Mycobacterium tuberculosis cords within lymphatic endothelial cells to evade host immunity

The ability of Mycobacterium tuberculosis to form serpentine cords is intrinsically related to its virulence, but specifically how M. tuberculosis cording contributes to pathogenesis remains obscure. Here, we show that several M. tuberculosis clinical isolates form intracellular cords in primary human lymphatic endothelial cells (hLECs) in vitro and in the lymph nodes of patients with tuberculosis. We identified via RNA-Seq a transcriptional program that activated, in infected-hLECs, cell survival and cytosolic surveillance of pathogens pathways. Consistent with this, cytosolic access was required for intracellular M. tuberculosis cording. Mycobacteria lacking ESX-1 type VII secretion system or phthiocerol dimycocerosates expression, which failed to access the cytosol, were indeed unable to form cords within hLECs. Finally, we show that M. tuberculosis cording is a size-dependent mechanism used by the pathogen to avoid its recognition by cytosolic sensors and evade either resting or IFN-γ–induced hLEC immunity. These results explain the long-standing association between M. tuberculosis cording and virulence and how virulent mycobacteria use intracellular cording as strategy to successfully adapt and persist in the lymphatic tracts

The role of the exit in the initial screening of investment opportunities: The case of business angel syndicate gatekeepers

The exit process has been largely ignored in business angel research.. The practitioner community identifies the difficulty in achieving exits as the most pressing problem for investors. This has been attributed to the failure of investors to adopt an exit-centric approach to investing. The validity of this claim is examined via a study of the investment approach of 21 ‘gatekeepers’ (managers) of angel groups in Scotland and Northern Ireland. Most gatekeepers say that they do consider the exit when they invest. However, this is contradicted by a verbal protocol analysis which indicates that the exit is not a significant consideration in their initial screening process. The small number of exits achieved by the groups is consistent with the general lack of an exit-centric approach to investing. Only three groups exhibit evidence of a strong exit-centric approach to investing. The lack of exits may have a negative impact on the level of future angel investment activity

Globally increased ultraconserved noncoding RNA expression in pancreatic adenocarcinoma

This is the final version of the article. Available from the publisher via the DOI in this record.Transcribed ultraconserved regions (T-UCRs) are a class of non-coding RNAs with 100% sequence conservation among human, rat and mouse genomes. T-UCRs are differentially expressed in several cancers, however their expression in pancreatic adenocarcinoma (PDAC) has not been studied. We used a qPCR array to profile all 481 T-UCRs in pancreatic cancer specimens, pancreatic cancer cell lines, during experimental pancreatic desmoplasia and in the pancreases of P48Cre/wt; KrasLSL-G12D/wt mice. Fourteen, 57 and 29% of the detectable T-UCRs were differentially expressed in the cell lines, human tumors and transgenic mouse pancreases, respectively. The vast majority of the differentially expressed T-UCRs had increased expression in the cancer. T-UCRs were monitored using an in vitro model of the desmoplastic reaction. Twenty-five % of the expressed T-UCRs were increased in the HPDE cells cultured on PANC-1 cellular matrix. UC.190, UC.233 and UC.270 were increased in all three human data sets. siRNA knockdown of each of these three T-UCRs reduced the proliferation of MIA PaCa-2 cells up to 60%. The expression pattern among many T-UCRs in the human and mouse pancreases closely correlated with one another, suggesting that groups of T-UCRs are co-activated in PDAC. Successful knockout of the transcription factor EGR1 in PANC-1 cells caused a reduction in the expression of a subset of T-UCRs suggesting that EGR1 may control T-UCR expression in PDAC. We report a global increase in expression of T-UCRs in both human and mouse PDAC. Commonalties in their expression pattern suggest a similar mechanism of transcriptional upregulation for T-UCRs in PDAC.Supported by grants R21/R33CA114304 and U01CA111294. G.A.C. is supported as a Fellow at The University of Texas MD Anderson Research Trust, as a University of Texas System Regents Research Scholar and by the CLL Global Research Foundation. Work in Dr. Calin’s laboratory is supported in part by a 2009 Seena Magowitz–Pancreatic Cancer Action Network AACR Pilot Grant, the Laura and John Arnold Foundation, the RGK Foundation and the Estate of C. G. Johnson, Jr. A.C.P.A.P. was supported by NIH fellowship 5F31CA142238

