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Results for “Gatekeeping”

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At least 253 records · Page 14Linked to original sources
PubMed1999

P-Glycoprotein, a gatekeeper in the blood-brain barrier.

The blood-brain barrier is a major impediment to the entry of many therapeutic drugs into the brain. P-Glycoprotein is an ATP-dependent drug transport protein that is predominantly found in the apical membranes of a number of epithelial cell types in the body, including the blood luminal membrane of the brain capillary endothelial cells that make up the blood-brain barrier. Since P-glycoprotein can actively transport a huge variety of hydrophobic amphipathic drugs out of the cell, it was hypothesized that it might be responsible for the very poor penetration of many relatively large (>400 Da) hydrophobic drugs in the brain, by performing active back-transport of these drugs to the blood. Extensive experiments with in vitro models and with knockout mice lacking blood-brain barrier P-glycoprotein or other animal models treated with blockers of P-glycoprotein have fully confirmed this hypothesis. Absence of functional P-glycoprotein in the blood-brain barrier leads to highly increased brain penetration of a number of important drugs. Depending on the pharmacological target of these drugs in the central nervous system (CNS), this can result in dramatically increased neurotoxicity, or fundamentally altered pharmacological effects of the drug. Given the variety of drugs affected by P-glycoprotein transport, it may be of tremendous therapeutic value to apply these insights to the development of drugs that should have either very poor or very good brain penetration, whichever is preferred for pharmacotherapeutic purposes. The clinical application of P-glycoprotein blockers should also be considered in order to improve the blood-brain barrier permeability of certain drugs that currently display insufficient brain penetration for effective therapy.

Journal Article↗
PubMed2004

Activator of G protein signaling 3: a gatekeeper of cocaine sensitization and drug seeking.

Chronic cocaine administration reduces G protein signaling efficacy. Here, we report that the expression of AGS3, which binds to GialphaGDP and inhibits GDP dissociation, was upregulated in the prefrontal cortex (PFC) during late withdrawal from repeated cocaine administration. Increased AGS3 was mimicked in the PFC of drug-naive rats by microinjecting a peptide containing the Gialpha binding domain (GPR) of AGS3 fused to the cell permeability domain of HIV-Tat. Infusion of Tat-GPR mimicked the phenotype of chronic cocaine-treated rats by manifesting sensitized locomotor behavior and drug seeking and by increasing glutamate transmission in nucleus accumbens. By preventing cocaine withdrawal-induced AGS3 expression with antisense oligonucleotides, signaling through Gialpha was normalized, and both cocaine-induced relapse to drug seeking and locomotor sensitization were prevented. When antisense oligonucleotide infusion was discontinued, drug seeking and sensitization were restored. It is proposed that AGS3 gates the expression of cocaine-induced plasticity by regulating G protein signaling in the PFC.

Animals↗
PubMed2001

Plant cell death: unmasking the gatekeepers.

Cell death is an important aspect of plant resistance to pathogen infection. Recent results have shed new light on the mechanisms that control this cell death following attempted pathogen infection.

Cell Death↗
PubMed2000

Towards reconciliation of structure with function in plasmodesmata-who is the gatekeeper?

Whilst the structure of higher plant plasmodesmata was first described by Robards (1963. Desmotubule-a plasmodesmatal substructure. Nature 218, 784), and despite many subsequent intensive investigations, there is still much that remains unclear relating to their ultrastructure and functioning in higher plants. We have examined chemically fixed plant material, and suggest that the conformational changes seen in plasmodesmatal substructure, particularly the deposition of electron-dense extra-plasmodesmal material, is linked to either manipulation of the hormonal balance (as in Avocado fruit), or of osmotic potential in leaf blade material. These changes result in the deposition of beta 1,3-glucan (callose) at the neck region of these plasmodesmata. This electron-dense material is deposited at the neck region of plasmodesmata, and forms a collar-like structure. The formation of a collar is shown to be coupled with loss of lucence within the cytoplasmic sleeve. The formation of a collar at the plasmodesmatal orifice thus results in encapsulation and closure of the plasmodesmatal orifice. Closure of the orifice coincides with a loss of electron-lucence and a lack of resolution of the desmotubule. These ultrastructural changes are potentially significant and could contribute to, result in, or assist in the down-regulation of cell to cell trafficking via plasmodesmata.

