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PubMed1996

The genetic and molecular dissection of a prototypic circadian system.

A great deal is known about this archetypal circadian system, and it is likely that Neurospora will represent the first circadian system in which it will be possible to provide a complete description of the flow of information from the photoreceptor, through the components of oscillator, out to a terminal aspect of regulation. In Neurospora the strongest case has been made for there being a state variable of clock identified (Hall, 1995), it has now been shown that light resetting of the clock is mediated by the rapid light induction of the gene encoding this state variable, and a number of defined clock-regulated output genes have been identified, in two of which the clock-specific parts of the promoters have been localized. In addition to the importance of these factoids themselves, our efforts towards understanding of this system has allowed the development of tools and paradigms (e.g. Loros et al., 1989; Loros and Dunlap, 1991; Aronson et al., 1994a) that will help to pave the way for proving the identity of clock components in more complex systems, for understanding how clocks are regulated by entraining factors, and for showing how time information eventually is used to regulate the behaviors of clock cells, and of whole organisms.

Animals↗
PubMed1998

Rhodopsin: a prototypical G protein-coupled receptor.

A variety of spectroscopic and biochemical studies of recombinant site-directed mutants of rhodopsin and related visual pigments have been reported over the past 9 years. These studies have elucidated key structural elements common to visual pigments. In addition, systematic analysis of the chromophore-binding pocket in rhodopsin and cone pigments has led to an improved understanding of the mechanism of the opsin shift, and of particular molecular determinants underlying color vision in humans. Identification of the conformational changes that occur on rhodopsin photoactivation has been of particular recent concern. Assignments of light-dependent molecular alterations to specific regions of the chromophore have also been attempted by studying native opsins regenerated with synthetic retinal analogs. Site-directed mutagenesis of rhodopsin has also provided useful information about the retinal-binding pocket and the molecular mechanism of rhodopsin photoactivation. Individual molecular groups have been identified to undergo structural alterations or environmental changes during photoactivation. Analysis of particular mutant pigments in which specific groups are locked into their respective "off" or "on" states has provided a framework to identify determinants of the active conformation, as well as the minimal number of intramolecular transitions required to switch between inactive and active conformations. A simple model for the active state of rhodopsin can be compared to structural models of its ground state to localize chromophore-protein interactions that may be important in the photoactivation mechanism. This review focuses on the recent functional characterization of site-directed mutants of bovine rhodopsin and some cone pigments. In addition, an attempt is made to reconcile previous key findings and existing structural models with information gained from the analysis of site-directed mutant pigments.

Amino Acid Sequence↗
PubMed2000

Evaluation of a chronic indwelling prototype mesh ureteral stent in a porcine model.

OBJECTIVES: Ureteral stents all share one general goal, drainage, and one major drawback, irritative symptoms in the kidney and bladder. In an effort to preserve drainage while minimizing irritation, a lightweight, self-expanding mesh stent was designed. Herein, we compare the in vivo tissue reaction and flow characteristics of the mesh stent to a standard 7F double-pigtail polyurethane stent. METHODS: Eight female Yucatan minipigs had bilateral stents placed: a mesh stent on one side and a standard 7F stent on the opposite side. Imaging and flow measurements were obtained in 4 pigs at 1 week and in another 4 pigs at 6 weeks. Following this procedure, the stents were removed, and the kidneys, ureters, and bladder were harvested en bloc for a blinded histopathologic analysis. RESULTS: The degree of stent-related tissue reactivity was low for both stents and appeared similar for the ureter and bladder. Overall, the mesh stent resulted in a decrease in inflammation along the urinary tract at 1 week, but this result was statistically insignificant (P = 0.55). Flow rate through the mesh stent tended to be greater than for the polyurethane stent both at 1 week and at 6 weeks. CONCLUSIONS: Overall, the mesh stent appeared to be well tolerated and provided for excellent flow.

Animals↗
PubMed2001

In vitro trial of the pilot prototype of the prostate mechanical imaging system.

