PAI1 blocks NMDA receptor-mediated effects of tissue-type plasminogen activator on cell signaling and physiology

The fibrinolysis proteinase tissue-type plasminogen activator (tPA, also known as PLAT) triggers cell signaling and regulates cell physiology. In PC12 cells, Schwann cells and macrophages, the N-methyl-D-aspartate receptor (NMDA-R) mediates tPA signaling. Plasminogen activator inhibitor-1 (PAI1, also known as SERPINE1) is a rapidly acting inhibitor of tPA enzyme activity. Although tPA-initiated cell signaling is not dependent on its enzyme active site, we show that tPA signaling is neutralized by PAI1. In PC12 cells, PAI1 blocked the ERK1/2 activation mediated by tPA as well as neurite outgrowth. In Schwann cells, PAI1 blocked tPA-mediated ERK1/2 activation and cell migration. In macrophages, PAI1 blocked the ability of tPA to inhibit IκBα phosphorylation and cytokine expression. The cell signaling activity of tPA-PAI1 complex was rescued when the complex was formed with PAI1R76E, which binds to LRP1 with decreased affinity, by pre-treating cells with the LRP1 antagonist receptor-associated protein and upon LRP1 gene silencing. The inhibitory role of LRP1 in tPA-PAI1 complex-initiated cell signaling was unanticipated given the reported role of LRP1 as an NMDA-R co-receptor in signaling responses elicited by free tPA or α2-macroglobulin. We conclude that PAI1 functions as an in-hibitor not only of the enzyme activity of tPA but also of tPA receptor-mediated activities

How much measurement independence is needed in order to demonstrate nonlocality?

If nonlocality is to be inferred from a violation of Bell's inequality, an important assumption is that the measurement settings are freely chosen by the observers, or alternatively, that they are random and uncorrelated with the hypothetical local variables. We study the case where this assumption is weakened, so that measurement settings and local variables are at least partially correlated. As we show, there is a connection between this type of model and models which reproduce nonlocal correlations by allowing classical communication between the distant parties, and a connection with models that exploit the detection loophole. We show that even if Bob's choices are completely independent, all correlations obtained from projective measurements on a singlet can be reproduced, with the correlation (measured by mutual information) between Alice's choice and local variables less than or equal to a single bit.Comment: 5 pages, 1 figure. v2 Various improvements in presentation. Results unchange

Non-realism : deep thought or a soft option ?

The claim that the observation of a violation of a Bell inequality leads to an alleged alternative between nonlocality and non-realism is annoying because of the vagueness of the second term.Comment: 5 page

Telecommunications systems design techniques handbook

Handbook presents design and analysis of tracking, telemetry, and command functions utilized in these systems with particular emphasis on deep-space telecommunications. Antenna requirements are also discussed. Handbook provides number of tables outlining various performance criteria. Block diagrams and performance charts are also presented

uPAR Induces Expression of Transforming Growth Factor β and Interleukin-4 in Cancer Cells to Promote Tumor-Permissive Conditioning of Macrophages

Cancer cells condition macrophages and other inflammatory cells in the tumor microenvironment so that these cells are more permissive for cancer growth and metastasis. Conditioning of inflammatory cells reflects, at least in part, soluble mediators (such as transforming growth factor β and IL-4) that are released by cancer cells and alter the phenotype of cells of the innate immune system. Signaling pathways in cancer cells that potentiate this activity are incompletely understood. The urokinase receptor (uPAR) is a cell-signaling receptor known to promote cancer cell survival, proliferation, metastasis, and cancer stem cell–like properties. The present findings show that uPAR expression in diverse cancer cells, including breast cancer, pancreatic cancer, and glioblastoma cells, promotes the ability of these cells to condition co-cultured bone marrow–derived macrophages so that the macrophages express significantly increased levels of arginase 1, a biomarker of the alternatively activated M2 macrophage phenotype. Expression of transforming growth factor β was substantially increased in uPAR-expressing cancer cells via a mechanism that requires uPA-initiated cell signaling. uPAR also controlled expression of IL-4 in cancer cells via a mechanism that involves activation of ERK1/2. The ability of uPAR to induce expression of factors that condition macrophages in the tumor microenvironment may constitute an important mechanism by which uPAR promotes cancer progression

Use of Bayesian Kriging to develop new soil property maps for Quito, Ecuador

Seismic hazard assessment requires knowledge of regional geological and geotechnical parameters. Shear wave velocity averaged across the upper 30 m of soil (Vs30) is a key parameter for site response studies in earthquake engineering. In the city of Quito, the capital of Ecuador, seismic data are scarce. This paper combines a recently compiled geotechnical database with a Bayesian Kriging technique to generate new soil geotechnical property maps for the city of Quito. The new QUITO/GEO-299 soil geotechnical database contains 299 records of soil geotechnical test results from across the Quito region. These datapoints were analysed using a Bayesian Kriging approach recently developed for generating seismic hazard data for the Kathmandu Valley in Nepal. The resulting Quito Vs30 map is compared to the corresponding map created using slope-based proxies implemented in the global Vs30 model presented by the U.S. Geological Survey. These new resources are useful for geotechnical engineers working in the Quito region, especially during project planning and preliminary design phases.</div

Age at Regular Drinking, Clinical Course, and Heritability of Alcohol Dependence in the San Francisco Family Study: A Gender Analysis

We examined gender differences in age of onset, clinical course, and heritability of alcohol dependence in 2524 adults participating in the University of California San Francisco (UCSF) family study of alcoholism. Men were significantly more likely than women to have initiated regular drinking during adolescence. Onset of regular drinking was not found to be heritable but was found to be significantly associated with a shorter time to onset of alcohol dependence. A high degree of similarity in the sequence of alcohol-related life events was found between men and women, however, men experienced alcohol dependence symptoms at a younger age and women had a more rapid clinical course. Women were found to have a higher heritability estimate for alcohol dependence (h2 =0.46) than men (h2 =0.32). These findings suggest that environmental factors influencing the initiation of regular drinking rather than genetic factors associated with dependence may in part underlie some of the gender differences seen in the prevalence of alcohol dependence in this population

Population pharmacokinetic modelling of primaquine exposures in lactating women and breastfed infants

Current guidelines advise against primaquine treatment for breastfeeding mothers to avoid the potential for haemolysis in infants with G6PD deficiency. To predict the haemolytic risk, the amount of drug received from the breast milk and the resulting infant drug exposure need to be characterised. Here, we develop a pharmacokinetic model to describe the drug concentrations in breastfeeding women using venous, capillary, and breast milk data. A mother-to-infant model is developed to mimic the infant feeding pattern and used to predict their drug exposures. Primaquine and carboxyprimaquine exposures in infants are <1% of the exposure in mothers. Therefore, even in infants with the most severe G6PD deficiency variants, it is highly unlikely that standard doses of primaquine (0.25-1 mg base/kg once daily given to the mother for 1-14 days) would cause significant haemolysis. After the neonatal period, primaquine should not be restricted for breastfeeding women (Clinical Trials Registration: NCT01780753)