KCa3.1 inhibition switches the phenotype of glioma-infiltrating microglia/macrophages

Among the strategies adopted by glioma to successfully invade the brain parenchyma is turning the infiltrating microglia/macrophages (M/MΦ) into allies, by shifting them toward an anti-inflammatory, pro-tumor phenotype. Both glioma and infiltrating M/MΦ cells express the Ca(2+)-activated K(+) channel (KCa3.1), and the inhibition of KCa3.1 activity on glioma cells reduces tumor infiltration in the healthy brain parenchyma. We wondered whether KCa3.1 inhibition could prevent the acquisition of a pro-tumor phenotype by M/MΦ cells, thus contributing to reduce glioma development. With this aim, we studied microglia cultured in glioma-conditioned medium or treated with IL-4, as well as M/MΦ cells acutely isolated from glioma-bearing mice and from human glioma biopsies. Under these different conditions, M/MΦ were always polarized toward an anti-inflammatory state, and preventing KCa3.1 activation by 1-[(2-Chlorophenyl)diphenylmethyl]-1H-pyrazole (TRAM-34), we observed a switch toward a pro-inflammatory, antitumor phenotype. We identified FAK and PI3K/AKT as the molecular mechanisms involved in this phenotype switch, activated in sequence after KCa3.1. Anti-inflammatory M/MΦ have higher expression levels of KCa3.1 mRNA (kcnn4) that are reduced by KCa3.1 inhibition. In line with these findings, TRAM-34 treatment, in vivo, significantly reduced the size of tumors in glioma-bearing mice. Our data indicate that KCa3.1 channels are involved in the inhibitory effects exerted by the glioma microenvironment on infiltrating M/MΦ, suggesting a possible role as therapeutic targets in glioma

In Conversation with Mubin Shaikh: From Salafi Jihadist to Undercover Agent inside the "Toronto 18" Terrorist Group

This interview with former undercover agent Mubin Shaikh can help academics and security practitioners understand the key role played and the challenges faced by covert human intelligence sources within domestic terrorist groups. The interview highlights the identity crisis, the personal factors, and the allure of jihadi militancy that initially drove Shaikh to join a Salafi jihadist group. It investigates Shaikh’s process of disengagement from the Salafi jihadist belief system and his rediscovery of a moderate, inclusive, and benevolent form of Islam. It explores his work as an undercover agent for the Canadian Security Intelligence Service, the Royal Canadian Mounted Police, and the Integrated National Security Enforcement Team responsible for disrupting domestic terrorist groups. The “Toronto 18” terrorist cell, the key role played by undercover agents in preventing terrorist action, and the challenges posed by entrapment are also discussed

Genomic innovation for crop improvement

Crop production needs to increase to secure future food supplies, while reducing its impact on ecosystems. Detailed characterization of plant genomes and genetic diversity is crucial for meeting these challenges. Advances in genome sequencing and assembly are being used to access the large and complex genomes of crops and their wild relatives. These have helped to identify a wide spectrum of genetic variation and permitted the association of genetic diversity with diverse agronomic phenotypes. In combination with improved and automated phenotyping assays and functional genomic studies, genomics is providing new foundations for crop-breeding systems

Temperature Dependence of Facet Ridges in Crystal Surfaces

The equilibrium crystal shape of a body-centered solid-on-solid (BCSOS) model on a honeycomb lattice is studied numerically. We focus on the facet ridge endpoints (FRE). These points are equivalent to one dimensional KPZ-type growth in the exactly soluble square lattice BCSOS model. In our more general context the transfer matrix is not stochastic at the FRE points, and a more complex structure develops. We observe ridge lines sticking into the rough phase where thesurface orientation jumps inside the rounded part of the crystal. Moreover, the rough-to-faceted edges become first-order with a jump in surface orientation, between the FRE point and Pokrovsky-Talapov (PT) type critical endpoints. The latter display anisotropic scaling with exponent $z=3$ instead of familiar PT value $z=2$.Comment: 12 pages, 19 figure

Bayes and health care research.

Bayes’ rule shows how one might rationally change one’s beliefs in the light of evidence. It is the foundation of a statistical method called Bayesianism. In health care research, Bayesianism has its advocates but the dominant statistical method is frequentism. There are at least two important philosophical differences between these methods. First, Bayesianism takes a subjectivist view of probability (i.e. that probability scores are statements of subjective belief, not objective fact) whilst frequentism takes an objectivist view. Second, Bayesianism is explicitly inductive (i.e. it shows how we may induce views about the world based on partial data from it) whereas frequentism is at least compatible with non-inductive views of scientific method, particularly the critical realism of Popper. Popper and others detail significant problems with induction. Frequentism’s apparent ability to avoid these, plus its ability to give a seemingly more scientific and objective take on probability, lies behind its philosophical appeal to health care researchers. However, there are also significant problems with frequentism, particularly its inability to assign probability scores to single events. Popper thus proposed an alternative objectivist view of probability, called propensity theory, which he allies to a theory of corroboration; but this too has significant problems, in particular, it may not successfully avoid induction. If this is so then Bayesianism might be philosophically the strongest of the statistical approaches. The article sets out a number of its philosophical and methodological attractions. Finally, it outlines a way in which critical realism and Bayesianism might work together. </p

An optically actuated surface scanning probe

We demonstrate the use of an extended, optically trapped probe that is capable of imaging surface topography with nanometre precision, whilst applying ultra-low, femto-Newton sized forces. This degree of precision and sensitivity is acquired through three distinct strategies. First, the probe itself is shaped in such a way as to soften the trap along the sensing axis and stiffen it in transverse directions. Next, these characteristics are enhanced by selectively position clamping independent motions of the probe. Finally, force clamping is used to refine the surface contact response. Detailed analyses are presented for each of these mechanisms. To test our sensor, we scan it laterally over a calibration sample consisting of a series of graduated steps, and demonstrate a height resolution of ∼ 11 nm. Using equipartition theory, we estimate that an average force of only ∼ 140 fN is exerted on the sample during the scan, making this technique ideal for the investigation of delicate biological samples

Colligative properties of solutions: I. Fixed concentrations

Using the formalism of rigorous statistical mechanics, we study the phenomena of phase separation and freezing-point depression upon freezing of solutions. Specifically, we devise an Ising-based model of a solvent-solute system and show that, in the ensemble with a fixed amount of solute, a macroscopic phase separation occurs in an interval of values of the chemical potential of the solvent. The boundaries of the phase separation domain in the phase diagram are characterized and shown to asymptotically agree with the formulas used in heuristic analyses of freezing point depression. The limit of infinitesimal concentrations is described in a subsequent paper.Comment: 28 pages, 1 fig; see also math-ph/0407035 (both to appear in JSP