Potentiation of NMDA receptor currents by arachidonic acid.

Arachidonic acid is released by phospholipase A2 when activation of N-methyl-D-aspartate (NMDA) receptors by neurotransmitter glutamate raises the calcium concentration in neurons, for example during the initiation of long-term potentiation and during brain anoxia. Here we investigate the effect of arachidonic acid on glutamate-gated ion channels by whole-cell clamping isolated cerebellar granule cells. Arachidonic acid potentiates, and makes more transient, the current through NMDA receptor channels, and slightly reduces the current through non-NMDA receptor channels. Potentiation of the NMDA receptor current results from an increase in channel open probability, with no change in open channel current. We observe potentiation even with saturating levels of agonist at the glutamate- and glycine-binding sites on these channels; it does not result from conversion of arachidonic acid to lipoxygenase or cyclooxygenase derivatives, or from activation of protein kinase C. Arachidonic acid may act by binding to a site on the NMDA receptor, or by modifying the receptor's lipid environment. Our results suggest that arachidonic acid released by activation of NMDA (or other) receptors will potentiate NMDA receptor currents, and thus amplify increases in intracellular calcium concentration caused by glutamate. This may explain why inhibition of phospholipase A2 blocks the induction of long-term potentiation.     

A filament of dark matter between two clusters of galaxies

It is a firm prediction of the concordance cold-dark-matter cosmological model that galaxy clusters occur at the intersection of large-scale structure filaments. The thread-like structure of this 'cosmic web' has been traced by galaxy redshift surveys for decades. More recently, the warm–hot intergalactic medium (a sparse plasma with temperatures of 10(5) kelvin to 10(7) kelvin) residing in low-redshift filaments has been observed in emission and absorption. However, a reliable direct detection of the underlying dark-matter skeleton, which should contain more than half of all matter, has remained elusive, because earlier candidates for such detections were either falsified or suffered from low signal-to-noise ratios and unphysical misalignments of dark and luminous matter. Here we report the detection of a dark-matter filament connecting the two main components of the Abell 222/223 supercluster system from its weak gravitational lensing signal, both in a non-parametric mass reconstruction and in parametric model fits. This filament is coincident with an overdensity of galaxies and diffuse, soft-X-ray emission, and contributes a mass comparable to that of an additional galaxy cluster to the total mass of the supercluster. By combining this result with X-ray observations, we can place an upper limit of 0.09 on the hot gas fraction (the mass of X-ray-emitting gas divided by the total mass) in the filament.     

Restoration of grasp following paralysis through brain-controlled stimulation of muscles

Patients with spinal cord injury lack the connections between brain and spinal cord circuits that are essential for voluntary movement. Clinical systems that achieve muscle contraction through functional electrical stimulation (FES) have proven to be effective in allowing patients with tetraplegia to regain control of hand movements and to achieve a greater measure of independence in daily activities. In existing clinical systems, the patient uses residual proximal limb movements to trigger pre-programmed stimulation that causes the paralysed muscles to contract, allowing use of one or two basic grasps. Instead, we have developed an FES system in primates that is controlled by recordings made from microelectrodes permanently implanted in the brain. We simulated some of the effects of the paralysis caused by C5 or C6 spinal cord injury by injecting rhesus monkeys with a local anaesthetic to block the median and ulnar nerves at the elbow. Then, using recordings from approximately 100 neurons in the motor cortex, we predicted the intended activity of several of the paralysed muscles, and used these predictions to control the intensity of stimulation of the same muscles. This process essentially bypassed the spinal cord, restoring to the monkeys voluntary control of their paralysed muscles. This achievement is a major advance towards similar restoration of hand function in human patients through brain-controlled FES. We anticipate that in human patients, this neuroprosthesis would allow much more flexible and dexterous use of the hand than is possible with existing FES systems.     

