenciation des lymphocytes T naïfs en lymphocytes T effecteurs et mémoires. Cette reconnaissance se fait par l’interaction du récepteur des cellules T (TCR) des lymphocytes T et le complexe CMH-peptide présent à la surface des DC. Cependant, des signaux additionnels sont requis, une meilleure activation des lymphocytes T implique des corécepteurs présents à la surface de ces deux types cellulaires. Après l’élimination de l’antigène, la plupart des lymphocytes T effecteurs vont mourir. Une petite population de lymphocytes T va persister pour se différencier en lymphocytes T mémoires capables de protéger l’organisme contre une réinfection. Les signaux qui contrôlent le maintien des lymphocytes T mémoires sont encore mal compris. Pour comprendre le rôle de la molécule de costimulation 4-1BB dans le maintien des lymphocytes T CD8 mémoires, nous avons émis l’hypothèse que l’état de phosphorylation de la protéine adaptatrice TRAF1, qui se lie à 4-1BB, module le maintien des lymphocytes T CD8 mémoires. Ainsi, nous avons montré par des expériences de spectrométrie de masse que TRAF1 s’associe préférentiellement à TBK1 lorsqu’elle n’est pas phosphorylée. Nous avons aussi montré que la présence de TRAF1 est requise pour stabiliser TBK1 au récepteur 4-1BB après stimulation des lymphocytes T. Par ailleurs, les lymphocytes T CD8 OT-I TRAF1-/- reconstituées avec un mutant phospho-déficient de TRAF1 (S139A) et ensuite différenciées en lymphocytes T mémoires in vitro induisent une activation de la voie de signalisation NF-ĸB contrairement à ceux exprimant la forme phospho-mimétique de TRAF1 (S139D). Ces premières études démontrent l’importance de l’état de phosphorylation de TRAF1 en aval de 4-1BB dans les cellules T. Dans la seconde partie, nous avons évalué le rôle d’un autre corécepteur; la neuropiline 1, dans la maturation des DC. A cet effet, nous avons émis l’hypothèse que l’interaction de la neuropiline 1 et ses ligands contribuerait à la fonction des DC. Nous avons démontré que l’absence de la neuropiline 1 n’a pas d’effet sur la maturation au LPS des DC. Cependant, la présence du VEGF (un ligand de Nrp-1) inhibe la maturation des DC dérivées de la moelle osseuse. Notre étude a démontré que VEGF inhibe l’expression des molécules de costimulation, la sécrétion des cytokines pro inflammatoires et la signalisation TLR4 principalement les voies MAP Kinase et NF-ĸB. Contrairement aux résultats avec les cellules WT, VEGF n’est pas capable d’affecter la maturation, la sécrétion des cytokines et la signalisation TLR4 des DC Nrp1-Lyz où la neuropiline 1 est délétée. Ainsi, nos résultats ont démontré que VEGF inhibe la maturation des DC de façon Nrp1-dépendante. Enfin, l’analyse des molécules partenaires de la neuropiline 1 montre que Nrp1, VEGF et TLR4 se retrouvent dans le même complexe. Nos résultats démontrent que VEGF, en présence de la neuropiline 1 est capable d’interagir avec TLR4 pour inhiber la maturation des DC. Toutefois, en absence de la neuropiline1, VEGF n’est pas capable de recruter TLR4 pour réduire l’expression des molécules de costimulation. Ces études sur les corécepteurs pourraient être importantes dans l’élaboration de nouvelles approches vaccinales.