OBJECTIVES: To compare the sensitivity and accuracy of the mechanical imaging system (MI system) to that of the simulated digital rectal examination (DRE) in detecting nodules within fabricated rubber prostate phantoms. Mechanical imaging is a new technology for visualizing and characterizing tissues using mechanical strain and stress data. METHODS: Twelve rubber phantoms were designed to simulate human prostates. Ten phantoms contained hard nodules in various locations. Two phantoms contained no nodules. Each model was examined with the MI system by a urologist (R.E.W.) and research student. Three-dimensional images of the examined prostate phantoms with and without nodules were generated by the MI system software. Blind DRE was performed on each phantom independently by the urologist and student. The results of the MI examinations and DREs were compared for sensitivity in detecting the presence and location of nodules within the prostate phantoms. RESULTS: Three-dimensional MI images reconstructed from both the student and the urologist examination data demonstrated 100% of the nodules in the appropriate locations. The DREs by the urologist detected 83% of the nodules in the appropriate locations. The DREs by the student detected 67% of the nodules in the appropriate locations. CONCLUSIONS: The prostate MI system allowed the detection of nodules in the prostate phantoms with sensitivity exceeding that of an experienced urologist. In contrast to the DRE, the results of the MI examination appear to be independent of the operator's experience. Therefore, the MI system is a promising means of accurate, sensitive, objective, and recordable detection of hard nodules within the prostate.

Diagnosis, Computer-Assisted↗
PubMed1995

Safety, immunogenicity, and efficacy of live attenuated Vibrio cholerae O139 vaccine prototype.

New vaccines are needed to prevent cholera caused by Vibrio cholerae O139. Attenuated V cholerae O139 vaccines were made by deleting multiple copies of the cholera-toxin genetic element from two virulent strains of the organism, MO10 and AI4456. The deletion mutants were further modified by insertion of a construct that encoded the B subunit of cholera toxin, thus generating strains Bengal-3 and VRI-16. A stable spontaneous non-motile derivative of Bengal-3 was isolated and designated Bengal-15; VRI-16 is naturally non-motile. Bengal-3, Bengal-15, and VRI-16 were evaluated as oral single-dose cholera vaccine candidates in 4 volunteers each, and MO10 was given to 3 volunteers. 1 of 4 volunteers who received Bengal-3 and all 3 who received MO10 had diarrhoea. VRI-16 caused no significant symptoms but was not immunogenic. Bengal-15 produced few symptoms and was nearly as immunogenic as MO10. Subsequently, Bengal-15 was given to 10 volunteers at a dose of 10(8) colony-forming units. No volunteers had diarrhoea, and other subjective symptoms were as common in vaccinees as in 3 buffer recipients. 1 month after vaccination, 7 vaccinees, the 3 buffer recipients, and 3 unimmunised subjects were challenged with 5 x 10(6) colony-forming units of V cholerae O139. 5 of 6 controls had cholera-like diarrhoea. By contrast, 1 of 7 vaccinees had diarrhoea, which was mild and had a long incubation period. Vaccine protective efficacy was 83%. Our results indicate the Bengal-15 is a safe live attenuated vaccine candidate for cholera caused by the O139 serogroup.

Administration, Oral↗
PubMed1993

A prototype erodible mask delivery system for the excimer laser.

PURPOSE: The authors developed an erodible mask delivery system for the argon-fluoride 193-nm excimer laser, which offers the possibility of correcting hyperopia and astigmatism as well as myopia. METHOD: Masks were made of polymethylmethacrylate on a quartz window, with intended corrections for myopia and hyperopia of 2.5 and 5 diopters (D). Ablations using the mask and control ablations using an expanding diaphragm were performed in 30 eyes of 15 pigmented rabbits with an Excimed UV200 laser (Summit Technology, Inc, Waltham, MA). The rabbits were followed for 134 days with regular biomicroscopy and retinoscopic examination by two observers. RESULTS: Ablations with the mask to correct myopia were successful and produced stable corrections, although the higher-power mask produced undercorrections. Hyperopic masks produced paradoxic myopic corrections, possibly due to the lack of a transition zone at the edge of the mask. Corneas ablated with the mask had less sub-epithelial haze than those ablated with the diaphragm at all examinations. Results of histopathologic examination showed epithelial hyperplasia over the ablation zone in all eyes. Dichlorotriazinyl aminofluorescein collagen staining showed subepithelial new collagen in all eyes, but there was no relation between the depth of ablation at any point on the cornea and the amount of new collagen deposited there. CONCLUSIONS: Myopic ablations are feasible with the erodible mask, although additional calibration is needed. Hyperopic ablations were unsuccessful with the current design. Corneas ablated with the mask may be clearer than corneas ablated with the diaphragm, possibly due to a smoother ablated surface. Regression of effect after laser ablation in the rabbit model is likely due more to epithelial hyperplasia than to stromal remodeling.

