Sequence of human tissue inhibitor of metalloproteinases and its identity to erythroid-potentiating activity

Collagen fibres form the stable architecture of connective tissues and their breakdown is a key irreversible step in many pathological conditions. The destruction of collagen is usually initiated by proteinases, the best known of which is the metalloproteinase collagenase (EC 3.4.24). Collagenase and related metalloproteinases are regulated at the level of their synthesis and secretion, through the action of specific stimuli such as hormones and cytokines, and also at the level of their extracellular activity through the action of a specific inhibitor, TIMP (tissue inhibitor of metalloproteinases), which irreversibly forms inactive complexes with metalloproteinases. Although the mechanisms governing the production of TIMP are unknown, immunologically identical forms of this glycoprotein have been detected in a wide variety of human body fluids and cell and tissue culture media. We therefore suggested that under physiological conditions this ubiquitous inhibitor predominates over active metalloproteinases and that tissue destruction may arise when any perturbation of this controlling excess arises. However, further progress towards testing this theory has been hindered by a lack of knowledge about the structure of TIMP and insufficient material for studying it in model systems. Here we describe the structure of TIMP predicted from its complementary DNA, its synthesis in Escherichia coli and transfected animal cells, and the finding that it is identical to a protein recently reported to have erythroid-potentiating activity (EPA).     

Identification of the drug Darvon and its metabolites in the urine of a comatose patient using a gas chromatograph-mass. Spectrometer-computer system

Zusammenfassung Mit Hilfe von hoch- und niederauflösender Massenspektroskopie sowie Daten eines Gas-chromatograph-Massenspektrometer-Computer-Systems wurden die Droge Darvon³ sowie eine Reihe ihrer Metaboliten im Harn eines Überdosispatienten nachgewiesen.

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This publication describes the identification of a drug causing coma in a patient. The drug was identified by analysis of the patient's urine performed at the NIH sponsored Special Research Resource Facility for Mass Spectrometry at M.I.T., under emergency conditions. Most of the experiments, measurements and interpretation reported had to be made within 1 day, thus requiring the simultaneous efforts of many members of M.I.T.'s massspectrometry group.     

The afterglow and elliptical host galaxy of the short gamma-ray burst GRB 050724

Despite a rich phenomenology, gamma-ray bursts (GRBs) are divided into two classes based on their duration and spectral hardness--the long-soft and the short-hard bursts. The discovery of afterglow emission from long GRBs was a watershed event, pinpointing their origin to star-forming galaxies, and hence the death of massive stars, and indicating an energy release of about 10(51) erg. While theoretical arguments suggest that short GRBs are produced in the coalescence of binary compact objects (neutron stars or black holes), the progenitors, energetics and environments of these events remain elusive despite recent localizations. Here we report the discovery of the first radio afterglow from the short burst GRB 050724, which unambiguously associates it with an elliptical galaxy at a redshift z = 0.257. We show that the burst is powered by the same relativistic fireball mechanism as long GRBs, with the ejecta possibly collimated in jets, but that the total energy release is 10-1,000 times smaller. More importantly, the nature of the host galaxy demonstrates that short GRBs arise from an old (> 1 Gyr) stellar population, strengthening earlier suggestions and providing support for coalescing compact object binaries as the progenitors.     

Monoenergetic beams of relativistic electrons from intense laser-plasma interactions

High-power lasers that fit into a university-scale laboratory can now reach focused intensities of more than 10(19) W cm(-2) at high repetition rates. Such lasers are capable of producing beams of energetic electrons, protons and gamma-rays. Relativistic electrons are generated through the breaking of large-amplitude relativistic plasma waves created in the wake of the laser pulse as it propagates through a plasma, or through a direct interaction between the laser field and the electrons in the plasma. However, the electron beams produced from previous laser-plasma experiments have a large energy spread, limiting their use for potential applications. Here we report high-resolution energy measurements of the electron beams produced from intense laser-plasma interactions, showing that--under particular plasma conditions--it is possible to generate beams of relativistic electrons with low divergence and a small energy spread (less than three per cent). The monoenergetic features were observed in the electron energy spectrum for plasma densities just above a threshold required for breaking of the plasma wave. These features were observed consistently in the electron spectrum, although the energy of the beam was observed to vary from shot to shot. If the issue of energy reproducibility can be addressed, it should be possible to generate ultrashort monoenergetic electron bunches of tunable energy, holding great promise for the future development of 'table-top' particle accelerators.     

Quantification of modelling uncertainties in a large ensemble of climate change simulations

Comprehensive global climate models are the only tools that account for the complex set of processes which will determine future climate change at both a global and regional level. Planners are typically faced with a wide range of predicted changes from different models of unknown relative quality, owing to large but unquantified uncertainties in the modelling process. Here we report a systematic attempt to determine the range of climate changes consistent with these uncertainties, based on a 53-member ensemble of model versions constructed by varying model parameters. We estimate a probability density function for the sensitivity of climate to a doubling of atmospheric carbon dioxide levels, and obtain a 5-95 per cent probability range of 2.4-5.4 degrees C. Our probability density function is constrained by objective estimates of the relative reliability of different model versions, the choice of model parameters that are varied and their uncertainty ranges, specified on the basis of expert advice. Our ensemble produces a range of regional changes much wider than indicated by traditional methods based on scaling the response patterns of an individual simulation.