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Biomedical subjects

M A Shapiro

Publications and source records attributed to M A Shapiro.

At least 19 recordsLinked to original sources
PubMed2006

Spatial dispersion in metamaterials with negative dielectric permittivity and its effect on surface waves.

The effect of spatial dispersion on the electromagnetic properties of a metamaterial consisting of a three-dimensional mesh of crossing metallic wires is reported. The effective dielectric permittivity tensor epsilon(ij)(omega, k) of the wire mesh is calculated in the limit of small wavenumbers. The procedure for extracting the spatial dispersion from the omega versus k dependence for electromagnetic waves propagating in the bulk of the metamaterial is developed. These propagating modes are identified as similar to the longitudinal (plasmon) and transverse (photon) waves in a plasma. Spatial dispersion is found to have the most dramatic effect on the surface waves that exist at the wire mesh-vacuum interface.

Journal Article↗
PubMed2003

High-power 140-GHz quasioptical gyrotron traveling-wave amplifier.

We present the design and experimental results of a novel quasioptical gyrotron traveling-wave tube (gyro-TWT) amplifier at 140 GHz. The gyro-TWT produced up to 30 kW of peak power in 2 micros pulsed operation at 6 Hz achieving a peak gain of 29 dB, a peak efficiency of 12%, and a bandwidth of 2.3 GHz. The device was operated in a very higher-order mode of an open quasioptical interaction structure, namely, a confocal waveguide. The diffraction loss from the open sidewalls of the confocal waveguide was used to suppress mode competition in this highly overmoded circuit resulting in a stable single-mode operation. The experiment achieved record high power levels at 140 GHz for a gyro-TWT. These experiments demonstrate the effectiveness of using overmoded quasioptical waveguide interaction structures for generating high power in the millimeter and submillimeter wave bands with a gyro-TWT.

Journal Article↗
PubMed2001

Photonic-band-gap resonator gyrotron.

We report the design and experimental demonstration of a gyrotron oscillator using a photonic-band-gap (PBG) structure to eliminate mode competition in a highly overmoded resonator. The PBG cavity supports a TE(041)-like mode at 140 GHz and is designed to have no competing modes over a minimum frequency range delta omega/omega of 30% about the design mode. Experimental operation of a PBG gyrotron at 68 kV and 5 A produced 25 kW of peak power in the design mode. No other modes were observed over the full predicted operating range about the design mode. PBG cavities show great promise for applications in vacuum electron devices in the millimeter- and submillimeter-wave bands.

Journal Article↗
PubMed2000

Characterization of the B lymphocyte-induced maturation protein-1 (Blimp-1) gene, mRNA isoforms and basal promoter.

Blimp-1 is a transcriptional repressor that is both required and sufficient to trigger terminal differentiation of B lymphocytes and monocyte/macrophages. Here we report the organization of the mouse Blimp-1 gene, an analysis of Blimp-1 homologs in different species, the characterization of Blimp-1 mRNA isoforms and initial studies on the transcription of Blimp-1. The murine Blimp-1 gene covers approximately 23 kb and contains eight exons. There are Blimp-1 homologs in species evolutionarily distant from mouse (Caenorhabditis elegans and Drosophila melanogaster) but no homolog was found in the unicellular yeast Saccharomyces cerevisiae. The three major Blimp-1 mRNA isoforms result from the use of different polyadenylation sites and do not encode different proteins. Run-on transcription analyses were used to show that the developmentally regulated expression of Blimp-1 mRNA in B cells is determined by transcription initiation. Multiple Blimp-1 transcription initiates sites were mapped near an initiator element and a region conferring basal promoter activity has been identified.

Alternative Splicing↗
PubMed2000

Novel nonpeptidic inhibitors of peptide deformylase.

A novel series of nonpeptidic compounds structurally related to the known anticholesteremic thyropropic acid were found to inhibit Escherichia coli peptide deformylase (PDF), with IC50 values in the low-micromolar range. Kinetic analysis of [4-(4-hydroxyphenoxy)-3,5-diiodophenyl]acetic acid reveals competitive inhibition, with a Ki value of 0.66 +/- 0.007 microM. A structure-activity relationship study demonstrates that the carboxylate is required for activity, while the distal phenolic function can be methylated without significant effect. Either decreasing the number of iodine atoms on the molecule to one or increasing the number of iodine atoms to four results in the loss of an order of magnitude in potency. These compounds are the first nonpeptidic inhibitors disclosed and represent a template from which better inhibitors might be designed.

Amidohydrolases↗
PubMed2000

Inhibition of tetanus toxin fragment C binding to ganglioside G(T1b) by monoclonal antibodies recognizing different epitopes.

