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S Parrish

Publications and source records attributed to S Parrish.

12 recordsLinked to original sources
PubMed2001

On the role of RNA amplification in dsRNA-triggered gene silencing.

We have investigated the role of trigger RNA amplification during RNA interference (RNAi) in Caenorhabditis elegans. Analysis of small interfering RNAs (siRNAs) produced during RNAi in C. elegans revealed a substantial fraction that cannot derive directly from input dsRNA. Instead, a population of siRNAs (termed secondary siRNAs) appeared to derive from the action of a cellular RNA-directed RNA polymerase (RdRP) on mRNAs that are being targeted by the RNAi mechanism. The distribution of secondary siRNAs exhibited a distinct polarity (5'-->3' on the antisense strand), suggesting a cyclic amplification process in which RdRP is primed by existing siRNAs. This amplification mechanism substantially augments the potency of RNAi-based surveillance, while ensuring that the RNAi machinery will focus on expressed mRNAs.

Animals↗
PubMed2001

Specific inhibition of gene expression by small double-stranded RNAs in invertebrate and vertebrate systems.

Short interfering RNAs (siRNAs) are double-stranded RNAs of approximately 21-25 nucleotides that have been shown to function as key intermediaries in triggering sequence-specific RNA degradation during posttranscriptional gene silencing in plants and RNA interference in invertebrates. siRNAs have a characteristic structure, with 5'-phosphate/3'-hydroxyl ends and a 2-base 3' overhang on each strand of the duplex. In this study, we present data that synthetic siRNAs can induce gene-specific inhibition of expression in Caenorhabditis elegans and in cell lines from humans and mice. In each case, the interference by siRNAs was superior to the inhibition of gene expression mediated by single-stranded antisense oligonucleotides. The siRNAs seem to avoid the well documented nonspecific effects triggered by longer double-stranded RNAs in mammalian cells. These observations may open a path toward the use of siRNAs as a reverse genetic and therapeutic tool in mammalian cells.

Animals↗
PubMed2001

Genes and mechanisms related to RNA interference regulate expression of the small temporal RNAs that control C. elegans developmental timing.

RNAi is a gene-silencing phenomenon triggered by double-stranded (ds) RNA and involves the generation of 21 to 26 nt RNA segments that guide mRNA destruction. In Caenorhabditis elegans, lin-4 and let-7 encode small temporal RNAs (stRNAs) of 22 nt that regulate stage-specific development. Here we show that inactivation of genes related to RNAi pathway genes, a homolog of Drosophila Dicer (dcr-1), and two homologs of rde-1 (alg-1 and alg-2), cause heterochronic phenotypes similar to lin-4 and let-7 mutations. Further we show that dcr-1, alg-1, and alg-2 are necessary for the maturation and activity of the lin-4 and let-7 stRNAs. Our findings suggest that a common processing machinery generates guide RNAs that mediate both RNAi and endogenous gene regulation.

Animals↗
PubMed2001

Distinct roles for RDE-1 and RDE-4 during RNA interference in Caenorhabditis elegans.

RNA interference (RNAi) is a cellular defense mechanism that uses double-stranded RNA (dsRNA) as a sequence-specific trigger to guide the degradation of homologous single-stranded RNAs. RNAi is a multistep process involving several proteins and at least one type of RNA intermediate, a population of small 21-25 nt RNAs (called siRNAs) that are initially derived from cleavage of the dsRNA trigger. Genetic screens in Caenorhabditis elegans have identified numerous mutations that cause partial or complete loss of RNAi. In this work, we analyzed cleavage of injected dsRNA to produce the initial siRNA population in animals mutant for rde-1 and rde-4, two genes that are essential for RNAi but that are not required for organismal viability or fertility. Our results suggest distinct roles for RDE-1 and RDE-4 in the interference process. Although null mutants lacking rde-1 show no phenotypic response to dsRNA, the amount of siRNAs generated from an injected dsRNA trigger was comparable to that of wild-type. By contrast, mutations in rde-4 substantially reduced the population of siRNAs derived from an injected dsRNA trigger. Injection of chemically synthesized 24- or 25-nt siRNAs could circumvent RNAi resistance in rde-4 mutants, whereas no bypass was observed in rde-1 mutants. These results support a model in which RDE-4 is involved before or during production of siRNAs, whereas RDE-1 acts after the siRNAs have been formed.

Animals↗
PubMed2000

Functional anatomy of a dsRNA trigger: differential requirement for the two trigger strands in RNA interference.

