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This paper is concerned with level-dependent quasi-birth-death (LD-QBD) processes, i.e., multi-variate Markov chains with a block-tridiagonal -matrix, and a more general class of block-structured Markov chains, which can be seen as LD-QBD processes with total catastrophes. Arguments from univariate birth-death processes are combined with existing matrix-analytic formulations to obtain sufficient conditions for these block-structured processes to be regular, positive recurrent, and absorbed with certainty in a finite mean time. Specifically, it is our purpose to show that, as is the case for competition processes, these sufficient conditions are inherently linked to a suitably defined birth-death process. Our results are exemplified with two Markov chain models: a study of target cells and viral dynamics and one of kinetic proof-reading in T cell receptor signal transduction.

Background Natural killer (NK) cells are paramount for immunity against infectious agents and tumors. Their cytokine and cytolytic responses can be mediated by natural killer group 2, member D (NKG2D), an activating receptor whose ligands (NKG2DL) expression is induced in conditions of cell stress and malignant transformation. Since sustained expression of NKG2DL MICA is related to lower survival rates in gastric adenocarcinoma patients, and Helicobacter pylori infection contributes to tumorigenesis; we asked whether H. pylori stimulus could promote NKG2DL expression on human gastric adenocarcinoma cells. Methods Heat-killed H. pylori (HKHP) was used to stimulate MKN45 cells before analysis of NKG2DL and Toll-like receptor 4 (TLR4) protein levels by flow cytometry and transcripts by real-time PCR. LPS from Rhodobacter sphaeroides and inhibitory peptide Pepinh MYD were used to inhibit TLR4/MyD88 signaling pathway to assess its participation on NKG2DL expression. NK cell-mediated cytotoxicity was measured by lactate dehydrogenase (LDH) and CD107a mobilization assays. Results Stimulation of MKN45 cells with HKHP increased MICA, ULBP4 (another NKG2DL), and TLR4 at the protein and transcriptional levels. MICA, but not ULBP4 expression, was upregulated in a TLR4/MyD88-dependent manner. Furthermore, the presence of NKG2DL on the surface of HKHP-stimulated MKN45 cells enabled NK cell cytotoxic activation. Conclusions Our data indicate that induction of NKG2DL expression on gastric adenocarcinoma cells by H. pylori promotes an immune response that may ultimately contribute to either gastric tissue damage, as a consequence of persistent activation of immunity, or tumor immune evasion due to chronic NKG2DL expression.

Interleukin-7 (IL7) plays a nonredundant role in T cell survival and homeostasis, which is illustrated in the severe T cell lymphopenia of IL7-deficient mice, or demonstrated in animals or humans that lack expression of either the IL7Rα or γ c chain, the two subunits that constitute the functional IL7 receptor. Remarkably, IL7 is not expressed by T cells themselves, but produced in limited amounts by radio-resistant stromal cells. Thus, T cells need to constantly compete for IL7 to survive. How T cells maintain homeostasis and further maximize the size of the peripheral T cell pool in face of such competition are important questions that have fascinated both immunologists and mathematicians for a long time. Exceptionally, IL7 downregulates expression of its own receptor, so that IL7-signaled T cells do not consume extracellular IL7, and thus, the remaining extracellular IL7 can be shared among unsignaled T cells. Such an altruistic behavior of the IL7Rα chain is quite unique among members of the γ c cytokine receptor family. However, the consequences of this altruistic signaling behavior at the molecular, single cell and population levels are less well understood and require further investigation. In this regard, mathematical modeling of how a limited resource can be shared, while maintaining the clonal diversity of the T cell pool, can help decipher the molecular or cellular mechanisms that regulate T cell homeostasis. Thus, the current review aims to provide a mathematical modeling perspective of IL7-dependent T cell homeostasis at the molecular, cellular and population levels, in the context of recent advances in our understanding of the IL7 biology. This article is categorized under: Models of Systems Properties and Processes > Organ, Tissue, and Physiological Models Biological Mechanisms > Cell Signaling Models of Systems Properties and Processes > Mechanistic Models Analytical and Computational Methods > Computational Methods.