An investigation of Hebbian phase sequences as assembly graphs

Hebb proposed that synapses between neurons that fire synchronously are strengthened, forming cell assemblies and phase sequences. The former, on a shorter scale, are ensembles of synchronized cells that function transiently as a closed processing system; the latter, on a larger scale, correspond to the sequential activation of cell assemblies able to represent percepts and behaviors. Nowadays, the recording of large neuronal populations allows for the detection of multiple cell assemblies. Within Hebb's theory, the next logical step is the analysis of phase sequences. Here we detected phase sequences as consecutive assembly activation patterns, and then analyzed their graph attributes in relation to behavior. We investigated action potentials recorded from the adult rat hippocampus and neocortex before, during and after novel object exploration (experimental periods). Within assembly graphs, each assembly corresponded to a node, and each edge corresponded to the temporal sequence of consecutive node activations. The sum of all assembly activations was proportional to firing rates, but the activity of individual assemblies was not. Assembly repertoire was stable across experimental periods, suggesting that novel experience does not create new assemblies in the adult rat. Assembly graph attributes, on the other hand, varied significantly across behavioral states and experimental periods, and were separable enough to correctly classify experimental periods (Naïve Bayes classifier; maximum AUROCs ranging from 0.55 to 0.99) and behavioral states (waking, slow wave sleep, and rapid eye movement sleep; maximum AUROCs ranging from 0.64 to 0.98). Our findings agree with Hebb's view that assemblies correspond to primitive building blocks of representation, nearly unchanged in the adult, while phase sequences are labile across behavioral states and change after novel experience. The results are compatible with a role for phase sequences in behavior and cognition.

Analisi del ruolo del porto di Ravenna nell’import/export di prodotti ortofrutticoli

L'elaborato tratta il ruolo del porto di Ravenna nell'import/export di prodotti ortofrutticoli. Dopo una accurata analisi dei dati, lo studio delle rotte marittime e l'uso di Dbms per gestire un database complesso, si propone un modello di programmazione lineare intera su un problema di ship routing, ship scheduling e full ship-load balancing. L'obiettivo è di massimizzare il profitto derivante da un prezzo di vendita e soggetto ai vari costi della logistica. Il modello sceglie la rotta ottimale da effettuare, in termini di ordine di visita dei vari porti che hanno un import e un export dei prodotti studiati. Inoltre, è in grado di gestire lo scorrere del tempo, fornendo come soluzione il giorno ottimale di visita dei vari porti considerati. Infine, trova la ripartizione ottima del numero di container a bordo della nave per ogni tipologia di prodotto.

Schedulazione delle rotte marittime nel settore ortofrutticolo. Modelli e Metodi

Il trasporto marittimo è una delle modalità più utilizzate soprattutto per la movimentazione di grandi volumi di prodotti tra i continenti in quanto è a basso costo, sicuro e meno inquinante rispetto ad altri mezzi di movimentazione. Ai giorni nostri è responsabile di circa l’80% del commercio globale (in volume di carichi trasportati). Il settore del trasporto marittimo ha avuto una lunga tradizione di pianificazione manuale effettuata da progettisti esperti.
 L’obiettivo principale di questa trattazione è stato quello di implementare un modello matematico lineare (MILP, Mixed-Integer Linear Programming Model) per l’ottimizzazione delle rotte marittime nell’ambito del mercato orto-frutticolo che si sviluppa nel bacino del Mediterraneo (problema di Ship-Scheduling). Il modello fornito in questa trattazione è un valido strumento di supporto alle decisioni che può utilizzare uno spedizioniere nell’ambito della pianificazione delle rotte marittime della flotta di navi in suo possesso. Consente di determinare l’insieme delle rotte ottimali che devono essere svolte da un insieme di vettori al fine di massimizzare il profitto complessivo dello spedizioniere, generato nell’arco di tempo considerato. Inoltre, permette di ottenere, per ogni nave considerata, la ripartizione ottimale della merce (carico ottimale).