Anti-tetanus toxoid monoclonal antibodies would be useful in exploring the relationship of tetanus toxin structure to its function. Tetanus toxin fragment C has been shown to be responsible for binding to neurons via gangliosides. Eleven new and two previously derived monoclonal antibodies specific for tetanus toxin fragment C were shown to recognize five different fragment C epitopes, two of which were overlapping. Three of these epitopes participate in the binding to ganglioside G(T1b). One epitope was defined by a monoclonal antibody that did not inhibit the interaction between fragment C and ganglioside. This antibody however, was blocked from binding to fragment C by antibodies that were able to inhibit the fragment C-ganglioside interaction.

Animals↗
PubMed2000

Underutilization of the V kappa 10C gene in the B cell repertoire is due to the loss of productive VJ rearrangements during B cell development.

The V kappa10 family of murine light chain Ig genes is composed of three members, two of which (V kappa 10A and V kappa 10B) are well used. V kappa 10C, the third member of this family, is not detected in any expressed Abs. Our previous work showed that V kappa 10C is structurally functional and can recombine, but mRNA levels in spleen were extremely low relative to those of V kappa 10A and V kappa 10B. Furthermore, while the V kappa 10C promoter was efficient in B cells, it was shown to work inefficiently in pre-B cell lines. Here, we extend our analysis of the V kappa 10 family and examine V kappa 10 gene accessibility, their representation in V kappa cDNA phage libraries, and the frequency and nature of rearrangements during different stages of B cell development. We demonstrate that V kappa 10C is under-represented in V kappa cDNA libraries, but that the frequency of its sterile transcripts in pre-B cells surpasses both V kappa 10A and V kappa 10B, indicating that the gene is as accessible as V kappa 10A and V kappa 10B to the recombination machinery. We also demonstrate that V kappa 10C recombines at a frequency equal to that of V kappa 10A in pre-B cells and has a normal nonproductive to productive recombination ratio. As B cells develop, however, both the frequency of V kappa 10C rearrangements and the presence of productive rearrangements decline, indicating that these cells are in some fashion being eliminated.

Animals↗
PubMed2000

A novel activation induced lymphocyte surface antigen, 90.12, is also expressed on apoptotic cells.

We describe a monoclonal antibody, mAb 90.12, which recognizes a novel activation induced lymphocyte surface antigen. Flow cytometric analysis of normal tissues shows the antigen to be expressed on higher percentages of B lymphocytes in the bone marrow than in the spleen and the lymph node. Similarly, the 90.12 antigen is expressed on higher percentages of thymocytes than peripheral T cells. MAb 90. 12 immunoprecipitates three proteins with a molecular weight of 12-18 kDa which are not linked to the membrane by phosphotidylinositol. Expression of the 90.12 antigen is increased on activated B cells and the extent of upregulation varies with the stimulus. Lipopolysaccharide (LPS) stimulation results in expression on most B cells, while expression is upregulated on only a subset of B cells stimulated with anti-immunoglobulin M (IgM), interleukin(IL)4 and IL5. Finally, we show that 90.12 antigen expression is also increased on apoptotic cells.

Animals↗
PubMed2000

Comparative therapeutic efficacy of clinafloxacin in a pneumococcal meningitis mouse model.

The therapeutic efficacy of clinafloxacin, a fluoroquinolone in clinical trials, was compared with that of ciprofloxacin and ceftriaxone in a novel pneumococcal meningitis mouse model. Mice were challenged by the intracerebral ventricular route with 50 IL of a lethal bacterial suspension and treated subcutaneously 2 h later. Both penicillin-susceptible and multidrug-resistant pneumococcal strains were used for evaluation. Survival percentages were calculated as the median curative dose (CD50) using log-probit statistical methods. Ceftriaxone was the most active agent against the penicillin-susceptible strain (CD50 = 2 mg/kg), but showed a 30-fold decrease in potency against the resistant strain. Clinafloxacin was equally effective against both strains, and proved to be the most active agent against the penicillin-resistant pneumococcus.

Animals↗
PubMed1999

Characterization of a B cell surface antigen with homology to the S100 protein MRP8.

The S100 proteins comprise a large sub-family of the EF-hand calcium-binding proteins. Here we describe a novel monoclonal antibody recognizing a B cell surface antigen. This monoclonal antibody immunoprecipitates three proteins in the 12-18 kDa range and the smallest of these proteins has a striking homology at its amino-terminus to human MRP8, a myeloid specific member of the S100 family. Similarly to MRP8 in myeloid cells, this antigen is expressed in the cytoplasm of B cells and is secreted by LPS-induced activated B cells. This surface antigen is not B cell specific. Since MRP8 is not expressed by lymphoid cells, however, this antibody appears to recognize a new member of the S100 family.