Humans live for decades, whereas mice live for months. Over these long timescales, naive T cells die or divide infrequently enough that it makes sense to approximate death and division as instantaneous events. The population of T cells in the body is naturally divided into clonotypes; a clonotype is the set of cells that have identical T-cell receptors. While total numbers of cells, such as naive CD4+ T cells, are large enough that ordinary differential equations are an appropriate starting point for mathematical models, the numbers of cells per clonotype are not. Here, we review a number of basic mathematical models of the maintenance of clonal diversity. As well as deterministic models, we discuss stochastic models that explicitly track the integer number of naive T cells in many competing clonotypes over the lifetime of a mouse or human, including the effect of waning thymic production. Experimental evaluation of clonal diversity by bulk high-throughput sequencing has many difficulties, but the use of single-cell sequencing is restricted to numbers of cells many orders of magnitude smaller than the total number of T cells in the body. Mathematical questions associated with extrapolating from small samples are therefore key to advances in understanding the diversity of the repertoire of T cells. We conclude with some mathematical models on how to advance in this area.

WOS: 000365393000021, PubMed ID: 26299211, We studied the evolutionary history of the Parmeliaceae (Lecanoromycetes, Ascomycota), one of the largest families of lichen-forming fungi with complex and variable morphologies, also including several lichenicolous fungi. We assembled a six-locus data set including nuclear, mitochondrial and low-copy protein-coding genes from 293 operational taxonomic units (OTUs). The lichenicolous lifestyle originated independently three times in lichenized ancestors within Parmeliaceae, and a new generic name is introduced for one of these fungi. In all cases, the independent origins occurred c. 24 million yr ago. Further, we show that the Paleocene, Eocene and Oligocene were key periods when diversification of major lineages within Parmeliaceae occurred, with subsequent radiations occurring primarily during the Oligocene and Miocene. Our phylogenetic hypothesis supports the independent origin of lichenicolous fungi associated with climatic shifts at the Oligocene-Miocene boundary. Moreover, diversification bursts at different times may be crucial factors driving the diversification of Parmeliaceae. Additionally, our study provides novel insight into evolutionary relationships in this large and diverse family of lichen-forming ascomycetes., Spanish Ministerio de Ciencia e Innovacion [CGL2010-21646/BOS, CGL2011-25003, CGL2013-42498-P]; Universidad Complutense-Banco Santander [GR3/14]; Comunidad Autonoma de Madrid [REMEDINAL S-2009/AMB-1783]; National Science Foundation [DEB-0949147]; Swedish Research Council [VR621-2009-5372, VR 621-2012-3990]; Academy of Finland [1133858]; Estonian Science Foundation [9109]; European Regional Development Fund (Center of Excellence FIBIR); German Academic Exchange Service (DAAD); Tromso University Museum, We are indebted to Adriano A. Spielmann, Joel Mercado, Robert Egan, Udeni Jayalal and Daniel Sanchez Mata for providing a few samples, and to Rosario G. Gavilan for assisting in collecting expeditions. We also thank editors and anonymous reviewers for valuable comments and suggestions. This work was supported by the Spanish Ministerio de Ciencia e Innovacion (projects CGL2010-21646/BOS, CGL2011-25003 and CGL2013-42498-P), the Universidad Complutense-Banco Santander (GR3/14), Comunidad Autonoma de Madrid (REMEDINAL S-2009/AMB-1783), the National Science Foundation ('Hidden diversity in parmelioid lichens'; DEB-0949147), the Swedish Research Council (VR621-2009-5372 and VR 621-2012-3990), the Academy of Finland (grant 1133858), the Estonian Science Foundation (grant 9109), and the European Regional Development Fund (Center of Excellence FIBIR). G.S. was supported by a fellowship from the German Academic Exchange Service (DAAD). I.K.K.T. was supported by a grant from Tromso University Museum.