The Role of G Protein In Alcohol Related Behaviours Using Drosophila melanogaster As A Model

Ethanol, classified as a drug, affects the central nervous system, and its consumption has been linked to the development of several behaviours including tolerance and dependence. Alcohol tolerance is defined as the need for higher doses of alcohol to induce the same changes observed in the initial exposure or where repetitive exposures of the same alcohol dose induce a lower response. Ethanol has been shown to interact with numerous targets and ultimately influence both short and long term adaptation at the cellular and molecular level in brain [1]. These adaptation processes are likely to involve signalling molecules: our work has focussed on G proteins gene expression. Using both wild type and several mutant fruit fly (Drosophila melanogaster) as a model for behaviour and molecular studies, we observed significant increases in sedation time (ST50) in response to alcohol (P<0.001) Fig.A. We also observed a consistent and significant decrease of Gq protein mRNA expression in Drosophila dUNC and DopR2 mutants chronically exposed to alcohol (*P<0.05). Fig B. Method: Six male flies were observed in drosophila polystyrene 25 x 95mm transparent vial in between cotton plugs. To the top plug, 500uL of 100% ethanol was added. Time till 50% of the flies were sedated was recorded on each day following the schedule. Fig. C (n=4-6). Using RT-PCR, we also quantified G protein mRNA expression levels one hour post initial 30 minutes of ethanol expression on day 1 and day 3 relative to expression in naïve flies.(n=2) [A] Increase in sedation time indicative of tolerance in different mutant lines and wild type flies. Six male flies were used in each experiment and (n= 4-6. ***P<0.001 unpaired t tests). [B] RT-PCR results showing significant reduction in Gq mRNA in flies chronically exposed to alcohol. (n=2. *P<0.05) [C] Alcohol exposure schedule. (1) Kaun K.R., R. Azanchi, Z. Maung, J. Hirsh, U. Heberlein. (2011). A Drosophila model for alcohol reward. Nature Neuroscience. 14 (5), 612–619.

The Role of HBD-2 and HBD-3 in Human T Cell Development

Human β-defensins (hBDs) are a family of cationic peptides able to directly kill a wide range of microorganisms including bacteria, fungi and viruses. In addition to their antimicrobial activities, defensins also contribute to the modulation of both the host innate and adaptive immunity. In this project, we demonstrate that the αCD3/28 co-stimulation of human CD4+ T cells in the presence of 10μg/ml hBD-2 or hBD-3 together causes an up-regulation in numbers of CD4+CD69+CD25+ and CD4+CD69-CD25+ T cell subsets, indicating that the treatment of hBD-2 and 3 enhances CD4+ T cell activation. Consistent with this finding, proliferation assay using CFSE suggests that hBD-2 and hBD-3 treatment in vitro induces the proliferation of CD4+ T cells following by 96hrs culture. Analysis of expression of the regulatory T cells (Tregs) specific marker, FoxP3, reveals a shift in the CD4+CD127-CD25+ Treg subset at 18hrs. However, at the later time point, we found that the percentage of FoxP3+cells decreased in the CD4+CD127-CD25+ Treg population, whereas the presence of the FoxP3+CTLA-4+ Treg subset increased. These data indicate that Treg suppressive function may be potentially defective following the co-incubation of purified T cells with either hBD-2 or hBD-3 for 42hrs in vitro due to the apparent loss of FoxP3 expression. We further characterise the role of hBD-2 and hBD-3 in driving human CD4+ T cells polarisation. Our in vitro data suggests that treatment with hBD-2 and hBD-3 can not only induces effector T cell (Teff) differentiation into RORγt+T-bet+ (Th17/Th1) cells, but can also trigger the differentiation of Treg expressing RORγt and T-bet rather than the master controller of Treg function, FoxP3. This apparent plasticity of T cell phenotype allows them to convert from Treg to Th1/17-like effector T cell phenotype following 18hrs in culture. By 42hrs in culture, treatment with hBD-2 and hBD-3 induced both Teff cell and Treg cell differentiation towards the Th17-like phenotype. Compared with the treatment with hBD-2, treatment with hBD-3 induced a more pronounced effect to increase levels of RORγt in CD4+ T cells. This elevated expression may, in turn, be responsible for the induction of higher IL-17A secretion. Consistent with this idea, it was found that treatment with hBD-3 but not hBD-2 was capable of inducing the higher level of secretion of IL-17A. Additionally, treatment with hBD-3 induced an increased expression of IL-6, which is capable of driving the differentiation of naïve T cells towards IL-17-producing Th17 cells. Functionally, using the Treg suppression assay, the data suggested that hBD-2 may dampen down Treg cell ability to induce suppression of Teff cell activity. Interestingly, co-culture with hBD-2 would also appear to increase Teff cell resistance to Treg immunoregulation in vitro. Further investigation using microarray gene analysis revealed chemokine C-C motif ligand 1 (CCL1) as potential genes responding to hBD-2 treatment. The blockade of CCL1 has been reported to inhibit Treg suppressive function. Thus, this study explored the function of these antimicrobial candidates in regulating CD4+ T cell plasticity which could result in hBD-2 and hBD-3 being able to regulate its own production, but also may regulate Treg and Teff cell development and function, thus strengthening the link between innate and adaptive immunity