Cell Communication↗
PubMed2003

Searching for the gatekeeper oncogene of prostate cancer.

Prostate cancer is a common malignancy that has a heterogeneous etiology and a variable outcome. Nearly all prostatic adenocarcinoma results from androgen-dependent tumor promotion. However, the cause of prostate cancer initiation is not well understood and only a few of the target oncogenes activated during prostate cancer initiation have been identified. Prostate cancer risk is strongly influenced by family history. Several genetic loci have been found to cosegregate with prostate cancer occurrence in high-risk families. Some candidate oncogenes that map to these loci have been implicated by the identification of mutations in high-risk kindreds. However, the roles of the putative oncogene products in the biochemical pathways that mediate carcinogenesis remain obscure and their influence on cancer etiology has yet to be supported by gene targeting experiments in mice. Moreover, the genes that have been implicated in hereditary prostate cancers do not appear to be mutated in sporadic cancers. Karyotypic and loss of heterozygosity analysis of sporadic prostate cancers have identified 8p, 10q, and 17p as the loci most often disrupted. Candidate oncogenes have been identified at each of these regions. Additional genes with pathogenic significance in prostate cancer have been identified by analysis of cDNA microarrays comparing benign and malignant prostate tissue, by differential genetic analysis of benign and malignant prostatic epithelium, and by induction of experimental prostate cancer in genetically engineered mice.

Adenocarcinoma↗
PubMed2001

Structure of TrwB, a gatekeeper in bacterial conjugation.

Bacterial conjugation implies a trans-membrane passage of DNA, mediated by proteins encoded in conjugative plasmids. This results in a spread of genetic information, including antibiotic resistance acquisition by pathogens. Special cases of conjugation are trans-kingdom gene transfer from bacteria to plants or fungi, and even bacterial sporulation and cell division. One of the main actors in this process is an integral inner membrane DNA-binding protein, called TrwB in the E. coli R388 conjugative system. It is responsible for coupling the single-strand DNA to be transferred from the donor to the acceptor cell in its complex with other proteins, with a type IV secretion system making up the mating apparatus. The TrwB protomer consists of two domains: a nucleotide-binding domain of alpha/beta topology, similar to RecA and DNA ring helicases, and an all-alpha domain. The quaternary structure reveals an almost spherical homohexamer, strikingly similar to F(1)-ATPase. A central 20 A wide channel traverses the hexamer, thus connecting cytoplasm with periplasm.

Bacterial Proteins↗
PubMed2002

ECaC: the gatekeeper of transepithelial Ca2+ transport.

The epithelial Ca(2+) channels (ECaCs) are primarily expressed in Ca(2+) transporting epithelia and represent a new family of Ca(2+) channels that belong to the superfamily of transient receptor potential (TRP) channels. Two members, namely ECaC1 and ECaC2, have been identified from kidney and intestine, respectively. These channels are the prime target for hormonal control of active Ca(2+) flux from the urine space or intestinal lumen to the blood compartment. This review covers the distinctive properties of these highly Ca(2+)-selective channels and highlights the implications for our understanding of the process of transepithelial Ca(2+) transport.

Animals↗
PubMed2000

The effects of peer review and evidence quality on judge evaluations of psychological science: are judges effective gatekeepers?

Scientifically trained and untrained judges read descriptions of an expert's research in which the peer review status and internal validity were manipulated. Seventeen percent of the judges said they would admit the expert evidence, irrespective of its internal validity. Publication in a peer-reviewed journal also had no effect on judges' decisions. Training interacted with the internal validity manipulation. Scientifically trained judges rated valid evidence more positively than did untrained judges. Untrained judges rated a study with a confound more positively than did trained judges. Training did not affect judge evaluations of studies with a missing control group or potential experimenter bias. Admissibility decisions were correlated with judges' perceptions of the study's validity, jurors' ability to evaluate scientific evidence, and the effectiveness of cross-examination and opposing experts to highlight flaws in scientific methodology.

Adult↗