The rare inherited condition acrodermatitis enteropathica (AE) results from a defect in the absorption of dietary zinc. Recently, we used homozygosity mapping in consanguineous Middle Eastern kindreds to localize the AE gene to an approximately 3.5-cM region on 8q24. In this article, we identify a gene, SLC39A4, located in the candidate region and, in patients with AE, document mutations that likely lead to the disease. The gene encodes a histidine-rich protein, which we refer to as "hZIP4," which is a member of a large family of transmembrane proteins, some of which are known to serve as zinc-uptake proteins. We show that Slc39A4 is abundantly expressed in mouse enterocytes and that the protein resides in the apical membrane of these cells. These findings suggest that the hZIP4 transporter is responsible for intestinal absorption of zinc.
Summary To gain insight into the mechanisms by which host cells detect cytosolic invasion by intracellular pathogens, a genetic screen was performed to identify Listeria monocytogenes mutants that induced altered levels of host cell death. A mutation in lmo2473 resulted in hyper-stimulation of host cell death and IL-1β secretion (pyroptosis) following bacteriolysis in the macrophage cytosol. In addition, strains engineered to lyse in the cytosol by expression of both bacteriophage holin and lysin or induced to lyse by treatment with ampicillin stimulated pyroptosis. Pyroptosis was independent of the Nlrp3 and Nlrc4 receptors, but dependent on ASC and AIM2. Importantly, wild type L. monocytogenes were also found to lyse, albeit at low levels, and trigger AIM2-dependent pyroptosis. Since AIM2 is activated by DNA, these data suggested that pyroptosis is triggered by bacterial DNA released during lysis.
Absolute pitch (AP) is the rare ability to identify the pitch of a tone without the aid of a reference tone. Understanding both the nature and genesis of AP can provide insights into neuroplasticity in the auditory system. We explored factors that may influence the accuracy of pitch perception in AP subjects both during the development of the trait and in later age. We used a Web-based survey and a pitch-labeling test to collect perceptual data from 2,213 individuals, 981 (44%) of whom proved to have extraordinary pitch-naming ability. The bimodal distribution in pitch-naming ability signifies AP as a distinct perceptual trait, with possible implications for its genetic basis. The wealth of these data has allowed us to uncover unsuspected note-naming irregularities suggestive of a ''perceptual magnet'' centered at the note ''A.'' In addition, we document a gradual decline in pitch-naming accuracy with age, characterized by a perceptual shift in the ''sharp'' direction. These findings speak both to the process of acquisition of AP and to its stability.perceptual magnet ͉ pitch perception
Listeriolysin O (LLO) is a pore-forming toxin that mediates phagosomal escape and cell-to-cell spread of the intracellular pathogen Listeria monocytogenes. In order to identify factors that control the production, activity, or secretion of this essential virulence factor, we constructed a Himar1 mariner transposon delivery system and screened 50,000 mutants for a hypohemolytic phenotype on blood agar plates. Approximately 200 hypohemolytic mutants were identified, and the 51 most prominent mutants were screened ex vivo for intracellular growth defects. Eight mutants with a phenotype were identified, and they contained insertions in the following genes: lmo0964 (similar to yjbH), lmo1268 (clpX), lmo1401 (similar to ymdB), lmo1575 (similar to ytqI), lmo1695 (mprF), lmo1821 (similar to prpC), lmo2219 (prsA2), and lmo2460 (similar to cggR). Some of these genes are involved in previously unexplored areas of research with L. monocytogenes: the genes yjbH and clpX regulate the disulfide stress response in Bacillus subtilis, and the prpC phosphatase has been implicated in virulence in other gram-positive pathogens. Here we demonstrate that prsA2, an extracytoplasmic peptidylprolyl cis/trans isomerase, is critical for virulence and contributes to the folding of LLO and to the activity of another virulence factor, the broad-range phospholipase C (PC-PLC). Furthermore, although it has been shown that prsA2 expression is linked to PrfA, the master virulence transcription factor in L. monocytogenes pathogenesis, we demonstrate that prsA2 is not directly controlled by PrfA. Finally, we show that PrsA2 is involved in flagellum-based motility, indicating that this factor likely serves a broad physiological role.Listeria monocytogenes is a gram-positive, facultative intracellular pathogen capable of infecting a broad range of animal hosts, including humans (84). The cell biology of infection has been well characterized and is a model for pathogenesis. Upon internalization into host cells, including macrophages and nonprofessional phagocytes, L. monocytogenes organisms are initially enclosed in a single-membrane vacuole. Bacteria rapidly lyse this primary vacuole and replicate in the cytosol, exploiting actin-based motility as a means to move within the cytoplasm and to spread from cell to cell. Actin-based propulsion of bacteria from the cytoplasm of one cell into the cytoplasm of a neighboring cell results in the formation of a double-membrane vacuole or secondary vacuole. Bacteria lyse the secondary vacuole, and intracellular growth continues (81, 84).Central to the virulence of L. monocytogenes is the ability to lyse the primary and secondary vacuoles in order to gain entry into the host cytosol. Escape from both types of vacuoles is primarily mediated by the secretion of the cytolysin listeriolysin O (LLO) (68). Members of a large family of pore-forming toxins called the cholesterol-dependent cytolysins, LLO monomers bind cholesterol-containing host membranes. Upon binding, the monomers oligomerize and the resultant complex ...
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