Previsão do índice bovespa por meio de redes neurais artificiais: uma análise comparada aos métodos tradicionais de séries de tempo

Forecast is the basis for making strategic, tactical and operational business decisions. In financial economics, several techniques have been used to predict the behavior of assets over the past decades.Thus, there are several methods to assist in the task of time series forecasting, however, conventional modeling techniques such as statistical models and those based on theoretical mathematical models have produced unsatisfactory predictions, increasing the number of studies in more advanced methods of prediction. Among these, the Artificial Neural Networks (ANN) are a relatively new and promising method for predicting business that shows a technique that has caused much interest in the financial environment and has been used successfully in a wide variety of financial modeling systems applications, in many cases proving its superiority over the statistical models ARIMA-GARCH. In this context, this study aimed to examine whether the ANNs are a more appropriate method for predicting the behavior of Indices in Capital Markets than the traditional methods of time series analysis. For this purpose we developed an quantitative study, from financial economic indices, and developed two models of RNA-type feedfoward supervised learning, whose structures consisted of 20 data in the input layer, 90 neurons in one hidden layer and one given as the output layer (Ibovespa). These models used backpropagation, an input activation function based on the tangent sigmoid and a linear output function. Since the aim of analyzing the adherence of the Method of Artificial Neural Networks to carry out predictions of the Ibovespa, we chose to perform this analysis by comparing results between this and Time Series Predictive Model GARCH, developing a GARCH model (1.1).Once applied both methods (ANN and GARCH) we conducted the results' analysis by comparing the results of the forecast with the historical data and by studying the forecast errors by the MSE, RMSE, MAE, Standard Deviation, the Theil's U and forecasting encompassing tests. It was found that the models developed by means of ANNs had lower MSE, RMSE and MAE than the GARCH (1,1) model and Theil U test indicated that the three models have smaller errors than those of a naïve forecast. Although the ANN based on returns have lower precision indicator values than those of ANN based on prices, the forecast encompassing test rejected the hypothesis that this model is better than that, indicating that the ANN models have a similar level of accuracy . It was concluded that for the data series studied the ANN models show a more appropriate Ibovespa forecasting than the traditional models of time series, represented by the GARCH model

Évaluation du ratio de couverture optimal pour un portefeuille d'obligations dans le contexte du marché financier canadien

