The TetR-type MfsR protein of the integrative and conjugative element (ICE) ICEclc controls both a putative efflux system and initiation of ICE transfer.

Integrative and conjugating elements (ICE) are self-transferable DNAs widely present in bacterial genomes, which often carry a variety of auxiliary genes of potential adaptive benefit. One of the model ICE is ICEclc, an element originally found in Pseudomonas knackmussii B13 and known for its propensity to provide its host with the capacity to metabolize chlorocatechols and 2-aminophenol. In this work, we studied the mechanism and target of regulation of MfsR, a TetR-type repressor previously found to exert global control on ICEclc horizontal transfer. By using a combination of ICEclc mutant and transcriptome analysis, gene reporter fusions, and DNA binding assays, we found that MfsR is a repressor of both its own expression and that of a gene cluster putatively coding for a major facilitator superfamily efflux system on ICEclc (named mfsABC). Phylogenetic analysis suggests that mfsR was originally located immediately adjacent to the efflux pump genes but became displaced from its original cis target DNA by a gene insertion. This resulted in divergence of the original bidirectional promoters into two separated individual regulatory units. Deletion of mfsABC did not result in a strong phenotype, and despite screening a large number of compounds and conditions, we were unable to define the precise current function or target of the putative efflux pump. Our data reconstruct how the separation of an ancestor mfsR-mfsABC system led to global control of ICEclc transfer by MfsR.

LIF and sIL-2R plasma concentrations in IVF patients on the day of embryo transfer: predictive markers of IVF outcome.

Successful implantation is still the limiting step in IVF. We hypothesized that maternal plasma concentrations of certain cytokines at the time of embryo transfer could predict the likelihood of successful implantation and pregnancy. sIL-2R, IL-6, LIF, and MMP2 concentrations were measured in plasma from 160 IVF patients (natural and stimulated IVF cycles) on the morning of the embryo transfer (ET0) and 14days later (ET+14). Patients were ultimately subdivided into four groups depending on the IVF treatment outcome (pregnancy failure, biochemical pregnancy, first-trimester miscarriage and normal term delivery). In natural and stimulated IVF cycles at ET0, sIL-2R concentrations were threefold higher in biochemical pregnancies than in pregnancy failures (P=0.020), and in natural cycles only, 2.5-fold higher in normal term deliveries than in pregnancy failures (P=0.023). Conversely, in natural and stimulated IVF cycles at ET0, LIF concentrations were one third lower in biochemical pregnancies/first-trimester miscarriages compared with pregnancy failures (P=0.042). We suggest that high sIL-2R and low LIF concentrations in maternal plasma on the morning of the embryo transfer might be associated with increased risks of early pregnancy loss, while a basal level of sIL-2R is necessary for normal term delivery outcome. Both cytokine measurements might therefore be useful in the management of IVF patients, and modulation of their concentrations could be investigated as a therapeutic alternative for women with abnormal concentrations at the time of embryo transfer.

The hotel industry and its importance in the technical and economic development of a region : the Lake Geneva case (1852-1914)

The historiography dedicated to tourism has emphasised how some socio-economic evolutions such as urbanisation, mechanisation of transport or the advent of leisure time in society have supported pleasure trips and therefore the development of the hotel industry. On the contrary, the research has too often neglected or at least minimised the impact of the hotel sector on a region's development. This contribution seeks to fill this gap by analysing the Geneva Lake region, one of the most important birthplaces of the European tourism. In this space not much touched by the first industrial revolution, the hotel business has in fact played the role of an economic motor, stimulating investment and employment. This dynamism provoked a domino effect on several other sectors of the economy (industry, bulding sector, banking). To please their customers, the hoteliers have not only given impulses on housing modernisation, but also to the revitalisation of transport, energy and communication networks. The necessity to remain on the state-of-the-art of technical issues, with the concern of competitiveness, has called forth an acceleration of the technology transfer and stimulated the constitution of technical know-how.

Managing Social-Business Tensions: A Review and Research Agenda for Social Enterprise

In a world filled with poverty, environmental degradation, and moral injustice, social enterprises offer a ray of hope. These organizations seek to achieve social missions through business ventures. Yet social missions and business ventures are associated with divergent goals, values, norms, and identities. Attending to them simultaneously creates tensions, competing demands, and ethical dilemmas. Effectively understanding social enterprises therefore depends on insight into the nature and management of these tensions. While existing research recognizes tensions between social missions and business ventures, we lack any systematic analysis. Our paper addresses this issue. We first categorize the types of tensions that arise between social missions and business ventures, emphasizing their prevalence and variety. We then explore how four different organizational theories offer insight into these tensions, and we develop an agenda for future research. We end by arguing that a focus on social-business tensions not only expands insight into social enterprises, but also provides an opportunity for research on social enterprises to inform traditional organizational theories. Taken together, our analysis of tensions in social enterprises integrates and seeks to energize research on this expanding phenomenon.

Intralesional adenovirus-mediated interleukin-2 gene transfer for advanced solid cancers and melanoma.