In RNA-mediated interference (RNAi), externally provided mixtures of sense and antisense RNA trigger concerted degradation of homologous cellular RNAs. We show that RNAi requires duplex formation between the two trigger strands, that the duplex must include a region of identity between trigger and target RNAs, and that duplexes as short as 26 bp can trigger RNAi. Consistent with in vitro observations, a fraction of input dsRNA is converted in vivo to short segments of approximately 25 nt. Interference assays with modified dsRNAs indicate precise chemical requirements for both bases and backbone of the RNA trigger. Strikingly, certain modifications are well tolerated on the sense, but not the antisense, strand, indicating that the two trigger strands have distinct roles in the interference process.

Animals↗
PubMed1999

Medical practice and informatics tools: a vignette.

In this article the authors recreate an improvisational vignette originally presented at the Third Annual Information Connection in Burlington, Vermont, in January 1998. The vignette illustrates various state-of-the-art decision-support systems for clinical care and their promises and problems in real-world medical practice. The characters are Dr. Alex Grant, a rural physician in solo practice; Anna Everett, a patient suffering from chronic headaches; Bob, a hospital librarian; and Sarah, Dr. Grant's nurse. The short play centers on Dr. Grant's attempt to diagnose the cause of Anna's headaches (which he and she believe to be sinus-related) and the roles information technologies--Medline searching, Anna's own Internet searches, the use of MDConsult, which provides Internet access to standard medical texts, journals, etc., and a desktop decision-support tool called Problem Knowledge Couplers--play in this process. The vignette concludes with the realization that while computer technologies can be of great help in medicine "there is still a need for a good doctor to pull it all together."

Diagnosis, Computer-Assisted↗
PubMed1998

Administration of imiquimod, an interferon inducer, in asymptomatic human immunodeficiency virus-infected persons to determine safety and biologic response modification.

A phase I study to determine safety, maximum tolerated dose, and biologic response during multiple once-a-week administration of oral imiquimod, an immune response modifier, was conducted in 12 adults with early human immunodeficiency virus (HIV) infection. All completed the dose-escalation phase of weekly dosing at 100-mg increments and received at least one maintenance dose, 100 mg below the patient's toxic dose, for 12 weeks. Dose-limiting toxicity occurred in 3 patients at 200-mg, 5 at 300-mg, and 3 at 400-mg dose levels. One tolerated the 500-mg dose without dose-limiting toxicity. Dose-limiting toxicities included fatigue, fever, malaise, increased transaminases, hypotension, vomiting, and depression. Seven of 12 completed 12 weeks of maintenance. At > or = 200 mg of imiquimod, all patients had biologic responses, measured by elevations in serum interferon, beta2-microglobulin, and neopterin levels. Imiquimod induced pronounced levels of circulating interferon in asymptomatic HIV-infected persons, with variable effect on virus load.

Administration, Oral↗
PubMed1989

The contribution of the three columns of the spine to spinal stability: a biomechanical model.

UNLABELLED: The load carrying capacity (LCC) of the human spine was evaluated in 10 human cadaver spines. The specimens consisted of segments from T11 to S1 with markers placed on the specimens at each vertebral level in both Ap and lateral planes. The specimens were loaded to 1250 N and spinal deflections were recorded and photographed at 125 N intervals during the loading cycle. In 5 specimens, axial and flexion loads were applied to the intact spine. The anterior and middle columns were destroyed in sequence at L2 and the loading process repeated. In the remaining 5 specimens, axial and extension loads were applied with the spine intact and after the posterior and middle columns were destroyed in sequence at L2. Load deflection curves were generated for each test and comparisons were made between intact spines and spines with single and double column destruction. RESULTS: When the axis of loading was anterior to the posterior longitudinal ligament (PLL), destruction of the anterior and middle columns reduced the LCC by 46% and 68% respectively and destruction of the posterior and middle columns reduced the LCC by 30% and 63% respectively. There was minimal change in the LCC when the axis of loading was posterior to the PLL and the anterior and middle columns were destroyed. Two column destruction of the spine reduced its load carrying capacity for flexion loads by 70%. In thoracolumbar spinal fractures where flexion loads are predominant and anticipated, the authors conclude that surgical stabilisation is indicated with double column failure.

Humans↗
PubMed1980

Letting go.

Explore the source record for details and available documents.

Abortion, Spontaneous↗
PubMed1979

Dermatomal somatosensory evoked potentials in children with myelomeningocele.

Evoked responses were obtained from electrical stimulation of dermatomes representing individual lumbar and sacral roots. Normal ranges of latency have been established for adults, but have not been extended to children at this time. DSSEPs can be utilized, however, to sequentially follow lumbo-sacral cord function in individual children at risk of progressive myelopathy.

Adolescent↗