The lichen-forming fungal genus Flavoparmelia includes species with distinct distribution patterns, including subcos- mopolitan, restricted, and disjunct species. We used a dataset of nuclear ITS and LSU ribosomal DNA including 51 specimens to understand the influence of historical events on the current distribution patterns in the genus. We employed Bayesian, maxi- mum likelihood and maximum parsimony approaches for phylogenetic analyses, a likelihood-based approach to ancestral area reconstruction, and a Bayesian approach to estimate divergence times of major lineages within the genus. We identified two major clades in the genus, one of them separating into two subclades and one of those into four groups. Several of the groups and clades have restricted geographical ranges in the Southern Hemisphere, but two groups include species with wider distribution areas. Our analyses suggest that the genus originated in southern South America during the Eocene-Oligocene transition and that the diversification of the Australasian groups occurred recently. The subcosmopolitan distribution of species is explained by long-distance dispersal, while vicariance probably played a major role in the origin of the genus. Several currently accepted species were found to be non-monophyletic, indicating that the species delimitation in the genus requires further studies.

Objective Dendritic cells (DCs) modulated with lipopolysaccharide (LPS) are able to reduce inflammation when therapeutically administered into mice with collagen-induced arthritis (CIA). The aim of this study was to uncover the mechanisms that define the tolerogenic effect of short-term LPS-modulated DCs on CIA. Methods Bone marrow–derived DCs were stimulated for 4 hours with LPS and characterized for their expression of maturation markers and their cytokine secretion profiles. Stimulated cells were treated with SB203580 or SB431542 to inhibit the p38 or transforming growth factor β (TGFβ) receptor pathway, respectively, or were left unmodified and, on day 35 after CIA induction, were used to inoculate mice. Disease severity was evaluated clinically. CD4+ T cell populations were counted in the spleen and lymph nodes from inoculated or untreated mice with CIA. CD4+ splenic T cells were transferred from mice with CIA treated with LPS-stimulated DCs or from untreated mice with CIA into other mice with CIA on day 35 of arthritis. Results Treatment with LPS-stimulated DCs increased the numbers of interleukin-10 (IL-10)–secreting and TGFβ-secreting CD4+ T cells, but decreased the numbers of Th17 cells. Adoptive transfer of CD4+ T cells from treated mice with CIA reproduced the inhibition of active CIA accomplished with LPS-stimulated DCs. The therapeutic effect of LPS-stimulated DCs and their influence on T cell populations were abolished when the p38 and the TGFβ receptor pathways were inhibited. Conclusion DCs modulated short-term (4 hours) with LPS are able to confer a sustained cure in mice with established arthritis by re-educating the CD4+ T cell populations. This effect is dependent on the p38 and the TGFβ receptor signaling pathways, which suggests the participation of IL-10 and TGFβ in the recovery of tolerance.

Disjunct species distributions may result from a combination of geologic events and long-distance dispersal. The foliose lichen species complex Leptogium furfuraceum-L. pseudofurfuraceum has an intercontinental disjunction pattern. Populations of this species complex are found in western North America, southern South America, Africa, and southern Europe. We conducted a phylogenetic study to reconstruct the biogeographic history of this species complex using two ribosomal genes (ITS and LSU) and a protein-coding gene (partial RPB2). Results indicated that the complex comprises four geographically restricted genetic lineages. A sister relationship was found between populations from the same hemispheres, incongruent with previous data derived from morphological characteristics and geographical classification schemes. Incorporating Bayesian ancestral area reconstruction and Bayesian divergence time estimation, we proposed an evolutionary hypothesis for the species complex. The results suggested that processes of biotic expansion via transoceanic dispersal were responsible for the species divergence and distribution patterns observed today. This study also expands the view that cryptic speciation is not a rare phenomenon among fungi and lichens.