Numerous preclinical and clinical studies have shown that interleukin-2 (IL-2) induces regression of metastatic tumors. We have conducted a phase I/II, multicenter, open-label, dose-escalating study to evaluate the safety, efficacy, and biological effects of repeated intratumoral injections of adenovirus-IL-2 (TG1024) in patients with advanced solid tumors and melanoma. Thirty five patients (twenty-five with metastatic melanoma and ten with other solid tumors) were treated in eight successive cohorts at dose levels ranging from 3 x 10(8) to 3 x 10(11) viral particles (vp). Intratumoral TG1024 injections in combination with dacarbazine (DTIC) were tested in metastatic melanoma in one cohort. No clinical responses were observed at doses below 3 x 10(11) vp. Six local objective responses were recorded in patients receiving 3 x 10(11) vp per treatment [five in metastatic melanoma and one in metastatic squamous cell carcinoma (SCC) of the skin], of which two were complete responses (CRs). Most of the common side effects were injection site reactions and flu-like syndrome. TG1024 dose intensification across cohorts resulted in increased serum IL-2 levels after the injection. Intratumoral TG1024 injection induced pronounced inflammation of the treated lesion, with predominant CD8(+), TIA+ lymphocytic infiltrate. Our results show that intratumoral injections of TG1024 are safe and well tolerated. The clinical activity of TG1024 observed in this study warrants further investigations.

Cosmopolitan Capital and the Internationalization of the Field of Business Elites: Evidence from the Swiss Case

The aim of this contribution is to explore how the recent internationalization and the increasing importance of 'cosmopolitan capital' has impacted on the structure and character of the field of the Swiss business elite. For this purpose we will develop the notion of cosmopolitan capital and comparatively investigate the field of the Swiss business elite in 1980, 2000 and 2010 with multiple correspondence analysis. We can show that in this period international managers with transnational careers and networks not only grow in number, but come to conquer the apex of the biggest and highest capitalized Swiss firms. At the same time, national forms of capital decline in importance and Swiss managers themselves are differentiated increasingly into national and international fractions.

Localized in vivo hyperpolarization transfer sequences.

In vivo localized and fully adiabatic homonuclear and heteronuclear polarization transfer experiments were designed and performed in the rat brain at 9.4 T after infusion of hyperpolarized sodium [1,2-(13)C(2)] and sodium [1-(13)C] acetate. The method presented herein leads to highly enhanced in vivo detection of short-T(1) (13)C as well as attached protons. This indirect detection scheme allows for probing additional molecular sites in hyperpolarized substrates and their metabolites and can thus lead to improved spectral resolution such as in the case of (13)C-acetate metabolism.

Microsomal triglyceride transfer protein promotes the secretion of Xenopus laevis vitellogenin A1.

Vitellogenins (Vtg) are ancient lipid transport and storage proteins and members of the large lipid transfer protein (LLTP) gene family, which includes insect apolipophorin II/I, apolipoprotein B (apoB), and the microsomal triglyceride transfer protein (MTP). Lipidation of Vtg occurs at its site of synthesis in vertebrate liver, insect fat body, and nematode intestine; however, the mechanism of Vtg lipid acquisition is unknown. To explore whether Vtg biogenesis requires the apoB cofactor and LLTP family member, MTP, Vtg was expressed in COS cells with and without coexpression of the 97-kDa subunit of human MTP. Expression of Vtg alone gave rise to a approximately 220-kDa apoprotein, which was predominantly confined to an intracellular location. Coexpression of Vtg with human MTP enhanced Vtg secretion by 5-fold, without dramatically affecting its intracellular stability. A comparison of wild type and a triglyceride transfer-defective form of MTP revealed that both were capable of promoting Vtg secretion, whereas only wild type MTP could promote the secretion of apoB41 (amino-terminal 41% of apoB). These studies demonstrate that the biogenesis of Vtg is MTP-dependent and that MTP is the likely ancestral member of the LLTP gene family.

In vivo imaging of T cell delivery to tumors after adoptive transfer therapy.

Adoptive transfer therapy of in vitro-expanded tumor-specific cytolytic T lymphocytes (CTLs) can mediate objective cancer regression in patients. Yet, technical limitations hamper precise monitoring of posttherapy T cell responses. Here we show in a mouse model that fused single photon emission computed tomography and x-ray computed tomography allows quantitative whole-body imaging of (111)In-oxine-labeled CTLs at tumor sites. Assessment of CTL localization is rapid, noninvasive, three-dimensional, and can be repeated for longitudinal analyses. We compared the effects of lymphodepletion before adoptive transfer on CTL recruitment and report that combined treatment increased intratumoral delivery of CTLs and improved antitumor efficacy. Because (111)In-oxine is a Food and Drug Administration-approved clinical agent, and human SPECT-CT systems are available, this approach should be clinically translatable, insofar as it may assess the efficacy of immunization procedures in individual patients and lead to development of more effective therapies.