Amino Acid Sequence↗
PubMed1999

Pharmacokinetics of clinafloxacin enantiomers in humans.

The pharmacokinetics of R-clinafloxacin and S-clinafloxacin enantiomers of the broad-spectrum fluoroquinolone antibiotic, clinafloxacin, were characterized in selected volunteer subjects and patients after the administration of oral and intravenous doses of racemic drug. The absorption of each enantiomer was rapid and nearly complete after a single, oral 400 mg racemic dose. The mean (+/- SD) bioavailability of R-clinafloxacin was 87.5% +/- 4.8% compared to 86.2% +/- 5.8% for S-clinafloxacin. The mean Cmax of each enantiomer was 1.19 micrograms/mL, with plasma concentrations of each enantiomer remaining above 0.1 microgram/mL for at least 12 hours. No notable differences in the disposition of R-clinafloxacin and S-clinafloxacin were observed. After a single 400 mg intravenous dose of racemic drug, mean (+/- SD) t1/2 was 5.6 +/- 0.3 hours and 5.7 +/- 0.4 hours, plasma Cl was 329 +/- 49 mL/min and 314 +/- 45 mL/min, and Vdss was 138 +/- 18 L and 134 +/- 16 L for R- and S-clinafloxacin, respectively. Two healthy volunteers each received a single 400 mg oral dose of racemic clinafloxacin (alone) and with oral administration of 1 gm probenecid separated by a 1-week washout period between treatments. With probenecid coadministration, the increase in AUC0-infinity was 75% and 83% for R-clinafloxacin and was 71% and 75% for S-clinafloxacin in each subject, respectively. Probenecid increased the total exposure (AUC) of both R-clinafloxacin and S-clinafloxacin, although it had no stereo-selective effects on the disposition of either enantiomer. The antimicrobial potency of the isomers was also evaluated. In vitro susceptibility testing showed that the two compounds were comparable in their inhibitory activities, as all MICs were within twofold for each organism tested. These results demonstrate that in addition to their similar antimicrobial potency, R- and S-clinafloxacin have nearly identical disposition characteristics and are eliminated by similar mechanisms that display no apparent enantioselectivity in man.

Adult↗
PubMed1998

Broad spectrum antimicrobial biocides target the FabI component of fatty acid synthesis.

The broad spectrum antibacterial properties of 2-hydroxydiphenyl ethers have been appreciated for decades, and their use in consumer products is rapidly increasing. We identify the enoyl-acyl carrier protein reductase (fabI) component of the type II fatty acid synthase system as the specific cellular target for these antibacterials. Biologically active 2-hydroxydiphenyl ethers effectively inhibit fatty acid synthesis in vivo and FabI activity in vitro. Resistant mechanisms include up-regulation of fabI expression and spontaneously arising missense mutations in the fabI gene. These results contradict the view that these compounds directly disrupt membranes and suggest that their widespread use will select for resistant bacterial populations.

Animals↗
PubMed1998

Asymmetric contribution to Ig repertoire diversity by V kappa exons: differences in the utilization of V kappa 10 exons.

The mouse has approximately 140 germline V kappa genes, and functional V kappa exons are expressed at roughly equivalent levels in the preimmune repertoire. We have examined the expression of individual members of the V kappa 10 family. V kappa 10A and V kappa 10B genes have been utilized in numerous hybridomas and myelomas, while V kappa 10C has not. In this study, we have cloned the V kappa 10C gene and shown that it is structurally functional, has the expected promoter elements and recombination signal sequences, and that it is capable of recombination. V kappa 10C mRNA, however, is present at levels at least 1000-fold lower than V kappa 10A and V kappa 10B in adult spleens. While there are no sequence differences in the octamer or TATA box between V kappa 10C and V kappa 10A, there are three nucleotide changes in the promoter region. These promoters equally drive the expression of a reporter gene in B cells or plasma cells, but the V kappa 10A promoter is able to drive expression in pre-B cell lines significantly better than the V kappa 10C promoter (p < 0.05). V kappa 10C rearrangements can be detected in bone marrow and splenic DNA. Therefore, the lack of V kappa 10C expression may reflect the inability of V kappa 10C-rearranged cells to undergo positive or negative selection. Our results suggest that the available Ab repertoire is shaped not only by the number of structurally functional genes, but also by the ability of assembled genes to be expressed at critical points during B cell maturation.

Amino Acid Sequence↗
PubMed1998

Comparative therapeutic efficacy of clinafloxacin in a Pseudomonas aeruginosa mouse renal abscess model.

