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Previously, we showed that mouse delayed-type hypersensitivity (DTH) can be antigen-specifically downregulated by suppressor T cell-derived miRNA-150 carried by extracellular vesicles (EVs) that target antigen-presenting macrophages. However, the exact mechanism of the suppressive action of miRNA-150-targeted macrophages on effector T cells remained unclear, and our current studies aimed to investigate it. By employing the DTH mouse model, we showed that effector T cells were inhibited by macrophage-released EVs in a miRNA-150-dependent manner. This effect was enhanced by the pre-incubation of EVs with antigen-specific antibodies. Their specific binding to MHC class II-expressing EVs was proved in flow cytometry and ELISA-based experiments. Furthermore, by the use of nanoparticle tracking analysis and transmission electron microscopy, we found that the incubation of macrophage-released EVs with antigen-specific antibodies resulted in EVs’ aggregation, which significantly enhanced their suppressive activity in vivo. Nowadays, it is increasingly evident that EVs play an exceptional role in intercellular communication and selective cargo transfer, and thus are considered promising candidates for therapeutic usage. However, EVs appear to be less effective than their parental cells. In this context, our current studies provide evidence that antigen-specific antibodies can be easily used for increasing EVs’ biological activity, which has great therapeutic potential.

Background The use of doxorubicin is associated with an increased risk of acute and long-term cardiomyopathy. Despite the constantly growing number of cancer survivors, little is known about the transcriptional mechanisms which progress in the time leading to a severe cardiac outcome. It is also unclear whether long-term transcriptomic alterations related to doxorubicin use are similar to transcriptomic patterns present in patients suffering from other cardiomyopathies. Methods We have sequenced miRNA from total plasma and extracellular vesicles (EVs) from 66 acute lymphoblastic leukemia (ALL) survivors and 61 healthy controls (254 samples in total). We then analyzed processes regulated by differentially expressed circulating miRNAs and cross-validated results with the data of patients with clinically manifested cardiomyopathies. Results We found that especially miRNAs contained within EVs may be informative in terms of cardiomyopathy development and may regulate pathways related to neurotrophin signaling, transforming growth factor beta (TGFβ) or epidermal growth factor receptors (ErbB). We identified vesicular miR-144-3p and miR-423-3p as the most variable between groups and significantly correlated with echocardiographic parameters and, respectively, for plasma: let-7g-5p and miR-16-2-3p. Moreover, vesicular miR-144-3p correlates with the highest number of echocardiographic parameters and is differentially expressed in the circulation of patients with dilated cardiomyopathy. We also found that distribution of particular miRNAs between of plasma and EVs (proportion between compartments) e.g., miR-184 in ALL, is altered, suggesting changes within secretory and miRNA sorting mechanisms. Conclusions Our results show that transcriptomic changes resulting from doxorubicin induced myocardial injury are reflected in circulating miRNA levels and precede development of the late onset cardiomyopathy phenotype. Among miRNAs related to cardiac function, we found vesicular miR-144-3p and miR-423-3p, as well as let-7g-5p and miR-16-2-3p contained in the total plasma. Selection of source for such studies (plasma or EVs) is of critical importance, as distribution of some miRNA between plasma and EVs is altered in ALL survivors, in comparison to healthy people, which suggests that doxorubicin-induced changes include miRNA sorting and export to extracellular space.

Joret et al. proved that posets with cover graphs of treewidth at most 2 have dimension at most 1276. Their proof is long and very complex. We give a short and much simpler proof that the dimension of such posets is at most 12.

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We prove that the stack-number of the strong product of three n-vertex paths is Θ(n 1/3 ). The best previously known upper bound was O(n). No non-trivial lower bound was known. This is the first explicit example of a graph family with bounded maximum degree and unbounded stack-number.The main tool used in our proof of the lower bound is the topological overlap theorem of Gromov. We actually prove a stronger result in terms of so-called triangulations of Cartesian products. We conclude that triangulations of three-dimensional Cartesian products of any sufficiently large connected graphs have large stack-number.The upper bound is a special case of a more general construction based on families of permutations derived from Hadamard matrices.The strong product of three paths is also the first example of a bounded degree graph with bounded queue-number and unbounded stack-number. A natural question that follows from our result is to determine the smallest ∆0 such that there exist a graph family with unbounded stack-number, bounded queue-number and maximum degree ∆0. We show that ∆0 ∈ {6, 7}.

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Which graph classes C exclude a fixed ladder as a minor? We show that this is the case if and only if all graphs G in C admit a proper vertex coloring with a bounded number of colors such that for every 2-connected subgraph H of G, there is a color that appears exactly once in H. If one were considering all connected subgraphs of G instead, then such a coloring is known as a centered coloring, and the minimum achievable number of colors is the treedepth of G. Classes of graphs with bounded treedepth are exactly those that exclude a fixed path as a subgraph, or equivalently, as a minor. In this sense, the structure of graphs excluding a fixed ladder as a minor resembles the structure of graphs without long paths. Another similarity is as follows: It is an easy observation that every connected graph with two vertex-disjoint paths of length k has a path of length k+1. We show that every 3-connected graph with sufficiently many vertex-disjoint subgraphs containing a k-ladder minor has a (k + 1)-ladder minor.Our structural results have applications to poset dimension. We show that posets whose cover graphs exclude a fixed ladder as a minor have bounded dimension. This is a new step towards the goal of understanding which graphs are unavoidable as minors in cover graphs of posets with large dimension.