Absent in the wild, Tahitian vanilla (V. tahitensis) is a gourmet spice restricted in distribution to cultivated and feral stands in French Polynesia and Papua New Guinea. Its origins have been elusive. Our objective was to test the purported hybrid derivation and parentage of V. tahitensis from aromatic, neotropical progenitors. Nucleotide sequences from V. tahitensis and neotropical Vanilla were assayed for phylogenetic relatedness in two independently inherited genomic regions, the nuclear ITS region, and the trnH-psbA noncoding region of chloroplast DNA. As predicted to occur for early generation hybrids, placement of V. tahitensis was nonconcordant. All V. tahitensis clustered with V. planifolia from analysis of cpDNA sequences, suggesting V. planifolia as the maternal genome contributor. Phylogenetic reconstruction of ITS sequences showed that most V. tahitensis nested incongruently with V. odorata, but others remained sister to V. planifolia. Recovery of ITS clones in V. tahitensis related to both V. planifolia and V. odorata also supports its biphyletic origin from these two taxa. We interpret the high percentage (95%) of additive polymorphic sites in V. tahitensis relative to its parents as indication of a recent, and probably human-mediated, evolutionary origin.

Objectives This study aimed to implement innovative teaching methods − blended learning strategies − that include the use of new information technologies in the teaching of human anatomy and to analyse both the impact of these strategies on academic performance, and the degree of user satisfaction. Methods The study was carried out among students in Year 1 of the biology degree curriculum (human biology profile) at Pompeu Fabra University, Barcelona. Two groups of students were tested on knowledge of the anatomy of the locomotor system and results compared between groups. Blended learning strategies were employed in 1 group (BL group, n = 69); the other (TT group; n = 65) received traditional teaching aided by complementary material that could be accessed on the Internet. Both groups were evaluated using the same types of examination. Results The average marks presented statistically significant differences (BL 6.3 versus TT 5.0; P

Nucleotide sequences of the plastid genes psbB and psbC were obtained for 34 taxa to represent most genera currently classified within Vanilloideae (Orchidaceae). These genes code for two of the subunits that make up the Photosystem II protein P680, and have only rarely been used for reconstructing phylogenetic relationships among plants. We failed to amplify psbB from the achlorophyllous genera Cyrtosia and Lecanorchis, but were able to align full length copies of psbC sequences from two species of Cyrtosia with the other taxa. This was not the case for an anomalous psbC sequence obtained for Lecanorchis. Nucleotide variation within each of these genes is sufficient to resolve the major relationships among Vanilloideae, and the combined two-gene tree is fully resolved at the genus level and highly supported. These gene trees demonstrate with a high degree of confidence (95% jackknife support) that a clade of mostly achlorophyllous tropical vines including Pseudovanilla and Erythrorchis are the sister group to Vanilla. The two New Caledonian endemic genera of Vanilloideae are sister to this pair, and Epistephium is sister to all remaining Vanillieae.

Immunologically, the septic shock is a natural model of immunomediated vascular pathology where the interaction between cytokines and the endothelium mediates the syndrome and lethality. Tumour necrosis factor (TNF), a non-species-specific cytokine, has outstanding pleiotropic activities as an important mediator of the septic shock syndrome. In rabbits, passive immunization with anti-lipopolysaccharide (LPS) polyclonal antibodies prior to the intravenous (i.v.) injection of LPS inhibits the haemorrhagic necrotic lesion characteristic of the local Shwartzman reaction (an excellent localized in vivo correlate of the septic shock). Paradoxically, tested in an ex vivo assay (short-term whole human blood culture, stimulated with LPS), these antibodies mediated an increase in TNF production by mononuclear phagocytes and, in the rabbit model, they induced an increase in body temperature, as compared with the pre-immune reagent. Although anchoring of immune complexes containing LPS to receptors (Fc or C4b-C3b) on circulating monocytes may facilitate the access of LPS to these cells, access to localized, LPS-sensitized macrophages may be impaired. Consequently inhibition of the local Shwartzman reaction and increased TNF production in the ex vivo system were observed. Concordantly, the higher temperature in the passively immunized animals may be a consequence of a higher, immune complex-induced, systemic TNF production. These experimental results suggest that the use of anti-LPS immunoglobulins, as a potential immunotherapy for septic shock syndrome in vertebrates, may lead to increased TNF production, with adverse effects such as the pyrogenic.