Measurement of Dielectric Multipactor Thresholds at 110 GHz.

We report experimental measurements of the threshold for multipactor discharges on dielectric surfaces at 110 GHz. Multipactor was studied in two geometries: electric field polarized parallel to or perpendicular to the sample surface. Measured multipactor thresholds ranged from 15 to 34 MV/m, more than 10 times higher than those found at conventional microwave frequencies. Measured thresholds were compared with prior data at lower frequencies, showing agreement with theoretical predictions that thresholds increase linearly with frequency. Measurements of the rf power dissipated in the multipactor show low dissipation (≤1%) for the parallel electric field case, but very strong dissipation for the perpendicular case, also in agreement with theoretical predictions. The agreement between experiment and theory over a wide range of frequencies provides a strong basis for the understanding of dielectric multipactor discharges.

Subterahertz Photonic Crystal Klystron Amplifier.

This Letter reports the successful experimental demonstration of amplification of subterahertz radiation in a klystron with photonic crystal cavities. The klystron has six cavities, with each cavity having a series of oversized photonic crystal cells made up of a 5×3 array of square posts. The center post is removed from each cell to form a highly oversized (0.8 mm∼λ/4) beam tunnel, with power coupling from cell to cell through the tunnel. The pulsed electron beam is operated at 23.5 kV, 330 mA in a 0.5 T solenoidal field. At 93.7 GHz, a small-signal gain of 26 dB and a saturated output power of 30 W are obtained. Experimental results are in very good agreement with the predictions of a particle-in-cell code. The successful achievement of high gain operation of a photonic crystal klystron amplifier is promising for the future extension of klystron operation well into the terahertz frequency region.

[Proteomic analysis of contaminants in recombinant membrane hemeproteins expressed in E. coli and isolated by metal affinity chromatography].

Contaminating proteins have been identified by "shotgun" proteomic analysis in 14 recombinant preparations of human membrane heme- and flavoproteins expressed in Escherichia coli and purified by immobilized metal ion affinity chromatography. Immobilized metal ion affinity chromatography of ten proteins was performed on Ni2+-NTA-sepharose 6B, and the remaining four proteins were purified by ligand affinity chromatography on 2',5'-ADP-sepharose 4B. Proteomic analysis allowed to detect 50 protein impurities from E. coli. The most common contaminant was Elongation factor Tu2. It is characterized by a large dipole moment and a cluster arrangement of acidic amino acid residues that mediate the specific interaction with the sorbent. Peptidyl prolyl-cis-trans isomerase SlyD, glutamine-fructose-6-phosphate aminotransferase, and catalase HPII that contained repeating HxH, QxQ, and RxR fragments capable of specific interaction with the sorbent were identified among the protein contaminants as well. GroL/GroS chaperonins were probably copurified due to the formation of complexes with the target proteins. The Ni2+ cations leakage from the sorbent during lead to formation of free carboxyl groups that is the reason of cation exchanger properties of the sorbent. This was the putative reason for the copurification of basic proteins, such as the ribosomal proteins of E. coli and the widely occurring uncharacterized protein YqjD. The results of the analysis revealed variation in the contaminant composition related to the type of protein expressed. This is probably related to the reaction of E. coli cell proteome to the expression of a foreign protein. We concluded that the nature of the protein contaminants in a preparation of a recombinant protein purified by immobilized metal ion affinity chromatography on a certain sorbent could be predicted if information on the host cell proteome were available.

Coherent Cherenkov-Cyclotron Radiation Excited by an Electron Beam in a Metamaterial Waveguide.

An electron beam passing through a metamaterial structure is predicted to generate reversed Cherenkov radiation, an unusual and potentially very useful property. We present an experimental test of this phenomenon using an intense electron beam passing through a metamaterial loaded waveguide. Power levels of up to 5 MW are observed in backward wave modes at a frequency of 2.40 GHz using a one microsecond pulsed electron beam of 490 keV, 84 A in a 400 G magnetic field. Contrary to expectations, the output power is not generated in the Cherenkov mode. Instead, the presence of the magnetic field, which is required to transport the electron beam, induces a Cherenkov-cyclotron (or anomalous Doppler) instability at a frequency equal to the Cherenkov frequency minus the cyclotron frequency. Nonlinear simulations indicate that the Cherenkov-cyclotron mode should dominate over the Cherenkov instability at a lower magnetic field where the highest output power is obtained.

Photonic-band-gap traveling-wave gyrotron amplifier.

