Chimeric antigen receptor T cells form nonclassical and potent immune synapses driving rapid cytotoxicity.

Chimeric antigen receptor T (CAR-T) cells are effective serial killers with a faster off-rate from dying tumor cells than CAR-T cells binding target cells through their T cell receptor (TCR). Here we explored the functional consequences of CAR-mediated signaling using a dual-specific CAR-T cell, where the same cell was triggered via TCR (tcrCTL) or CAR (carCTL). The carCTL immune synapse lacked distinct LFA-1 adhesion rings and was less reliant on LFA to form stable conjugates with target cells. carCTL receptors associated with the synapse were found to be disrupted and formed a convoluted multifocal pattern of Lck microclusters. Both proximal and distal receptor signaling pathways were induced more rapidly and subsequently decreased more rapidly in carCTL than in tcrCTL. The functional consequence of this rapid signaling in carCTL cells included faster lytic granule recruitment to the immune synapse, correlating with faster detachment of the CTL from the target cell. This study provides a mechanism for how CAR-T cells can debulk large tumor burden quickly and may contribute to further refinement of CAR design for enhancing the quality of signaling and programming of the T cell.

Do 'passive' medical titanium surfaces deteriorate in service in the absence of wear?

Globally, more than 1000 tonnes of titanium (Ti) is implanted into patients in the form of biomedical devices on an annual basis. Ti is perceived to be 'biocompatible' owing to the presence of a robust passive oxide film (approx. 4 nm thick) at the metal surface. However, surface deterioration can lead to the release of Ti ions, and particles can arise as the result of wear and/or corrosion processes. This surface deterioration can result in peri-implant inflammation, leading to the premature loss of the implanted device or the requirement for surgical revision. Soft tissues surrounding commercially pure cranial anchorage devices (bone-anchored hearing aid) were investigated using synchrotron X-ray micro-fluorescence spectroscopy and X-ray absorption near edge structure. Here, we present the first experimental evidence that minimal load-bearing Ti implants, which are not subjected to macroscopic wear processes, can release Ti debris into the surrounding soft tissue. As such debris has been shown to be pro-inflammatory, we propose that such distributions of Ti are likely to effect to the service life of the device.

Oral keratinocyte responses to nickel-based dental casting alloys in vitro.

Adverse reactions of oral mucosa to nickel-based dental casting alloys are probably due to corrosion metal ion release. We exposed H400 oral keratinocytes to two Ni-based dental alloys (Matchmate and Dsign10) as well as NiCl( 2) (1-40 microg/mL Ni(2+)). Alloy derived Ni(2+) media concentrations were determined. Direct culture on both alloys resulted in inhibited growth with a greater effect observed for Dsign10 (higher ion release). Indirect exposure of cells to conditioned media from Dsign10 negatively affected cell numbers (approximately 64% of control by 6 days) and morphology while Matchmate-derived media did not. Exposure to increasing NiCl(2) negatively affected cell growth and morphology, and the Granulocyte-macrophage colony-stimulating factor (GM-CSF) transcript was significantly up-regulated in cells following direct and indirect exposure to Dsign10. NiCl(2) exposure up-regulated all cytokine transcripts at 1 day. At day 6, IL-1beta and IL-8 transcripts were suppressed while GM-CSF and IL-11 increased with Ni(2+) dose. Accumulation of Ni(2+) ions from alloys in oral tissues may affect keratinocyte viability and chronic inflammation.

Classifying urban rivers.

Classification systems have been developed over the last century as a tool to aid managers in the preservation, conservation, enhancement and management of rivers. The classification systems developed to date have been designed to differentiate between relatively unimpacted, mainly rural rivers. Urban rivers typically show poor water quality and biological diversity, and so most current classification systems tend to group urban rivers into a single "poor" category. In this paper we describe a hierarchical framework for recording information about urban rivers that allows a more sensitive description of these rivers enabling subdivision into several classes according to the purpose of the classification. The different levels in the hierarchy, the types of attributes that are to be recorded at each level, and the relational database structure for storing the data are described. The 100-500 m river stretch level in the hierarchy relates to the engineered modification of urban rivers and is the key to their classification. An example classification at this scale illustrates a link between engineering modification, bank and bed materials and the number and diversity of physical habitats present. This classification underlines the importance of adopting a hierarchy of nested spatial scales for data collection, classification and interpretation since it illustrates a clear link between characteristics at the stretch scale and at the finer habitat scale. The classification also illustrates the varied nature of urban rivers and the fact that even quite heavily engineered stretches can contain a diversity of habitat types.

Surface charge--induced ordering of the au(111) surface.

Synchrotron surface x-ray scattering (SXS) studies have been carried out at the Au(lll)/electrolyte interface to determine the influence of surface charge on the microscopic arrangement of gold surface atoms. At the electrochemical interface, the surface charge density can be continuously varied by controlling the applied potential. The top layer of gold atoms undergoes a reversible phase transition between the (1 x 1) bulk termination and a (23 x radical3) reconstructed phase on changing the electrode potential. In order to differentiate the respective roles of surface charge and adsorbates, studies were carried out in 0.1 M NaF, NaCl, and NaBr solutions. The phase transition occurs at an induced surface charge density of 0.07 +/- 0.02 electron per atom in all three solutions.