X rays may be twice as potent as gamma rays for malignant transformation at low doses

The introduction in the 1950s of 60Co teletherapy units and megavoltage X-ray accelerators for radiotherapy prompted several studies which showed that the relative biological effectiveness (RBE) of orthovoltage X rays, compared with 60Co gamma rays, was approximately 1.1-1.2 (refs 1, 2). Subsequently, radiation therapists confirmed that the effect of established treatment protocols using orthovoltage X rays could be duplicated with the higher energy radiation by increasing the dose by approximately 10%, when radiation doses are of the order of tens of grays (or thousands of rads). The dependence of biological effectiveness on photon energy led to recommendations in which the quality factor, Q, which is an RBE for radiation protection purposes, was set at unity for X and gamma rays as well as for electrons or other directly ionizing particles having a linear energy transfer (LET) of less than 3.5 ke V microns-1. Over the past decade, however, several studies have shown differences in RBE between various low-LET radiations having LET values within the range designated for standard radiation. Underbrink et al. found an RBE for orthovoltage X rays relative to 60Co gamma rays of approximately 2 at 0.04 Gy, for induction of pink mutations in the stamen hairs of Tradescantia. Schmidt et al. scored chromosome aberrations in human lymphocytes, and at 0.25 Gy found the RBE of 200-k Vp X rays relative to 3-MeV electrons to be also approximately 2. Here we have compared 60Co gamma rays and orthovoltage X rays over the dose range 0.03-1.5 Gy using malignant transformation in mammalian cells in vitro as an end point. Our findings indicate that whereas the transformation incidence seems similar for X and gamma rays at high doses, the malignant potential of X rays is about twice that of gamma rays at 0.03 Gy.     

Structure and control of the actin regulatory WAVE complex

Members of the Wiskott-Aldrich syndrome protein (WASP) family control cytoskeletal dynamics by promoting actin filament nucleation with the Arp2/3 complex. The WASP relative WAVE regulates lamellipodia formation within a 400-kilodalton, hetero-pentameric WAVE regulatory complex (WRC). The WRC is inactive towards the Arp2/3 complex, but can be stimulated by the Rac GTPase, kinases and phosphatidylinositols. Here we report the 2.3-?ngstrom crystal structure of the WRC and complementary mechanistic analyses. The structure shows that the activity-bearing VCA motif of WAVE is sequestered by a combination of intramolecular and intermolecular contacts within the WRC. Rac and kinases appear to destabilize a WRC element that is necessary for VCA sequestration, suggesting the way in which these signals stimulate WRC activity towards the Arp2/3 complex. The spatial proximity of the Rac binding site and the large basic surface of the WRC suggests how the GTPase and phospholipids could cooperatively recruit the complex to membranes.     

Tumour-specific phenylalanine tRNA contains two supernumerary methylated bases.

Every malignant tumour examined contains aberrant tRNA methyltransferases and a few tRNAs which are absent from the normal tissue of origin. To determine whether tumour-specific tRNAs have different modifications from those in normal tissue, we purified the most frequently occurring tumour-specific isoaccepting tRNA from two malignant tissues. The isoaccepting phenylalanine tRNA from Novikoff hepatoma and Ehrlich ascites cells both contain two supernumerary methylated bases. One of these l-methylguanine, is absent from the phenylalanine tRNA of normal rat, mouse, rabbit and calf liver. An increase in the levels of 5-methylcytidine and dihydrouridine was also detected.     

A stomatin-domain protein essential for touch sensation in the mouse

Touch and mechanical pain are first detected at our largest sensory surface, the skin. The cell bodies of sensory neurons that detect such stimuli are located in the dorsal root ganglia, and subtypes of these neurons are specialized to detect specific modalities of mechanical stimuli. Molecules have been identified that are necessary for mechanosensation in invertebrates but so far not in mammals. In Caenorhabditis elegans, mec-2 is one of several genes identified in a screen for touch insensitivity and encodes an integral membrane protein with a stomatin homology domain. Here we show that about 35% of skin mechanoreceptors do not respond to mechanical stimuli in mice with a mutation in stomatin-like protein 3 (SLP3, also called Stoml3), a mammalian mec-2 homologue that is expressed in sensory neurons. In addition, mechanosensitive ion channels found in many sensory neurons do not function without SLP3. Tactile-driven behaviours are also impaired in SLP3 mutant mice, including touch-evoked pain caused by neuropathic injury. SLP3 is therefore indispensable for the function of a subset of cutaneous mechanoreceptors, and our data support the idea that this protein is an essential subunit of a mammalian mechanotransducer.