Reversal of pathological pain through specific spinal GABAA receptor subtypes

Inflammatory diseases and neuropathic insults are frequently accompanied by severe and debilitating pain, which can become chronic and often unresponsive to conventional analgesic treatment. A loss of synaptic inhibition in the spinal dorsal horn is considered to contribute significantly to this pain pathology. Facilitation of spinal gamma-aminobutyric acid (GABA)ergic neurotransmission through modulation of GABA(A) receptors should be able to compensate for this loss. With the use of GABA(A)-receptor point-mutated knock-in mice in which specific GABA(A) receptor subtypes have been selectively rendered insensitive to benzodiazepine-site ligands, we show here that pronounced analgesia can be achieved by specifically targeting spinal GABA(A) receptors containing the alpha2 and/or alpha3 subunits. We show that their selective activation by the non-sedative ('alpha1-sparing') benzodiazepine-site ligand L-838,417 (ref. 13) is highly effective against inflammatory and neuropathic pain yet devoid of unwanted sedation, motor impairment and tolerance development. L-838,417 not only diminished the nociceptive input to the brain but also reduced the activity of brain areas related to the associative-emotional components of pain, as shown by functional magnetic resonance imaging in rats. These results provide a rational basis for the development of subtype-selective GABAergic drugs for the treatment of chronic pain, which is often refractory to classical analgesics.     

A laser frequency comb that enables radial velocity measurements with a precision of 1 cm s(-1)

Searches for extrasolar planets using the periodic Doppler shift of stellar spectral lines have recently achieved a precision of 60 cm s(-1) (ref. 1), which is sufficient to find a 5-Earth-mass planet in a Mercury-like orbit around a Sun-like star. To find a 1-Earth-mass planet in an Earth-like orbit, a precision of approximately 5 cm s(-1) is necessary. The combination of a laser frequency comb with a Fabry-Pérot filtering cavity has been suggested as a promising approach to achieve such Doppler shift resolution via improved spectrograph wavelength calibration, with recent encouraging results. Here we report the fabrication of such a filtered laser comb with up to 40-GHz (approximately 1-A) line spacing, generated from a 1-GHz repetition-rate source, without compromising long-term stability, reproducibility or spectral resolution. This wide-line-spacing comb, or 'astro-comb', is well matched to the resolving power of high-resolution astrophysical spectrographs. The astro-comb should allow a precision as high as 1 cm s(-1) in astronomical radial velocity measurements.     

Regulatory networks define phenotypic classes of human stem cell lines

Stem cells are defined as self-renewing cell populations that can differentiate into multiple distinct cell types. However, hundreds of different human cell lines from embryonic, fetal and adult sources have been called stem cells, even though they range from pluripotent cells-typified by embryonic stem cells, which are capable of virtually unlimited proliferation and differentiation-to adult stem cell lines, which can generate a far more limited repertoire of differentiated cell types. The rapid increase in reports of new sources of stem cells and their anticipated value to regenerative medicine has highlighted the need for a general, reproducible method for classification of these cells. We report here the creation and analysis of a database of global gene expression profiles (which we call the 'stem cell matrix') that enables the classification of cultured human stem cells in the context of a wide variety of pluripotent, multipotent and differentiated cell types. Using an unsupervised clustering method to categorize a collection of approximately 150 cell samples, we discovered that pluripotent stem cell lines group together, whereas other cell types, including brain-derived neural stem cell lines, are very diverse. Using further bioinformatic analysis we uncovered a protein-protein network (PluriNet) that is shared by the pluripotent cells (embryonic stem cells, embryonal carcinomas and induced pluripotent cells). Analysis of published data showed that the PluriNet seems to be a common characteristic of pluripotent cells, including mouse embryonic stem and induced pluripotent cells and human oocytes. Our results offer a new strategy for classifying stem cells and support the idea that pluripotency and self-renewal are under tight control by specific molecular networks.     

Structure of the Ki-ras gene of the human lung carcinoma cell line Calu-1

The homologue of the viral Kirsten ras (v-Ki-ras) gene found in the human lung carcinoma cell line, Calu-1, has an intron-exon structure similar to that of the human homologue of the viral Harvey ras (v-Ha-ras) gene. A second, potential fourth coding exon is present in the human Ki-ras gene and similar sequences are found in the Kirsten murine sarcoma virus. Cysteine is encoded at the twelfth amino acid position, suggesting that the Calu-1 Ki-ras gene has undergone a mutational activation at the same position as the human Ha-ras gene of the bladder carcinoma cell line, T24. A comparison of their predicted amino acid sequences suggests that ras proteins have a 'constant' region and a 'variable' region. Here we propose a common modular structure for ras gene products in which the variable region forms a physiologically important combining site.     

Peptidergic neurones

More than 20 peptides have been identified in neurones of the brain, spinal cord and periphery. In several cases a peptide occurs together with a 'classical' transmitter in the same neurone. This raises new questions about the process of neurotransmission and may have important implications for our understanding and treatment of mental disorders.     

Paleoproterozoic basement beneath the southern Jiangxi Province: Evidence from U-Pb ages and Lu-Hf isotopes in zircons from the Doushui lamprophyre

This paper presents geochemical analyses of a lamprophyre intruding the Caledonian Doushui granite body in Shangyou County, southern Jiangxi Province. U-Pb dating and Hf-isotope analyses are espe-cially carried out for zircons from it. Petrological and geochemical features show that the lamprophyre belongs to a high-K, weakly alkaline pyroxene-biotite lamprophyre. It is characterized by high Mg# (0.74), Ni (253 μg/g) and Cr (893 μg/g) contents, and also enriched in incompatible elements, such as REE, Rb, Sr...     

Discovery of Ordovician acritarchs in Buqingshan ophiolite complex, East Kunlun Mountains and its significance

This note reports the first discovery of Middle-Late Ordovician acritarchs from the Buqingshan ophiolite complex of the southern ophiolite zone of East Kunlun. The acritarch assemblage is dominated with acanthomorphids (approx. 32%) and sphaeromorphds (approx. 63%) and contains more characteristic forms, such as Lophosphaeridium edenense, L. varum, Nothooidium sp.,? Buedingiisphaaeridium sp., Visbysphaera sp., Strophomorpha sp., etc. In addition, some tube-like fragments and tetrads, which are recognized as affinity to terrestrial plants and usual occurrence in Late Ordovician-Early Silurian strata, are preserved together with acritarchs. All the known fossil evidence indicates that the strata should be Middle-Late Ordovician in age. It not only provides paleontological proof for the existence of Ordovician ophiolite, but also challenges the usual ideas on strata composition of the studied area and the southern ophiolite zone of East Kunlun, and the models on tectonic framework and evolution of this area and the northern part of the Qinghai-Tibetan Plateau.