This Week in Science

Science  13 Jun 1997:
Vol. 276, Issue 5319, pp. 1621
  1. Controlling graft-versus-host disease

    Allogeneic bone marrow transplantation (the use of a less than perfectly matched donor) is used to reconstitute the immune system after severe treatments for cancer. Because the T cells in the donor's marrow recognize the recipient as “foreign,” they are usually removed from the original bone marrow graft. If the cancer recurs, an effective treatment is to infuse the donor T cells, but this procedure frequently runs the risk of graft-versus-host disease (GvHD), a potentially lethal complication. Bonini et al. (p. 1719; see the news story by Wickelgren, p. 1646) devised a strategy for killing the donor T cells if they started attacking normal host tissue. They transferred a herpes simplex virus “suicide vector” (thymidine kinase) into donor T cells in culture, selected for the cells that expressed the gene, and infused the genetically modified cells into 12 patients. Ganciclovir was used to successfully control GvHD by eliminating the donor lymphocytes in three patients, and antitumor activity was seen in five patients.

  2. Scattered objects

    Beyond the orbit of Neptune lies a band of objects called the Kuiper belt, which is a source of comets. Duncan and Levison (p. 1670) simulated the evolution of such objects after they were perturbed by Neptune and found that some formed a disk of scattered icy objects, distinct from the Kuiper belt, in the early solar system. Recently, two objects with unusual orbits were discovered that may be members of this ancient disk. If such a disk exists, it may provide a source for the short-lived comets whose orbits are controlled by Jupiter.

  3. Raising Nevada

    Most of the Basin and Range Province in the western United States has been thought to have been uplifted recently (during the last 5 million years). Wolfe et al. (p. 1672) present an analysis of fossil leaf data collected from Nevada that provide an indication of paleoaltitude. The data imply instead that this part of the Basin and Range Province stood about 3 kilometers above sea level about 15 million years ago before subsiding to the current mean elevation of 1.0 to 1.5 kilometers about 13 million years ago.

  4. Picky surface

    Gas-phase chemical reactions can be highly atom-specific; for example, the reaction of iodine chloride (ICl) with deuterium atoms forms three times as much DI as DCl, although the latter product is more stable. Similar reactions with surfaces are thought to be much less selective because of the numerous possible reaction sites, but Liu et al. (p. 1681) show that the reaction of a molecular beam of ICl with the silicon (111)−(7×7) reconstructed surface formed an iodine-rich surface layer. The preferential ejection of chlorine to the gas phase, the least energetically favorable outcome, appears to be due to interactions that align the ICl molecule with the I end toward the surface.

  5. Growth hormone and blindness

    The most common forms of untreatable blindness arise from by the abnormal growth of new blood vessels in the retina, a process triggered by oxygen deprivation. Vascular endothelial growth factor (VEGF) is thought to participate in this process of neovascularization, but other factors also likely play a role. In experiments with mouse models, Smith et al. (p. 1706) show that hypoxia-induced retinal neovascularization requires the action of growth hormone (GH) and one of its downstream effectors, insulin-like growth factor-1 (IGF-I). These results suggest that GH and or IGF-I inhibitors may prove useful for preventing certain forms of blindness.

  6. Iron link in Friedreich's ataxia

    Friedreich's ataxia is a degenerative disease affecting the nervous system and the heart. Although mutations in a gene product, frataxin, have been associated with the disease, the sequence of frataxin has not provided insights into its function. Babcock et al. (p. 1709) found that a yeast gene that has high sequence similarity to frataxin encodes a mitochondrial protein involved in regulating iron homeostasis and mitochondrial function. Human frataxin was also shown to be a mitochondrial protein. As abnormal iron accumulation has been previously observed in Friedreich's ataxia, these results suggest a mechanism for the observed pathology.

