Stable isotopes of lithium: dissimilar biochemical and behavioral effects

Lithium, which is used routinely in the treatment of mania, is composed of two stable isotopes, lithium-7 (92.58%) and lithium-6 (7.42%). Usually there is minimal physiological or biochemical differentiation between isotopes of an element, but lithium is an exception. Data derived from a variety of biochemical and behavioral experiments are reviewed to support this idea. Additionally, the clinical implications of this work are presented.     

Regulation by angiotensin II of its receptors in resistance blood vessels

The sensitivity of blood vessels to the vasoconstrictor effects of the hormone angiotensin II appears to be modulated by the activity of the renin-angiotensin system. Elevation of circulating angiotensin II levels by sodium depletion or renal artery stenosis is associated with a diminished pressor response to infused angiotensin II (refs 1-3). Conversely, the vasocontrictor response to the hormone is enhanced when endogenous angiotensin II levels are reduced by sodium loading or nephrectomy. The mechanisms of these varying effects are not known, but physiological and pharmacological experiments suggest involvement of the vascular smooth receptor for angiotensin II (refs 5-8). Modification of the interaction between angiotensin II and its vascular receptor, resulting in altered responsiveness to the hormone, could occur either via 'prior occupancy' of receptors by elevated levels of endogenous angiotensin II resulting in fewer free receptors available to respond to circulating angiotensin II (ref. 5), or, elevated levels of angiotensin II could result in a decrease in receptor affinity for the hormone or a decrease in total receptor number in the vascular smooth muscle cell. We now report the first direct evidence, by radioligand binding assay, that angiotensin II regulates the number of its own receptors in resistance vasculature.     

Broad-band optical parametric gain on a silicon photonic chip

Developing an optical amplifier on silicon is essential for the success of silicon-on-insulator (SOI) photonic integrated circuits. Recently, optical gain with a 1-nm bandwidth was demonstrated using the Raman effect, which led to the demonstration of a Raman oscillator, lossless optical modulation and optically tunable slow light. A key strength of optical communications is the parallelism of information transfer and processing onto multiple wavelength channels. However, the relatively narrow Raman gain bandwidth only allows for amplification or generation of a single wavelength channel. If broad gain bandwidths were to be demonstrated on silicon, then an array of wavelength channels could be generated and processed, representing a critical advance for densely integrated photonic circuits. Here we demonstrate net on/off gain over a wavelength range of 28 nm through the optical process of phase-matched four-wave mixing in suitably designed SOI channel waveguides. We also demonstrate wavelength conversion in the range 1,511-1,591 nm with peak conversion efficiencies of +5.2 dB, which represents more than 20 times improvement on previous four-wave-mixing efficiencies in SOI waveguides. These advances allow for the implementation of dense wavelength division multiplexing in an all-silicon photonic integrated circuit. Additionally, all-optical delays, all-optical switches, optical signal regenerators and optical sources for quantum information technology, all demonstrated using four-wave mixing in silica fibres, can now be transferred to the SOI platform.     

Formation of a functional thymus initiated by a postnatal epithelial progenitor cell

The thymus is essential for the generation of self-tolerant effector and regulatory T cells. Intrathymic T-cell development requires an intact stromal microenvironment, of which thymic epithelial cells (TECs) constitute a major part. For instance, cell-autonomous genetic defects of forkhead box N1 (Foxn1) and autoimmune regulator (Aire) in thymic epithelial cells cause primary immunodeficiency and autoimmunity, respectively. During development, the thymic epithelial rudiment gives rise to two major compartments, the cortex and medulla. Cortical TECs positively select T cells, whereas medullary TECs are involved in negative selection of potentially autoreactive T cells. It has long been unclear whether these two morphologically and functionally distinct types of epithelial cells arise from a common bi-potent progenitor cell and whether such progenitors are still present in the postnatal period. Here, using in vivo cell lineage analysis in mice, we demonstrate the presence of a common progenitor of cortical and medullary TECs after birth. To probe the function of postnatal progenitors, a conditional mutant allele of Foxn1 was reverted to wild-type function in single epithelial cells in vivo. This led to the formation of small thymic lobules containing both cortical and medullary areas that supported normal thymopoiesis. Thus, single epithelial progenitor cells can give rise to a complete and functional thymic microenvironment, suggesting that cell-based therapies could be developed for thymus disorders.     

