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<jats:p> In analyzing mechanisms of protection against intracellular infections, a series of human CD1-restricted T cell lines of two distinct phenotypes were derived. Both CD4 <jats:sup>−</jats:sup> CD8 <jats:sup>−</jats:sup> (double-negative) T cells and CD8 <jats:sup>+</jats:sup> T cells efficiently lysed macrophages infected with <jats:italic>Mycobacterium tuberculosis</jats:italic> . The cytotoxicity of CD4 <jats:sup>−</jats:sup> CD8 <jats:sup>−</jats:sup> T cells was mediated by Fas-FasL interaction and had no effect on the viability of the mycobacteria. The CD8 <jats:sup>+</jats:sup> T cells lysed infected macrophages by a Fas-independent, granule-dependent mechanism that resulted in killing of bacteria. These data indicate that two phenotypically distinct subsets of human cytolytic T lymphocytes use different mechanisms to kill infected cells and contribute in different ways to host defense against intracellular infection. </jats:p>

<jats:p>Mitochondrial DNA control region sequences were analyzed from 162 wolves at 27 localities worldwide and from 140 domestic dogs representing 67 breeds. Sequences from both dogs and wolves showed considerable diversity and supported the hypothesis that wolves were the ancestors of dogs. Most dog sequences belonged to a divergent monophyletic clade sharing no sequences with wolves. The sequence divergence within this clade suggested that dogs originated more than 100,000 years before the present. Associations of dog haplotypes with other wolf lineages indicated episodes of admixture between wolves and dogs. Repeated genetic exchange between dog and wolf populations may have been an important source of variation for artificial selection.</jats:p>

<jats:p> The extent to which inositol 1,4,5-trisphosphate (InsP <jats:sub>3</jats:sub> )–induced calcium signals are localized is a critical parameter for understanding the mechanism of effector activation. The spatial characteristics of InsP <jats:sub>3</jats:sub> -mediated calcium signals were determined by targeting a dextran-based calcium indicator to intracellular membranes through the in situ addition of a geranylgeranyl lipid group. Elementary calcium-release events observed with this indicator typically lasted less than 33 milliseconds, had diameters less than 2 micrometers, and were uncoupled from each other by the calcium buffer EGTA. Cellwide calcium transients are likely to result from synchronized triggering of such local release events, suggesting that calcium-dependent effector proteins could be selectively activated by localization near sites of local calcium release. </jats:p>

<jats:p>Most natural actions are accomplished with a seamless combination of individual movements. Such coordination poses a problem: How does the motor system orchestrate multiple movements to produce a single goal-directed action? The results from current experiments suggest one possible solution. Oculomotor neurons in the superior colliculus of a primate responded to mismatches between eye and target positions, even when the animal made two different types of eye movements. This neuronal activity therefore does not appear to convey a command for a specific type of eye movement but instead encodes an error signal that could be used by multiple movements. The use of shared inputs is one possible strategy for ensuring that different movements share a common goal.</jats:p>

<jats:p> Two families of small peptides that bind to the human thrombopoietin receptor and compete with the binding of the natural ligand thrombopoietin (TPO) were identified from recombinant peptide libraries. The sequences of these peptides were not found in the primary sequence of TPO. Screening libraries of variants of one of these families under affinity-selective conditions yielded a 14–amino acid peptide (Ile-Glu-Gly-Pro-Thr-Leu-Arg-Gln-Trp-Leu-Ala-Ala-Arg-Ala) with high affinity (dissociation constant ≈ 2 nanomolar) that stimulates the proliferation of a TPO-responsive Ba/F3 cell line with a median effective concentration (EC <jats:sub>50</jats:sub> ) of 400 nanomolar. Dimerization of this peptide by a carboxyl-terminal linkage to a lysine branch produced a compound with an EC <jats:sub>50</jats:sub> of 100 picomolar, which was equipotent to the 332–amino acid natural cytokine in cell-based assays. The peptide dimer also stimulated the in vitro proliferation and maturation of megakaryocytes from human bone marrow cells and promoted an increase in platelet count when administered to normal mice. </jats:p>

<jats:p>Extracellular levels of the excitatory neurotransmitter glutamate in the nervous system are maintained by transporters that actively remove glutamate from the extracellular space. Homozygous mice deficient in GLT-1, a widely distributed astrocytic glutamate transporter, show lethal spontaneous seizures and increased susceptibility to acute cortical injury. These effects can be attributed to elevated levels of residual glutamate in the brains of these mice.</jats:p>

<jats:p> Exposure of the yeast <jats:italic>Saccharomyces cerevisiae</jats:italic> to high extracellular osmolarity induces the Sln1p-Ypd1p-Ssk1p two-component osmosensor to activate a mitogen-activated protein (MAP) kinase cascade composed of the Ssk2p and Ssk22p MAP kinase kinase kinases (MAPKKKs), the Pbs2p MAPKK, and the Hog1p MAPK. A second osmosensor, Sho1p, also activated Pbs2p and Hog1p, but did so through the Ste11p MAPKKK. Although Ste11p also participates in the mating pheromone–responsive MAPK cascade, there was no detectable cross talk between these two pathways. The MAPKK Pbs2p bound to the Sho1p osmosensor, the MAPKKK Ste11p, and the MAPK Hog1p. Thus, Pbs2p may serve as a scaffold protein. </jats:p>

<jats:p>Retinal neovascularization is the major cause of untreatable blindness. The role of growth hormone (GH) in ischemia-associated retinal neovascularization was studied in transgenic mice expressing a GH antagonist gene and in normal mice given an inhibitor of GH secretion (MK678). Retinal neovascularization was inhibited in these mice in inverse proportion to serum levels of GH and a downstream effector, insulin-like growth factor–I (IGF-I). Inhibition was reversed with exogenous IGF-I administration. GH inhibition did not diminish hypoxia-stimulated retinal vascular endothelial growth factor (VEGF) or VEGF receptor expression. These data suggest that systemic inhibition of GH or IGF-I, or both, may have therapeutic potential in preventing some forms of retinopathy.</jats:p>

<jats:p> The gene responsible for Friedreich's ataxia, a disease characterized by neurodegeneration and cardiomyopathy, has recently been cloned and its product designated frataxin. A gene in <jats:italic>Saccharomyces cerevisiae</jats:italic> was characterized whose predicted protein product has high sequence similarity to the human frataxin protein. The yeast gene (yeast frataxin homolog, <jats:italic>YFH1</jats:italic> ) encodes a mitochondrial protein involved in iron homeostasis and respiratory function. Human frataxin also was shown to be a mitochondrial protein. Characterizing the mechanism by which <jats:italic>YFH1</jats:italic> regulates iron homeostasis in yeast may help to define the pathologic process leading to cell damage in Friedreich's ataxia. </jats:p>

<jats:p>Intron excision is an essential step in eukaryotic gene expression, but the molecular mechanisms by which the spliceosome accurately identifies splice sites in nuclear precursors to messenger RNAs (pre-mRNAs) are not well understood. A bimolecular assay for the second step of splicing has now revealed that exon ligation by the human spliceosome does not require covalent attachment of a 3′ splice site to the branch site. Furthermore, accurate definition of the 3′ splice site in this system is independent of either a covalently attached polypyrimidine tract or specific 3′ exon sequences. Rather, in this system 3′ splice site selection apparently occurs with a 5′ → 3′ directionality.</jats:p>