A deep-seated Pseudomonas aeruginosa mouse kidney abscess model was used to compare the therapeutic efficacy of clinafloxacin, a fluoroquinolone in clinical trials, with that of clinically relevant standard drugs. Following 50 mg/kg oral doses, twice daily for five consecutive days, clinafloxacin produced a 4 log decrease in mean bacterial count, the greatest decrease of all drugs tested. The same dosage regimen resulted in complete bacterial eradication in 88% of the kidneys. No other compound produced total bacterial clearance in 50% of the kidneys at the highest dose tested.

Abscess↗
PubMed1998

Diagnostic criteria for fatty infiltration of the liver on contrast-enhanced helical CT.

OBJECTIVE: The purpose of the study was to develop quantitative and qualitative criteria for diagnosing fatty liver on contrast-enhanced helical CT. SUBJECTS AND METHODS: Differential liver-spleen attenuation was evaluated between 80 and 120 sec after injection in 76 patients who underwent contrast-enhanced helical CT. Unenhanced CT images had earlier established fatty liver when the liver minus spleen attenuation difference was less than or equal to -10 H (n = 18). Four observers who had not seen the unenhanced images used contrast-enhanced CT images to assess the presence of fatty liver on a five-point Likert scale, the presence of geographic areas spared from fatty infiltration, and the relative liver-spleen attenuation. The diagnostic accuracies of various imaging criteria were compared using McNemar's chi-square test (for sensitivity and specificity) and analysis of receiver operating characteristic curves. RESULTS: Sensitivity, specificity, and receiver operating characteristic curve areas for observers' qualitative judgments were 54%, 95%, and .91, respectively; for quantitative differential liver-spleen attenuation (80-100 sec; -20.5 H discriminatory value), the values were 86%, 87%, and .94, respectively; and for quantitative differential liver-spleen attenuation (101-120 sec; -18.5 H discriminatory value), the values were 93%, 93%, and .98, respectively. Differential liver-spleen attenuation was time-dependent; overlap was noted between healthy subjects and patients with fatty liver. Qualitatively, geographic sparing was highly specific (94%) for fatty liver, whereas liver attenuation greater than or equal to spleen attenuation excluded fatty liver in all but one case. CONCLUSION: Although quantitative and qualitative criteria for diagnosing fatty liver on helical CT can be determined, they are protocol-specific. Limited unenhanced hepatic CT remains the optimal technique for detection of fatty infiltration of the liver.

Contrast Media↗
PubMed1998

Sonography of patellar abnormalities in children.

OBJECTIVE: We describe our experience using sonography to evaluate the patella and patellofemoral joint in three children with congenital abnormalities of the extensor mechanism of the lower extremity. CONCLUSION: Sonography can be used to evaluate the extensor mechanism and unossified patella in young children. Advantages of sonography over MR imaging are no need for sedation, speed of examination and ability to compare with the contralateral knee, low cost, and the sonographer's ability to dynamically evaluate the extensor mechanism.

Child, Preschool↗
PubMed1997

Molecular evolution of two vertebrate aryl hydrocarbon (dioxin) receptors (AHR1 and AHR2) and the PAS family.

The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor through which halogenated aromatic hydrocarbons such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) cause altered gene expression and toxicity. The AHR belongs to the basic helix-loop-helix/Per-ARNT-Sim (bHLH-PAS) family of transcriptional regulatory proteins, whose members play key roles in development, circadian rhythmicity, and environmental homeostasis; however, the normal cellular function of the AHR is not yet known. As part of a phylogenetic approach to understanding the function and evolutionary origin of the AHR, we sequenced the PAS homology domain of AHRs from several species of early vertebrates and performed phylogenetic analyses of these AHR amino acid sequences in relation to mammalian AHRs and 24 other members of the PAS family. AHR sequences were identified in a teleost (the killifish Fundulus heteroclitus), two elasmobranch species (the skate Raja erinacea and the dogfish Mustelus canis), and a jawless fish (the lamprey Petromyzon marinus). Two putative AHR genes, designated AHR1 and AHR2, were found both in Fundulus and Mustelus. Phylogenetic analyses indicate that the AHR2 genes in these two species are orthologous, suggesting that an AHR gene duplication occurred early in vertebrate evolution and that multiple AHR genes may be present in other vertebrates. Database searches and phylogenetic analyses identified four putative PAS proteins in the nematode Caenorhabditis elegans, including possible AHR and ARNT homologs. Phylogenetic analysis of the PAS gene family reveals distinct clades containing both invertebrate and vertebrate PAS family members; the latter include paralogous sequences that we propose have arisen by gene duplication early in vertebrate evolution. Overall, our analyses indicate that the AHR is a phylogenetically ancient protein present in all living vertebrate groups (with a possible invertebrate homolog), thus providing an evolutionary perspective to the study of dioxin toxicity and AHR function.

Amino Acid Sequence↗