Soft X-ray microscopy at a spatial resolution better than 15 nm

Analytical tools that have spatial resolution at the nanometre scale are indispensable for the life and physical sciences. It is desirable that these tools also permit elemental and chemical identification on a scale of 10 nm or less, with large penetration depths. A variety of techniques in X-ray imaging are currently being developed that may provide these combined capabilities. Here we report the achievement of sub-15-nm spatial resolution with a soft X-ray microscope--and a clear path to below 10 nm--using an overlay technique for zone plate fabrication. The microscope covers a spectral range from a photon energy of 250 eV (approximately 5 nm wavelength) to 1.8 keV (approximately 0.7 nm), so that primary K and L atomic resonances of elements such as C, N, O, Al, Ti, Fe, Co and Ni can be probed. This X-ray microscopy technique is therefore suitable for a wide range of studies: biological imaging in the water window; studies of wet environmental samples; studies of magnetic nanostructures with both elemental and spin-orbit sensitivity; studies that require viewing through thin windows, coatings or substrates (such as buried electronic devices in a silicon chip); and three-dimensional imaging of cryogenically fixed biological cells.     

Multimodal Brain-Computer Interfaces

A critical parameter of brain-computer interfaces(BCIs) is the number of dimensions a user can control independently.One way to increment this number without increasing the mental effort required to operate the system is to stimulate several sensory modalities simultaneously,and to distinguish brain activity patterns when the user focuses attention to different elements of this multisensory input.In this article we show how shifting attention between simultaneously presented tactile and visual stimuli affects the electrical brain activity of human subjects,and that this signal can be used to augment the control information from the two uni-modal BCI subsystems.     

Colon cancer cell-derived 12(S)-HETE induces the retraction of cancer-associated fibroblast via MLC2, RHO/ROCK and Ca<Superscript>2+</Superscript> signalling

Retraction of mesenchymal stromal cells supports the invasion of colorectal cancer cells (CRC) into the adjacent compartment. CRC-secreted 12(S)-HETE enhances the retraction of cancer-associated fibroblasts (CAFs) and therefore, 12(S)-HETE may enforce invasivity of CRC. Understanding the mechanisms of metastatic CRC is crucial for successful intervention. Therefore, we studied pro-invasive contributions of stromal cells in physiologically relevant three-dimensional in vitro assays consisting of CRC spheroids, CAFs, extracellular matrix and endothelial cells, as well as in reductionist models. In order to elucidate how CAFs support CRC invasion, tumour spheroid-induced CAF retraction and free intracellular Ca²⁺ levels were measured and pharmacological- or siRNA-based inhibition of selected signalling cascades was performed. CRC spheroids caused the retraction of CAFs, generating entry gates in the adjacent surrogate stroma. The responsible trigger factor 12(S)-HETE provoked a signal, which was transduced by PLC, IP3, free intracellular Ca²⁺, Ca²⁺-calmodulin-kinase-II, RHO/ROCK and MYLK which led to the activation of myosin light chain 2, and subsequent CAF mobility. RHO activity was observed downstream as well as upstream of Ca²⁺ release. Thus, Ca²⁺ signalling served as central signal amplifier. Treatment with the FDA-approved drugs carbamazepine, cinnarizine, nifedipine and bepridil HCl, which reportedly interfere with cellular calcium availability, inhibited CAF-retraction. The elucidation of signalling pathways and identification of approved inhibitory drugs warrant development of intervention strategies targeting tumour–stroma interaction.     

Protein arginine methylation: a prominent modification and its demethylation

Arginine methylation of histones is one mechanism of epigenetic regulation in eukaryotic cells. Methylarginines can also be found in non-histone proteins involved in various different processes in a cell. An enzyme family of nine protein arginine methyltransferases catalyses the addition of methyl groups on arginines of histone and non-histone proteins, resulting in either mono- or dimethylated-arginine residues. The reversibility of histone modifications is an essential feature of epigenetic regulation to respond to changes in environmental factors, signalling events, or metabolic alterations. Prominent histone modifications like lysine acetylation and lysine methylation are reversible. Enzyme family pairs have been identified, with each pair of lysine acetyltransferases/deacetylases and lysine methyltransferases/demethylases operating complementarily to generate or erase lysine modifications. Several analyses also indicate a reversible nature of arginine methylation, but the enzymes facilitating direct removal of methyl moieties from arginine residues in proteins have been discussed controversially. Differing reports have been seen for initially characterized putative candidates, like peptidyl arginine deiminase 4 or Jumonji-domain containing protein 6. Here, we review the most recent cellular, biochemical, and mass spectrometry work on arginine methylation and its reversible nature with a special focus on putative arginine demethylases, including the enzyme superfamily of Fe(II) and 2-oxoglutarate-dependent oxygenases.