  7. Enhancing platelet production

    Thrombopoietin is a cytokine that promotes growth of megakaryocytes—cells in the bone marrow that give rise to platelets. Cwirla et al. (p. 1696) used several sophisticated screens to select small peptides that potently bind to and activate the thrombopoietin receptor. Although the sequences of these peptides are not present in thrombopoietin, one dimerized 14-amino acid peptide had a mean effective concentration (EC50) of 100 picomolar, essentially the same as that of the natural 332-amino acid cytokine. Thrombocytoppenia, the insufficiency of platelets circulating in the blood, is encountered after chemotherapy or bone marrow transplantation.

  8. Between two kingdoms

    Transposable elements are pieces of DNA that can move around a genome as discrete units. This movement had been seen only between closely related species until Gueiros-Filho and Beverley (p. 1716; see the Perspective by Hartl, p. 1659) demonstrated that it could occur between two different kingdoms. The Drosophila element mariner was shown to inactivate or trap genes in Leishmania major, a protozoan that causes the fatal disease leishmaniasis. This finding will make genetic analysis of Leishmania easier and suggests that mariner can be a powerful genetic probe to study other eukaryotes as well.

  9. Enzyme origins and antibody formation

    Comparison of the crystal structure of a catalytic antibody with that of its germline precursor have led to insights into the evolution of catalytic activity. Wedemayer et al. found that there are significant changes in the configuration of the binding site when the hapten binds to the germline antibody, but hapten binding to the mature catalytic antibody proceeds in an enzymelike “lock and key” fashion. Some of the mutations that induce a better fit occur up to 15 angstroms away from the bound hapten. [See the cover and the Perspective by Joyce.]

  10. Tiny ice cubes

    Theoretical studies have predicted that the lowest energy structure of the water octamer is a cube formed by tricoordinate water molecules. Such a structure would represent the smallest model system for tricoordinate water molecules present at the surfaces of liquid and solid ice, and it is also expected to be a building block for larger water clusters. Spectroscopic studies of the water octamer complexed with benzene by Gruenloh et al. show that such a cubic structure forms and is only slightly distorted by the benzene. Two different isomers were observed that differed only in their hydrogen-bonding geometry.

  11. Solvation effects

    Solvation plays an important role in chemical dynamics, but experimental studies must contend with the rapidly changing solvent cage surrounding a solute molecule. One important model system has been the photodissociation of the iodine anion (I2) in solvent clusters of several argon atoms. Greenblatt et al. used photoelectron spectroscopy on a femtosecond time scale to follow the effect of different cluster sizes on the outcome of the reaction. For smaller clusters [I2(Ar)6], the reaction is completed in the same amount of time as for the bare molecule (200 femtoseconds). For larger clusters [I2(Ar)20], the I and I product fragments are caged and recombine along either a ground state or excited state pathway on time scales of 200 and 35 picoseconds, respectively. [See the Perspective by Parson and Faeder.]

  12. Specializing in lysis

    The role of cytolytic T lymphocytes (CTLs) is to destroy infected host tissue, and two distinct and independent mechanisms of CTL-mediated destruction have previously been described. Now Stenger et al. have discovered that these two mechanisms are mediated by different subpopulations of CTLs: The Fas-Fas ligand system is operated by CTL expressing the CD8 marker, whereas granule-dependent lysis is mediated by cells expressing neither CD8 nor CD4 (known as “double-negative” cells). Both CTL types could lyse targets infected with Mycobacterium tuberculosis, but only the double-negative cells killed the bacteria. Most of this work was done on the recently discovered CD1-restricted population of T cells, but preliminary evidence indicates that the same division of labor may also hold for the classical major histocompatibility complex (MHC) class I-restricted CTLs.