‘Waldsterben’, part IV (continuing series)

Summary Peroxidase and superoxide dismutase activities, and ascorbic acid content, were measured in both intercellular fluid and cell material of current and 1-year-old needles of Norway spruce saplings treated with ozone, ambient air and activated carbon-filtered air in outdoor fumigation chambers. Ethylene evolution was also compared. Plants from carbon-filtered air treatments had significantly lower enzyme activities and higher ascorbic acid content. These changes were more marked in intercellular fluid than in cell material. Significant changes were noted at ozone levels typical of ambient air quality in a typical urban area. These results suggest the need for simultaneous screening of several biochemical markers as a way of overcoming the lack of specificity of any single marker for the identification of a perturbation by a particular stress, such as ozone.Acknowledgments. This work was supported in part by Grant Number 4849-0.85 (NFP 14) from the Swiss National Fund of Scientific Research. We thank Dr. F. Cupelin and Dr. J. Cl. Landry from the Service d'Ecotoxicologie, Genève, who provided the facilities for the monitoring of ozone levels. We also thank A. Mesrobian, A. Rossier and D. Voluntaru for technical assistance. Du Pont de Nemours International is gratefully acknowledged for the gift of TEDLAR (polyvinyl fluoride film) to build up the fumigation chambers.     

RANK ligand mediates progestin-induced mammary epithelial proliferation and carcinogenesis

RANK ligand (RANKL), a TNF-related molecule, is essential for osteoclast formation, function and survival through interaction with its receptor RANK. Mammary glands of RANK- and RANKL-deficient mice develop normally during sexual maturation, but fail to form lobuloalveolar structures during pregnancy because of defective proliferation and increased apoptosis of mammary epithelium. It has been shown that RANKL is responsible for the major proliferative response of mouse mammary epithelium to progesterone during mammary lactational morphogenesis, and in mouse models, manipulated to induce activation of the RANK/RANKL pathway in the absence of strict hormonal control, inappropriate mammary proliferation is observed. However, there is no evidence so far of a functional contribution of RANKL to tumorigenesis. Here we show that RANK and RANKL are expressed within normal, pre-malignant and neoplastic mammary epithelium, and using complementary gain-of-function (mouse mammary tumour virus (MMTV)-RANK transgenic mice) and loss-of function (pharmacological inhibition of RANKL) approaches, define a direct contribution of this pathway in mammary tumorigenesis. Accelerated pre-neoplasias and increased mammary tumour formation were observed in MMTV-RANK transgenic mice after multiparity or treatment with carcinogen and hormone (progesterone). Reciprocally, selective pharmacological inhibition of RANKL attenuated mammary tumour development not only in hormone- and carcinogen-treated MMTV-RANK and wild-type mice, but also in the MMTV-neu transgenic spontaneous tumour model. The reduction in tumorigenesis upon RANKL inhibition was preceded by a reduction in pre-neoplasias as well as rapid and sustained reductions in hormone- and carcinogen-induced mammary epithelial proliferation and cyclin D1 levels. Collectively, our results indicate that RANKL inhibition is acting directly on hormone-induced mammary epithelium at early stages in tumorigenesis, and the permissive contribution of progesterone to increased mammary cancer incidence is due to RANKL-dependent proliferative changes in the mammary epithelium. The current study highlights a potential role for RANKL inhibition in the management of proliferative breast disease.     

The inner jet of an active galactic nucleus as revealed by a radio-to-gamma-ray outburst

Blazars are the most extreme active galactic nuclei. They possess oppositely directed plasma jets emanating at near light speeds from accreting supermassive black holes. According to theoretical models, such jets are propelled by magnetic fields twisted by differential rotation of the black hole's accretion disk or inertial-frame-dragging ergosphere. The flow velocity increases outward along the jet in an acceleration and collimation zone containing a coiled magnetic field. Detailed observations of outbursts of electromagnetic radiation, for which blazars are famous, can potentially probe the zone. It has hitherto not been possible to either specify the location of the outbursts or verify the general picture of jet formation. Here we report sequences of high-resolution radio images and optical polarization measurements of the blazar BL Lacertae. The data reveal a bright feature in the jet that causes a double flare of radiation from optical frequencies to TeV gamma-ray energies, as well as a delayed outburst at radio wavelengths. We conclude that the event starts in a region with a helical magnetic field that we identify with the acceleration and collimation zone predicted by the theories. The feature brightens again when it crosses a standing shock wave corresponding to the bright 'core' seen on the images.