Il existe une multitude de façons de protéger un portefeuille formé d'obligations contre une variation des taux d'intérêt qui pourrait affecter défavorablement la valeur marchande du portefeuille. L'une d'elles consiste à vendre des contrats à terme sur obligations afin que les variations de la valeur marchande du portefeuille soient compensées par les gains (ou les pertes) sur le marché à terme. Le succès d'une telle opération dépend de l'évaluation du ratio de couverture puisque c'est lui qui déterminera quelle quantité de contrats à terme il faudra vendre pour protéger le portefeuille. L'objectif de cette étude consiste à déterminer, parmi cinq méthodes d'estimation du ratio de couverture (une naïve et quatre théoriques), celle qui permet de minimiser la variance du rendement du portefeuille à couvrir tout en sacrifiant le moins possible en terme de rendement. Pour ce faire, nous avons utilisé neuf portefeuilles formés d'obligations du gouvernement du Canada ayant des caractéristiques (coupon, échéance) très différentes que nous avons couverts en utilisant le contrat à terme sur obligations du gouvernement du Canada qui se transige à la Bourse de Montréal. L'analyse des résultats nous a amené à conclure que la méthode naïve génère de meilleurs résultats que les méthodes théoriques lorsque le portefeuille à couvrir possède des caractéristiques semblables au titre qui sert de couverture. Dans tous les autres cas (où le portefeuille à couvrir a des caractéristiques très différentes du contrat à terme qui sert de couverture), la performance de la méthode naïve est plutôt médiocre, mais aucune autre méthode n'est supérieure aux autres sur une base régulière.

Updating Beliefs: Are economic agents inspired by rational action or according to ones hopes and fears?.

The purpose of this investigationwas to simulate a real life scenarioand explore the way economicagents update their beliefs. Do theyupdate according to what theyhope? Or do they update inspired byrational behavior?We mimicked the environment whicha recently high school graduate faceswhen entering college to see how astudent updates his beliefs in regardsto his classroom position. We examinedhow economic agents envisagethemselves through and through collegeand see if they update their beliefsabout a hypothesis A in the lightof new evidence B, or if they updatetheir beliefs subject to what theychoose they hope. In this sense weexplored the possibility of setting asidethe neoclassical assumption thatagents are anything more than hyperrational naïve optimizers acting on perfect (and in some cases, limited information)in order to turn back to anolder tradition in economic theory, thatis agents are recognizably human.

Analysis of physical pore space characteristics of two pyrolytic biochars and potential as microhabitat

Studies on hacking have typically focused on motivational aspects and general personality traits of the individuals who engage in hacking; little systematic research has been conducted on predispositions that may be associated not only with the choice to pursue a hacking career but also with performance in either naïve or expert populations. Here, we test the hypotheses that two traits that are typically enhanced in autism spectrum disorders—attention to detail and systemizing—may be positively related to both the choice of pursuing a career in information security and skilled performance in a prototypical hacking task (i.e., crypto-analysis or code-breaking). A group of naïve participants and of ethical hackers completed the Autism Spectrum Quotient, including an attention to detail scale, and the Systemizing Quotient (Baron-Cohen et al., 2001, 2003). They were also tested with behavioral tasks involving code-breaking and a control task involving security X-ray image interpretation. Hackers reported significantly higher systemizing and attention to detail than non-hackers. We found a positive relation between self-reported systemizing (but not attention to detail) and code-breaking skills in both hackers and non-hackers, whereas attention to detail (but not systemizing) was related with performance in the X-ray screening task in both groups, as previously reported with naïve participants (Rusconi et al., 2015). We discuss the theoretical and translational implications of our findings.

Mediterranean diet: the impact on cardiovascular risk and metabolic syndrome in HIV patients, in Lisbon, Portugal

