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<jats:p>Posttranslational protein translocation across the endoplasmic reticulum membrane of yeast requires a seven-component transmembrane complex (the Sec complex) in collaboration with the lumenal Kar2 protein (Kar2p). A translocation substrate was initially bound to the cytosolic face of the purified Sec complex in a signal-sequence–dependent but Kar2p- and nucleotide-independent manner. In a subsequent reaction, in which Kar2p interacted with the lumenal face of the Sec complex and hydrolyzed adenosine triphosphate, the substrate moved through a channel formed by the Sec complex and was released at the lumenal end. Movement through the channel occurred in detergent solution in the absence of a lipid bilayer.</jats:p>

<jats:p> A <jats:italic>C. elegans</jats:italic> neurosecretory signaling system regulates whether animals enter the reproductive life cycle or arrest development at the long-lived dauer diapause stage. <jats:italic>daf-2</jats:italic> , a key gene in the genetic pathway that mediates this endocrine signaling, encodes an insulin receptor family member. Decreases in DAF-2 signaling induce metabolic and developmental changes, as in mammalian metabolic control by the insulin receptor. Decreased DAF-2 signaling also causes an increase in life-span. Life-span regulation by insulin-like metabolic control is analogous to mammalian longevity enhancement induced by caloric restriction, suggesting a general link between metabolism, diapause, and longevity. </jats:p>

<jats:p> Understanding natural causes of density dependence is essential for identifying possible sources of population regulation. Field experiments on a model system of coral reef fishes showed that small juveniles of <jats:italic>Chromis cyanea</jats:italic> suffer heavy mortality that is spatially density-dependent only in the presence of two suites of predators: transient piscivores attacking from above, and reef-resident piscivores attacking from below. In the absence of either kind of predator, early mortality of <jats:italic>Chromis</jats:italic> is virtually density-independent. Because piscivores may have regulatory roles in this and similar marine systems, overfishing these predators may have ramifications for the remainder of the exploited community. </jats:p>

<jats:p> The epithelium that lines the gut is impermeable to macromolecules and microorganisms, except in Peyer's patches (PPs), where the lymphoid follicle-associated epithelium (FAE) contains M cells that transport antigens and microorganisms. A cultured system that reproduces the main characteristics of FAE and M cells was established by cultivation of PP lymphocytes with the differentiated human intestinal cell line Caco-2. Lymphocytes settled into the epithelial monolayer, inducing reorganization of the brush border and a temperature-dependent transport of particles and <jats:italic>Vibrio cholerae</jats:italic> . This model system could prove useful for intestinal physiology, vaccine research, and drug delivery studies. </jats:p>

<jats:p>The effects of the psychotomimetic drug phencyclidine on the neurochemistry and function of the prefrontal cortex in vervet monkeys were investigated. Monkeys treated with phencyclidine twice a day for 14 days displayed performance deficits on a task that was sensitive to prefrontal cortex function; the deficits were ameliorated by the atypical antipsychotic drug clozapine. Repeated exposure to phencyclidine caused a reduction in both basal and evoked dopamine utilization in the dorsolateral prefrontal cortex, a brain region that has long been associated with cognitive function. Behavioral deficits and decreased dopamine utilization remained after phencyclidine treatment was stopped, an indication that these effects were not simply due to direct drug effects. The data suggest that repeated administration of phencyclidine in monkeys may be useful for studying psychiatric disorders associated with cognitive dysfunction and dopamine hypofunction in the prefrontal cortex, particularly schizophrenia.</jats:p>

<jats:p> Catalytic protein subunits of telomerase from the ciliate <jats:italic>Euplotes aediculatus</jats:italic> and the yeast <jats:italic>Saccharomyces cerevisiae</jats:italic> contain reverse transcriptase motifs. Here the homologous genes from the fission yeast <jats:italic>Schizosaccharomyces pombe</jats:italic> and human are identified. Disruption of the <jats:italic>S. pombe</jats:italic> gene resulted in telomere shortening and senescence, and expression of mRNA from the human gene correlated with telomerase activity in cell lines. Sequence comparisons placed the telomerase proteins in the reverse transcriptase family but revealed hallmarks that distinguish them from retroviral and retrotransposon relatives. Thus, the proposed telomerase catalytic subunits are phylogenetically conserved and represent a deep branch in the evolution of reverse transcriptases. </jats:p>

<jats:p> The critical role of chemokine receptors (CCR5 and CXCR4) in human immunodeficiency virus–type 1 (HIV-1) infection and pathogenesis prompted a search for polymorphisms in other chemokine receptor genes that mediate HIV-1 disease progression. A mutation ( <jats:italic>CCR2-64I</jats:italic> ) within the first transmembrane region of the <jats:italic>CCR2</jats:italic> chemokine and HIV-1 receptor gene is described that occurred at an allele frequency of 10 to 15 percent among Caucasians and African Americans. Genetic association analysis of five acquired immunodeficiency syndrome (AIDS) cohorts (3003 patients) revealed that although <jats:italic>CCR2-64I</jats:italic> exerts no influence on the incidence of HIV-1 infection, HIV-1–infected individuals carrying the <jats:italic>CCR2</jats:italic> - <jats:italic>64I</jats:italic> allele progressed to AIDS 2 to 4 years later than individuals homozygous for the common allele. Because <jats:italic>CCR2-64I</jats:italic> occurs invariably on a <jats:italic>CCR5-+</jats:italic> –bearing chromosomal haplotype, the independent effects of <jats:italic>CCR5-Δ32</jats:italic> (which also delays AIDS onset) and <jats:italic>CCR2-64I</jats:italic> were determined. An estimated 38 to 45 percent of AIDS patients whose disease progresses rapidly (less than 3 years until onset of AIDS symptoms after HIV-1 exposure) can be attributed to their <jats:italic>CCR2-+/+</jats:italic> or <jats:italic>CCR5-+/+</jats:italic> genotype, whereas the survival of 28 to 29 percent of long-term survivors, who avoid AIDS for 16 years or more, can be explained by a mutant genotype for <jats:italic>CCR2</jats:italic> or <jats:italic>CCR5.</jats:italic> </jats:p>

<jats:p>Members of the recently recognized SRC-1 family of transcriptional coactivators interact with steroid hormone receptors to enhance ligand-dependent transcription. AIB1, a member of the SRC-1 family, was cloned during a search on the long arm of chromosome 20 for genes whose expression and copy number were elevated in human breast cancers. AIB1 amplification and overexpression were observed in four of five estrogen receptor–positive breast and ovarian cancer cell lines. Subsequent evaluation of 105 unselected specimens of primary breast cancer found AIB1 amplification in approximately 10 percent and high expression in 64 percent of the primary tumors analyzed. AIB1 protein interacted with estrogen receptors in a ligand-dependent fashion, and transfection of AIB1 resulted in enhancement of estrogen-dependent transcription. These observations identify AIB1 as a nuclear receptor coactivator whose altered expression may contribute to development of steroid-dependent cancers.</jats:p>

<jats:p>Recent evidence demonstrating multiple regions of human cerebral cortex activated by pain has prompted speculation about their individual contributions to this complex experience. To differentiate cortical areas involved in pain affect, hypnotic suggestions were used to alter selectively the unpleasantness of noxious stimuli, without changing the perceived intensity. Positron emission tomography revealed significant changes in pain-evoked activity within anterior cingulate cortex, consistent with the encoding of perceived unpleasantness, whereas primary somatosensory cortex activation was unaltered. These findings provide direct experimental evidence in humans linking frontal-lobe limbic activity with pain affect, as originally suggested by early clinical lesion studies.</jats:p>