Animals↗
PubMed2002

Primary structure of a Japanese lacquer tree laccase as a prototype enzyme of multicopper oxidases.

The cDNA library of the Japanese lacquer tree (Rhus vernicifera) was constructed by the reverse transcription of mRNA. A cDNA encoding laccase was amplified by PCR using primers based on the N-terminal amino acid sequences of the purified laccase and its peptide fragments formed by digestions with chymotrypsin and trypsin, and subcloned. The laccase cDNA clone contained a single, large open reading frame of 1599 nucleotides, encoding a protein of 533 amino acids with a calculated molecular mass of 58981 Da. The lacquer laccase was found to have 42 to 62% identity with other plant laccases and 20 to 24% identity with microorganism laccases at the deduced amino acid level. Differing from microorganism laccases the lacquer laccase utilizes a Met residue in addition to one Cys and two His residues to construct the type 1 Cu site. The secondary structure of the lacquer laccase was predicted to mainly consist of the beta-structure (28.7%) and loop and random structures (67.0%). The alpha-helix content was predicted to be only 4.3%. The location of these secondary structures was assumed to be very similar to those of ascorbate oxidase and fungal laccase, the crystal structures of which have been determined.

Amino Acid Sequence↗
PubMed2001

Mechanism of tumor-targeted delivery of macromolecular drugs, including the EPR effect in solid tumor and clinical overview of the prototype polymeric drug SMANCS.

This review article describes three aspects of polymeric drugs. The general mechanism of the EPR (enhanced permeability and retention) effect and factors involved in the effect are discussed, in view of the advantages of macromolecular therapeutics for cancer treatment, which are based on the highly selective EPR-related delivery of drug to tumor. Also described are advantages of more general water-soluble polymeric drugs as primary anticancer agents, using SMANCS as an example. Last, SMANCS/Lipiodol is discussed with reference to the type of formulation for arterial injection with most pronounced tumor selective delivery, as well as its advantages, precautions, and side effects from the clinical standpoint.

Amino Acid Sequence↗
PubMed2000

Development of a poly(ortho ester) prototype with a latent acid in the polymer backbone for 5-fluorouracil delivery.

A study has been carried out to determine whether the latest family of poly(ortho esters) can be converted into a practical delivery system. This polymer differs from the previously described polymers in that it incorporates a short segment of a latent acid in the polymer backbone. The following issues were specifically addressed: (a) can the erosion and drug release be reproducibly controlled to yield the desired drug release kinetics and erosion rates? (b) Is the polymer stable during radiation sterilization, on storage and on fabrication? (c) Can the polymer be prepared reproducibly at the desired molecular weights and molecular weight distribution? (d) Is the polymer safe for its intended application and does the in vivo erosion proceed to completion? (e) Can the polymer be easily fabricated into desired configurations? Studies have shown that if the synthesis is carefully controlled, the desired molecular weights can be reproducibly prepared, that the polymer is reasonably stable after irradiation at 24 kGy and during storage at room temperature under anhydrous conditions, and that it can be safely thermally fabricated at temperatures in the neighborhood of 120 degrees C. When polymer devices were implanted intraperitoneally in rats the polymer eroded to completion without any overt toxicity as determined by the measured parameters.

Acids↗