Introduction - Metabolic syndrome (MS) is common in HIV-infected individuals and it is associated with higher cardiovascular risk (CVR). Mediterranean diet has been associated with a better metabolic control and lower CVR. Materials and methods - From December 2013 to May 2014, individuals between 18 and 65 years of age, who attended the outpatient HIV Clinic at the University Hospital Santa Maria, Lisbon, were selected. Adherence to Mediterranean diet was evaluated with MedDietScore, a scale from 0 to 55 that punctuates 11 food items according to the frequency of intake. Higher scores represent higher adherence. CVR was assessed using D.A.D tool (classified as low, moderate or high risk). We excluded individuals with opportunistic disease, hospitalized in the past three months or with renal disease diagnosis. All participants gave written informed consent. Results - In the 571 HIV patients included, 67.1% (n=383) were male, 91.6% (n=523) Caucasian, with a mean age of 46.5±8.9 years. Patients were divided in two groups: naïve (7.5%; n=43) or on antiretroviral treatment (ART) (92.5%; n=528). Mean length of HIV diagnosis was 6.7±6.5 years (naïve) and 13.3±6.1 years (ART); TCD4+ counts were above 500 cel/mm3 in 55.8% (n=24) and 67.6% (n=357) of the patients, respectively. MS was present in 33.9% (n=179) of patients in ART group and 16.3% (n=7) in naïve group. Presence of MS was associated with ART group (OR=2.7; p=0.018). MS was also associated with older age in this group (p=0.000). Overall, mean MedDietScore was 27.3±5.5. Higher score was associated with older age (r=0.319; p=0.000). Naïve patients presented a trend to higher adherence to Mediterranean diet (65.1% vs 51.7% in naïve group; p=0.090). No relation between MS and Mediterranean diet was found. Higher CVR was associated with the presence of MS in the ART group (p=0.001). In this group, individuals with moderate CVR presented higher rates of adherence to Mediterranean diet (p=0.036) when compared to low and high CVR score. Conclusions - In this cross-sectional study, naïve individuals presented a trend to higher adherence to Mediterranean diet. On the ART group, higher adherence to Mediterranean diet was found in individuals with moderate CVR score. We think that this might suggest that this group of patients adopt this diet only in the presence of metabolic alterations or perceived CVR. Prospective studies in HIV patients are required to determine the impact of adherence to Mediterranean diet on the reduction of CVR.

How task format affects cognitive performance: a memory test with two species of New World monkeys

In cognitive tests, animals are often given a choice between two options and obtain a reward if they choose correctly. We investigated whether task format affects subjects' performance in a physical cognition test. In experiment 1, a two-choice memory test, 15 marmosets, Callithrix jacchus, had to remember the location of a food reward over time delays of increasing duration. We predicted that their performance would decline with increasing delay, but this was not found. One possible explanation was that the subjects were not sufficiently motivated to choose correctly when presented with only two options because in each trial they had a 50% chance of being rewarded. In experiment 2, we explored this possibility by testing eight naïve marmosets and seven squirrel monkeys, Saimiri sciureus, with both the traditional two-choice and a new nine-choice version of the memory test that increased the cost of a wrong choice. We found that task format affected the monkeys' performance. When choosing between nine options, both species performed better and their performance declined as delays became longer. Our results suggest that the two-choice format compromises the assessment of physical cognition, at least in memory tests with these New World monkeys, whereas providing more options, which decreases the probability of obtaining a reward when making a random guess, improves both performance and measurement validity of memory. Our findings suggest that two-choice tasks should be used with caution in comparisons within and across species because they are prone to motivational biases.

Città Metropolitane e Smart Governance Iniziative di successo e nodi critici verso la Smart City

The volume contains the results of the research project "Governance Analysis Project (GAP) for the Smart Energy City. The actualization of Smart Cities in the Metropolitan Areas of Europe and Italy” conducted within the PON “Smart Energy Master for the energy management of the territory” at the University Federico II of Naples (TeMA Lab of the Department of Civil, Architectural and Environmental Engineering). Smart Cities have gained increasing relevance in the scientific debate and in the national and international operational practice, emerging as one of the opportunities to rethink cities and, more generally, the life of urban communities. First reflections, researches and projects on the issue seem to converge towards the idea that a “smart” urban development should not only be a result of the yet necessary and unavoidable infrastructural endowment (physical capital) and of its continuing innovation, but also of the quality of human, social and environmental capital, conceived as strategic factors for development. A “smart” city is, primarily, a city able to effectively satisfy the needs of its citizens respecting the rules imposed by the environmental context. It is in such a debate that the project GAP fits with the aim to address Smart Cities in light of the administrative reorganization of Italian large cities as a consequence of the Law 56/2014. With a scientific approach, the volume provides a comprehensive and updated framework of how Italian and European Metropolitan cities are declining the Smart City issue and this thanks to the collection of a wide-ranging screening represented by more than 1.000 initiatives including researches, projects, interventions, technologies, etc. Furthermore, one original element of this research is that after an analysis conducted through indirect sources, a phase of dialogue with “stakeholders” was carried out (and of this there is a wide picture in the volume in which, by the way, are reported long excerpts of the interviews). This has enabled to give a clearer framework of what is now experimenting in Italian and European cities, avoiding being totally naïve for interventions and projects labelled as “smart”, but often lacking of innovative methods and contents.

