Connexins and pannexins: from biology towards clinical targets.

Efficient cell communication is a prerequisite for the coordinated function of tissues and organs. In vertebrates, this communication is mediated by a variety of mechanisms, including the exchange of molecules between cells, and between cells and the extracellular medium, via membrane channels made of connexin and pannexin proteins. These channels are a necessary component of all human tissues. Here, we review the biological essentials of the connexin and pannexin families, and the roles of these proteins in the function of cells which are central to major human diseases. We then discuss how connexins and pannexins participate in human pathology, and the clinical perspectives that this knowledge opens

Building a Winning Business Model Portfolio

Many companies today are operating several business models at once. But despite the potential that business model diversification has for generating growth and profit, executives need to carefully assess the strategic contributions of each element of their business model portfolio

Under the radar: Industry entry by user entrepreneurs

We inductively develop a model of the commercialization process for new products or services user entrepreneurs undertake when entering an industry while drawing on proprietary technology developed in another industry. Extending the growing field of user entrepreneurship, we identify a two-phase approach to industry entry by user entrepreneurs who start "under the radar" of incumbent firms, gain experience, attract a first potential customer base, and then, in a second phase, engage in commercialization. During this process, a community of fellow users is of major importance for the entrepreneur, serving as a knowledge pool for skills development and experimentation with different commercialization paths. We study a nascent group of firms founded by users of video games who became entrepreneurs on entering the animation industry by producing Machinima, a new film genre characterized by shooting film in video games. We explain how user entrepreneurs gain access to complementary assets (video games) for their new use (shooting film), how they deal with intellectual property issues when using other firms' assets, and how user entrepreneurs combine domain knowledge about film production with their experience in video games and the art of Machinima. Our propositions hold implications for management and policy

On the Equivalence Problem for Toric Contact Structures on S^3-bundles over S^2$

We study the contact equivalence problem for toric contact structures on $S^3$-bundles over $S^2$. That is, given two toric contact structures, one can ask the question: when are they equivalent as contact structures while inequivalent as toric contact structures? In general this appears to be a difficult problem. To find inequivalent toric contact structures that are contact equivalent, we show that the corresponding 3-tori belong to distinct conjugacy classes in the contactomorphism group. To show that two toric contact structures with the same first Chern class are contact inequivalent, we use Morse-Bott contact homology. We treat a subclass of contact structures which include the Sasaki-Einstein contact structures $Y^{p,q}$ studied by physicists. In this subcase we give a complete solution to the contact equivalence problem by showing that $Y^{p,q}$ and $Y^{p'q'}$ are inequivalent as contact structures if and only if $p\neq p'$.Comment: 61 page

Targeting endothelial connexin40 inhibits tumor growth by reducing angiogenesis and improving vessel perfusion.

Endothelial connexin40 (Cx40) contributes to regulate the structure and function of vessels. We have examined whether the protein also modulates the altered growth of vessels in tumor models established in control mice (WT), mice lacking Cx40 (Cx40-/-), and mice expressing the protein solely in endothelial cells (Tie2-Cx40). Tumoral angiogenesis and growth were reduced, whereas vessel perfusion, smooth muscle cell (SMC) coverage and animal survival were increased in Cx40-/- but not Tie2-Cx40 mice, revealing a critical involvement of endothelial Cx40 in transformed tissues independently of the hypertensive status of Cx40-/- mice. As a result, Cx40-/- mice bearing tumors survived significantly longer than corresponding controls, including after a cytotoxic administration. Comparable observations were made in WT mice injected with a peptide targeting Cx40, supporting the Cx40 involvement. This involvement was further confirmed in the absence of Cx40 or by peptide-inhibition of this connexin in aorta-sprouting, matrigel plug and SMC migration assays, and associated with a decreased expression of the phosphorylated form of endothelial nitric oxide synthase. The data identify Cx40 as a potential novel target in cancer treatment

A Qualitative Comparative Analysis of Business Model Configurations and Performance in Formula 1

The relationship between business models and firm performance is only partially understood, especially when firms use multiple business models simultaneously (i.e., adopt configurations of business models). In this paper, we investigate the relationship between business model configurations and firm performance in a technology-based environment by conducting a multiple case study and a qualitative comparative analysis on Formula 1 (2005-2013). We find that configurations that combine two types of business models—one focused on selling technology to competitors and the other one focused on developing and trading human capital—are associated with higher firm performance. In addition, we explore the mechanisms that underlie these associations, and we find that these two business models are linked by knowledge-based complementarity such that implementing one business model increases the knowledge generated by adopting the other business model in isolation, and vice versa. We discuss the implications of the findings for theory and practice in technology-based industries such as the automotive industry

Tumor-Microenvironment Characterization of the MB49 Non-Muscle-Invasive Bladder-Cancer Orthotopic Model towards New Therapeutic Strategies.