  13. Calcium control in cells

    Many receptors on the cell surface regulate intracellular process by altering the intracellular concentration of Ca2+ ([Ca2+]i). One mechanism for control of [Ca2+]i is the generation of inositol 1,4,5-trisphosphate (InsP3), which binds to receptors on Ca2+ stores within the cell. The InsP3 receptors are actually channels that, when bound to InsP3, allow release of Ca2+. The [Ca2+]i may increase throughout the entire cell, but it is also possible that localized increases in [Ca2+]i could regulate specific events. Horne and Meyer developed improved methods for imaging Ca2+ release within the cell and observed elementary calcium release events that appear to represent opening of several InsP3-gated Ca2+ channels. Large increases in [Ca2+]i at the site of such release events could cause localized regulation of Ca2+-dependent processes. Synchronization of such events may account for the overall increase in Ca2+ observed in response to many stimuli.

  14. Origins of an old friend

    Humans and dogs have had at least 100,000 years of association, according to the analysis of mitochondrial DNA sequences by Vilà et al. Dogs have evolved through a combination of human breeding selections and repeated outcrossing with wild wolves. Coyotes and other Canis species apparently have not added to the evolution of domesticated dogs. Wolves from 27 different populations and dogs from 67 different breeds were analyzed, as well as coyotes and jackals. [See the news story by Morell.]

  15. Eye on the ball

    Laboratory studies have identified individual neurons coding for eye movements and for error estimates used to fine-tune visual focus to the desired target, but how are the various movements coordinated in a natural setting where the head or body may be moving as well? Krauzlis et al. make a start toward addressing this issue by examining neurons that code for error during two distinct types of eye movements, smooth pursuit of a target and stepwise saccadic movement. These neurons may represent more general sources of error information provided to disparate motor centers to keep all of the parts moving in concert.

  16. Controlling glutamate in the brain

    The excitatory neurotransmitter glutamate (Glu) is one of the most important in the brain, but in excess it can cause cell death or overexcitation resulting in epilepsy. The concentration of Glu in extracellular spaces is determined by the aggregate contributions of synthesis and release offset by uptake back into neurons and glia and by metabolism. The determination of the relative contributions of the four Glu uptake transporters (two on neurons and two on glia) requires selective inhibitors of each, but such agents are not available. Tanaka et al. have now examined epilepsy and susceptibility to cell death in mice deficient in GLT-1, a widespread astrocytic Glu transporter. These animals showed lethal spontaneous seizures and extensive cell death in the hippocampus, indicating that GLT-1 is crucial for maintaining physiological concentrations of glutamate in the brain. This molecule may be defective in some sporadic cases of amyotrophic lateral sclerosis.

  17. Mating stress?

    Many biological processes are regulated by members of the mitogen-activated protein kinase (MAPK) family in eukaryotic cells. MAPKs are controlled through sequential phosphorylation and activation of a series of kinases, the MAPK kinases (MAPKKs) and the MAPKK kinases (MAPKKKs). It remains incompletely understood how signals that activate such common signaling components can generate specific biological responses. Indeed, in yeast, Posas and Saito discovered that the same MAPKKK enzyme is used in both the response to mating pheromone and the response to osmotic stress, even though the other components of the cascades are distinct. Specificity is ensured by physical interaction of the appropriate partners. The MAPKK of the osmotic stress pathway acts as a selective scaffold that binds the appropriate MAPK, MAPKKK, and also the osmosensor itself. In this way, the MAPKKK activated by osmotic stress activates only the MAPKK and MAPK for the stress pathway and not those that produce the pheromone response.

  18. The splice of life

    A new approach for analyzing the sequences and factors for exon ligation, the second step in the splicing of nuclear precursors to messenger RNA (pre-mRNA), has revealed that this process in the human spliceosome does not require covalent attachment of a 3′ splice site to the branch point. Anderson and Moore studied this process with a pre-mRNA that lacked the 3′ splice site and had no sequences 3′ to the pyrimidine-rich region that defines the branch point in mammals. Splicing intermediates accumulated that could then react with RNA containing the 3′ splice site. Although this bimolecular attachment would tend to be inhibited in vivo with full-length substrates, these results show that the need for a covalently attached polypyrimidine tract or of specific 3′ exon sequences is not absolute.

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