Identification of an antimalarial synthetic trioxolane drug development candidate

The discovery of artemisinin more than 30 years ago provided a completely new antimalarial structural prototype; that is, a molecule with a pharmacophoric peroxide bond in a unique 1,2,4-trioxane heterocycle. Available evidence suggests that artemisinin and related peroxidic antimalarial drugs exert their parasiticidal activity subsequent to reductive activation by haem, released as a result of haemoglobin digestion by the malaria-causing parasite. This irreversible redox reaction produces carbon-centred free radicals, leading to alkylation of haem and proteins (enzymes), one of which--the sarcoplasmic-endoplasmic reticulum ATPase PfATP6 (ref. 7)--may be critical to parasite survival. Notably, there is no evidence of drug resistance to any member of the artemisinin family of drugs. The chemotherapy of malaria has benefited greatly from the semi-synthetic artemisinins artemether and artesunate as they rapidly reduce parasite burden, have good therapeutic indices and provide for successful treatment outcomes. However, as a drug class, the artemisinins suffer from chemical (semi-synthetic availability, purity and cost), biopharmaceutical (poor bioavailability and limiting pharmacokinetics) and treatment (non-compliance with long treatment regimens and recrudescence) issues that limit their therapeutic potential. Here we describe how a synthetic peroxide antimalarial drug development candidate was identified in a collaborative drug discovery project.     

Inconsistent correlation of seismic layer 2a and lava layer thickness in oceanic crust

At mid-ocean ridges with fast to intermediate spreading rates, the upper section of oceanic crust is composed of lavas overlying a sheeted dyke complex. These units are formed by dykes intruding into rocks overlying a magma chamber, with lavas erupting at the ocean floor. Seismic reflection data acquired over young oceanic crust commonly image a reflector known as 'layer 2A', which is typically interpreted as defining the geologic boundary between lavas and dykes. An alternative hypothesis is that the reflector is associated with an alteration boundary within the lava unit. Many studies have used mapped variability in layer 2A thickness to make inferences regarding the geology of the oceanic crust, including volcanic construction, dyke intrusion and faulting. However, there has been no link between the geologic and seismological structure of oceanic crust except at a few deep drill holes. Here we show that, although the layer 2A reflector is imaged near the top of the sheeted dyke complex at fast-spreading crust located adjacent to the Hess Deep rift, it is imaged significantly above the sheeted dykes section at intermediate-spreading crust located near the Blanco transform fault. Although the lavas and underlying transition zone thicknesses differ by about a factor of two, the shallow seismic structure is remarkably similar at the two locations. This implies that seismic layer 2A cannot be used reliably to map the boundary between lavas and dykes in young oceanic crust. Instead we argue that the seismic layer 2A reflector corresponds to an alteration boundary that can be located either within the lava section or near the top of the sheeted dyke complex of oceanic crust.     

Alfvénic waves with sufficient energy to power the quiet solar corona and fast solar wind

Energy is required to heat the outer solar atmosphere to millions of degrees (refs 1, 2) and to accelerate the solar wind to hundreds of kilometres per second (refs 2-6). Alfvén waves (travelling oscillations of ions and magnetic field) have been invoked as a possible mechanism to transport magneto-convective energy upwards along the Sun's magnetic field lines into the corona. Previous observations of Alfvénic waves in the corona revealed amplitudes far too small (0.5?km?s(-1)) to supply the energy flux (100-200?W?m(-2)) required to drive the fast solar wind or balance the radiative losses of the quiet corona. Here we report observations of the transition region (between the chromosphere and the corona) and of the corona that reveal how Alfvénic motions permeate the dynamic and finely structured outer solar atmosphere. The ubiquitous outward-propagating Alfvénic motions observed have amplitudes of the order of 20?km?s(-1) and periods of the order of 100-500?s throughout the quiescent atmosphere (compatible with recent investigations), and are energetic enough to accelerate the fast solar wind and heat the quiet corona.     

A plus-end-directed motor enzyme that moves antiparallel microtubules in vitro localizes to the interzone of mitotic spindles.

Mitosis comprises a complex set of overlapping motile events, many of which involve microtubule-dependent motor enzymes. Here we describe a new member of the kinesin superfamily. The protein was originally identified as a spindle antigen by the CHO1 monoclonal antibody and shown to be required for mitotic progression. We have cloned the gene that encodes this antigen and found that its sequence contains a domain with strong sequence similarity to the motor domain of kinesin-like proteins. The product of this gene, expressed in bacteria, can cross-bridge antiparallel microtubules in vitro, and in the presence of Mg-ATP, microtubules slide over one another in a fashion reminiscent of microtubule movements during spindle elongation.     

Increased urinary excretion of a basement membrane like glycoprotein in acute uranium nephropathy

Résués Les effets de l'uranium sur l'excrétion de la glycoprotéine urinaire principale du rat out été étudiés chez 10 animaux. La principale glycoprotéine urinaire augmente de 50% dans les 24 h qui suivent l'administration de l'uranium.

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From the Department of Pediatrcs, College of Physicians and Surgeons of Columbia University.     

Force production by disassembling microtubules

Microtubules (MTs) are important components of the eukaryotic cytoskeleton: they contribute to cell shape and movement, as well as to the motions of organelles including mitotic chromosomes. MTs bind motor enzymes that drive many such movements, but MT dynamics can also contribute to organelle motility. Each MT polymer is a store of chemical energy that can be used to do mechanical work, but how this energy is converted to motility remains unknown. Here we show, by conjugating glass microbeads to tubulin polymers through strong inert linkages, such as biotin-avidin, that depolymerizing MTs exert a brief tug on the beads, as measured with laser tweezers. Analysis of these interactions with a molecular-mechanical model of MT structure and force production shows that a single depolymerizing MT can generate about ten times the force that is developed by a motor enzyme; thus, this mechanism might be the primary driving force for chromosome motion. Because even the simple coupler used here slows MT disassembly, physiological couplers may modulate MT dynamics in vivo.     

Biomedical informatics for proteomics

Success in proteomics depends upon careful study design and high-quality biological samples. Advanced information technologies, and also an ability to use existing knowledge to the full, will be crucial in making sense of the data. Despite its genome-scale potential, proteome analysis is at a much earlier stage of development than genomics and gene expression (microarray) studies. Fundamental issues involving biological variability, pre-analytic factors and analytical reproducibility remain to be resolved. Consequently, the analysis of proteomics data is currently informal and relies heavily on expert opinion. Databases and software tools developed for the analysis of molecular sequences and microarrays are helpful, but are limited owing to the unique attributes of proteomics data and differing research goals.