Quasispecies dynamics and treatment outcome during early hepatitis C infection in a cohort of HIV-infected men

Hepatitis C virus (HCV) is emerging as one of the leading causes of morbidity and mortality in individuals infected with HIV and has overtaken AIDS-defining illnesses as a cause of death in HIV patient populations who have access to highly active antiretroviral therapy. For many years, the clonal analysis was the reference method for investigating viral diversity. In this thesis, a next generation sequencing (NGS) approach was developed using 454 pyrosequencing and Illumina-based technology. A sequencing pipeline was developed using two different NGS approaches, nested PCR, and metagenomics. The pipeline was used to study the viral populations in the sera of HCV-infected patients from a unique cohort of 160 HIV-positive patients with early HCV infection. These pipelines resulted in an improved understanding of HCV quasispecies dynamics, especially regarding studying response to treatment. Low viral diversity at baseline correlated with sustained virological response (SVR) while high viral diversity at baseline was associated with treatment failure. The emergence of new viral strains following treatment failure was most commonly associated with emerging dominance of pre-existing minority variants rather than re-infection. In the new era of direct-acting antivirals, next generation sequencing technologies are the most promising tool for identifying minority variants present in the HCV quasispecies populations at baseline. In this cohort, several mutations conferring resistance were detected in genotype 1a treatment-naïve patients. Further research into the impact of baseline HCV variants on SVR rates should be carried out in this population. A clearer understanding of the properties of viral quasispecies would enable clinicians to make improved treatment choices for their patients.

Influence of substrates composition on immunomodulation by MSCs

Mesenchymal stem cells (MSCs) are non-hematopoietic multipotent stem cells capable to self-renew and differentiate along different cell lineages. MSCs can be found in adult tissues and extra embryonic tissues like the umbilical cord matrix/Wharton’s Jelly (WJ). The latter constitute a good source of MSCs, being more naïve and having a higher proliferative potential than MSCs from adult tissues like the bone marrow, turning them more appealing for clinical use. It is clear that MSCs modulate both innate and adaptive immune responses and its immunodulatory effects are wide, extending to T cells and dendritic cells, being therapeutically useful for treatment of immune system disorders. Mechanotransduction is by definition the mechanism by which cells transform mechanical signals translating that information into biochemical and morphological changes. Here, we hypothesize that by culturing WJ-MSCs on distinct substrates with different stiffness and biochemical composition, may influence the immunomodulatory capacity of the cells. Here, we showed that WJ-MSCs cultured on distinct PDMS substrates presented different secretory profiles from cells cultured on regular tissue culture polystyrene plates (TCP), showing higher secretion of several cytokines analysed. Moreover, it was also shown that WJ-MSCs cultured on PDMS substrates seems to possess higher immunomodulatory capabilities and to differentially regulate the functional compartments of T cells when compared to MSCs maintained on TCP. Taken together, our results suggest that elements of mechanotransduction seem to be influencing the immunomodulatory ability of MSCs, as well as their secretory profile. Thus, future strategies will be further explored to better understand these observation and to envisage new in vitro culture conditions for MSCs aiming at distinct therapeutic approaches, namely for immune-mediated disorders.