Polarization of coalitions in an agent-based model of political discourse

Political discourse is the verbal interaction between political actors in a policy domain. This article explains the formation of polarized advocacy or discourse coalitions in this complex phenomenon by presenting a dynamic, stochastic, and discrete agent-based model based on graph theory and local optimization. In a series of thought experiments, actors compute their utility of contributing a specific statement to the discourse by following ideological criteria, preferential attachment, agenda-setting strategies, governmental coherence, or other mechanisms. The evolving macro-level discourse is represented as a dynamic network and evaluated against arguments from the literature on the policy process. A simple combination of four theoretical mechanisms is already able to produce artificial policy debates with theoretically plausible properties. Any sufficiently realistic configuration must entail innovative and path-dependent elements as well as a blend of exogenous preferences and endogenous opinion formation mechanisms

Evidence for a nuclear compartment of transcription and splicing located at chromosome domain boundaries

The nuclear topography of splicing snRNPs, mRNA transcripts and chromosome domains in various mammalian cell types are described. The visualization of splicing snRNPs, defined by the Sm antigen, and coiled bodies, revealed distinctly different distribution patterns in these cell types. Heat shock experiments confirmed that the distribution patterns also depend on physiological parameters. Using a combination of fluorescencein situ hybridization and immunodetection protocols, individual chromosome domains were visualized simultaneously with the Sm antigen or the transcript of an integrated human papilloma virus genome. Three-dimensional analysis of fluorescence-stained target regions was performed by confocal laser scanning microscopy. RNA transcripts and components of the splicing machinery were found to be generally excluded from the interior of the territories occupied by the individual chromosomes. Based on these findings we present a model for the functional compartmentalization of the cell nucleus. According to this model the space between chromosome domains, including the surface areas of these domains, defines a three-dimensional network-like compartment, termed the interchromosome domain (ICD) compartment, in which transcription and splicing of mRNA occurs

Higgs mass and vacuum stability in the Standard Model at NNLO

We present the first complete next-to-next-to-leading order analysis of the Standard Model Higgs potential. We computed the two-loop QCD and Yukawa corrections to the relation between the Higgs quartic coupling (lambda) and the Higgs mass (Mh), reducing the theoretical uncertainty in the determination of the critical value of Mh for vacuum stability to 1 GeV. While lambda at the Planck scale is remarkably close to zero, absolute stability of the Higgs potential is excluded at 98% C.L. for Mh < 126 GeV. Possible consequences of the near vanishing of lambda at the Planck scale, including speculations about the role of the Higgs field during inflation, are discussed.Comment: 35 pages, 8 figures. Final published version, misprints fixed, figures update

Empowering employees with chronic diseases: process evaluation of an intervention aimed at job retention

Purpose Employees with a chronic disease may experience work-related problems that contribute to the risk of job loss. We developed a group-based intervention programme aimed at clarifying problems, making these a subject of discussion at work, and realizing solutions. This process evaluation investigates the intervention's feasibility and the satisfaction of 64 participants in eight groups. Methods Data were collected through process evaluation forms and self-report questionnaires. Results The recruitment of participants was time-consuming. Highly educated women working in the service sector were overrepresented. The programme was administered as planned, although components were sometimes only discussed briefly, due to lack of time. Satisfaction with the overall programme among participants was high; it was perceived as effective and there were only three dropouts. In particular, the focus on feelings and thoughts about having a chronic disease was highly valued, as were the exchange of experiences and role-playing directed at more assertive communication. Conclusions A vocational rehabilitation programme aimed at job retention is feasible and is perceived to be effective. Such a programme should address psychosocial aspects of working with a chronic disease beside practical problems. The recruitment of participants is time-consuming. Cooperation with outpatient clinics is necessary in order to reach all groups of employees with a chronic disease that might benefit from job retention programmes. Trial registration: ISRCTN77240155

Motives and comprehension in a public goods game with induced emotions

This study analyses the sensitivity of public goods contributions through the lens of psychological motives. We report the results of a public goods experiment in which subjects were induced with the motives of care and anger through autobiographical recall. Subjects' preferences, beliefs, and perceptions under each motive are compared with those of subjects experiencing a neutral autobiographical recall control condition. We find, but only for those subjects with the highest comprehension of the game, that care elicits significantly higher contributions than anger, with the control treatment in between. This positive influence of the care motive on unconditional giving is accounted for partly by preferences for giving and partly by the beliefs concerning greater contributions by others. Anger also affects attention to own and other's payoffs (using mouse tracking) and perceptions of the game's incentive structure (cooperative or competitive)