Bacillus Calmette-Guérin (BCG) instillations for the treatment of non-muscle-invasive bladder cancer patients can result in significant side effects and treatment failure. Immune checkpoint blockade and/or decreasing tumor-infiltrating myeloid suppressor cells may be alternative or complementary treatments. Here, we have characterized immune cell infiltration and chemoattractant molecules in mouse orthotopic MB49 bladder tumors. Our data show a 100-fold increase in CD45 <sup>+</sup> immune cells from day 5 to day 9 tumors including T cells and mainly myeloid cells. Both monocytic myeloid-derived suppressor-cells (M-MDSC) and polymorphonuclear (PMN)-MDSC were strongly increased in day 9 tumors, with PMN-MDSC representing ca. 70% of the myeloid cells in day 12 tumors, while tumor associated macrophages (TAM) were only modestly increased. The kinetic of PD-L1 tumor expression correlated with published data from patients with PD-L1 expressing bladder tumors and with efficacy of anti-PD-1 treatment, further validating the orthotopic MB49 bladder-tumor model as suitable for designing novel therapeutic strategies. Comparison of chemoattractants expression during MB49 bladder tumors grow highlighted CCL8 and CCL12 (CCR2-ligands), CCL9 and CCL6 (CCR-1-ligands), CXCL2 and CXCL5 (CXCR2-ligands), CXCL12 (CXCR4-ligand) and antagonist of C5/C5a as potential targets to decrease myeloid suppressive cells. Data obtained with a single CCR2 inhibitor however showed that the complex chemokine crosstalk would require targeting multiple chemokines for anti-tumor efficacy

Intravesical Ty21a vaccine promotes dendritic cells and T cell-mediated tumor regression in the MB49 bladder cancer model

Preclinical data shows that intravesical instillation of Ty21a/Vivotif\uae, a commercial vaccine against typhoid fever, is an effective alternative option to standard Bacillus-Calmette-Gu\ue9rin (BCG) immunotherapy for nonmuscle-invasive bladder cancer (NMIBC). Here we characterized the inflammatory effects of Ty21a on the bladder and investigated the immune mechanisms underlying tumor-regression towards the use of this bacterial vaccine in NMIBC patients. MB49 bladder tumor-bearing mice had significantly improved survival after intravesical instillations of Ty21a doses of 106 to 108 colony-forming units. By immunohistochemistry and morphology, both BCG and Ty21a instillations were associated with bladder inflammation, which was decreased with the use of low, but effective, doses of Ty21a. Flow cytometry analysis showed a significant infiltration of T cells, natural killer (NK) cells, and myeloid cells, compared with controls, after a single dose of Ty21a, whereas this was only observed after multiple doses of BCG. The induced myeloid cells were predominantly neutrophils and Ly6C+CD103+ dendritic cells (DC), the latter being significantly more numerous after instillation of Ty21a than BCG. Ex vivo infection of human leukocytes with Ty21a, but not BCG, similarly significantly increased DC frequency. CD4+ and CD8+ T cells, but not NK cells nor neutrophils, were required for effective Ty21a bladder tumor responses. Thus, the generation of antitumor adaptive immunity was identified as a key process underlying Ty21a-mediated treatment efficacy. Altogether, these results demonstrate mechanisms of intravesical Ty21a therapy and suggest its potential as a safe and effective treatment for NMIBC patients

Cohomological tautness for Riemannian foliations

In this paper we present some new results on the tautness of Riemannian foliations in their historical context. The first part of the paper gives a short history of the problem. For a closed manifold, the tautness of a Riemannian foliation can be characterized cohomologically. We extend this cohomological characterization to a class of foliations which includes the foliated strata of any singular Riemannian foliation of a closed manifold

Contribution of connexins to the function of the vascular wall

Gap junction channels provide an enclosed conduit for direct exchanges of signalling molecules, including ions and small metabolites between cells. This system of communication allows cells to monitor the functional state of their neighbours, and is rapidly modulated to continuously adapt to the immediate needs of groups of coupled cells. In the major arteries, endothelial cells may express three connexins isotypes, namely Connexin 37 (Cx37), Cx40 and Cx43, whereas the underlying smooth muscle cells may express Cx37, Cx40, Cx43 and Cx45. Moreover, myoendothelial gap junctions have also been shown to be involved in the regulation of vascular tone. This review highlights the regulation of vessel connexins in response to injury, as observed during experimental hypertension or wound repair, as well as the consequences of loss of one connexin in different transgenic null mice. In view of the major endocrine role of the kidney in the control of blood pressure, we also discuss the distribution of connexins in the kidney vasculature. Cx40 is present between endothelial cells of vessels and glomeruli, as well as between renin-secreting cells, the modified smooth muscle cells which form the wall of the terminal part of afferent arterioles. Modulation of Cx40 expression in a model of renin-dependent hypertension suggests that this connexin may be implicated in the function of renin-secreting cells. Finally, to address the possible regulation of connexin expression by fluid pressure, we summarize the effects of elevated transmural urine pressure on bladder Cx43 expression