We report the experimental demonstration of a gyrotron traveling-wave-tube amplifier at 250 GHz that uses a photonic band gap (PBG) interaction circuit. The gyrotron amplifier achieved a peak small signal gain of 38 dB and 45 W output power at 247.7 GHz with an instantaneous -3 dB bandwidth of 0.4 GHz. The amplifier can be tuned for operation from 245-256 GHz. The widest instantaneous -3 dB bandwidth of 4.5 GHz centered at 253.25 GHz was observed with a gain of 24 dB. The PBG circuit provides stability from oscillations by supporting the propagation of transverse electric (TE) modes in a narrow range of frequencies, allowing for the confinement of the operating TE03-like mode while rejecting the excitation of oscillations at nearby frequencies. This experiment achieved the highest frequency of operation for a gyrotron amplifier; at present, there are no other amplifiers in this frequency range that are capable of producing either high gain or high output power. This result represents the highest gain observed above 94 GHz and the highest output power achieved above 140 GHz by any conventional-voltage vacuum electron device based amplifier.

Study of the Effect of Reflections on High-Power, 110 GHz Pulsed Gyrotron Operation.

The effect of reflection is studied experimentally and theoretically on a high-power 110 GHz gyrotron operating in the TE22,6 mode in 3 µs pulses at 96 kV, 40 A. The experimental setup allows variation of the reflected power from 0 to 33 % over a range of gyrotron operating conditions. The phase of the reflection is varied by translating the reflector along the axis. Operating at a higher efficiency point, at 4:40 T with 940 kW of output power, reflected power exceeding 11% causes a switch from operation in the TE22,6 to simultaneous operation in the TE22,6 and TE21,6 modes with a large decrease of the total gyrotron output power. This switching effect is in good agreement with simulations using the MAGY code. Operating at a more stable point, 4:44 T with 580 kW of output power, when the reflection is increased, the output power remains in the TE22,6 mode but it decreases monotonically with increasing reflection, dropping to 200 kW at 33% reflection. Furthermore, at a reflection above 22%, a power modulation at 25 to 30 MHz is observed, independent of the phase of the reflected wave. Such a modulated signal may be useful in spectroscopic and other applications.

Correction to: Study of the Effect of Reflections on High-Power, 110-GHz Pulsed Gyrotron Operation.

[This corrects the article PMC8291730.].

Amplification of picosecond pulses in a 140-GHz gyrotron-traveling wave tube.

An experimental study of picosecond pulse amplification in a gyrotron-traveling wave tube (gyro-TWT) has been carried out. The gyro-TWT operates with 30 dB of small signal gain near 140 GHz in the HE06 mode of a confocal waveguide. Picosecond pulses show broadening and transit time delay due to two distinct effects: the frequency dependence of the group velocity near cutoff and gain narrowing by the finite gain bandwidth of 1.2 GHz. Experimental results taken over a wide range of parameters show good agreement with a theoretical model in the small signal gain regime. These results show that in order to limit the pulse broadening effect in gyrotron amplifiers, it is crucial to both choose an operating frequency at least several percent above the cutoff of the waveguide circuit and operate at the center of the gain spectrum with sufficient gain bandwidth.

A complex translocation at the murine kappa light-chain locus.

We have previously reported that a segment of DNA from a murine plasmacytoma comprises DNA from three chromosomes, the immunoglobulin kappa light-chain locus on chromosome 6, the S mu locus on chromosome 12, and a region on chromosome 15. We now report that the reciprocal product contains DNA from only the kappa locus and chromosome 15 and not from S mu. We conclude that a complex series of events, including both a transposition of DNA and a translocation between chromosomes, generated these imperfect reciprocal products.

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.

Simple Expressions for the Design of Linear Tapers in Overmoded Corrugated Waveguides.

Simple analytical formulae are presented for the design of linear tapers with very low mode conversion loss in overmoded corrugated waveguides. For tapers from waveguide radius a2 to a1, with a1 < a2, the optimal length of the taper is 3.198a1a2/λ. Here, λ is the wavelength of radiation. The fractional loss of the HE11 mode in an optimized taper is [Formula: see text]. These formulae are accurate when a2 ≲ 2a1. Slightly more complex formulae, accurate for a2 ≤ 4a1, are also presented in this paper. The loss in an overmoded corrugated linear taper is less than 1 % when a2 ≤ 2.12a1 and less than 0.1 % when a2 ≤ 1.53a1. The present analytic results have been benchmarked against a rigorous mode matching code and have been found to be very accurate. The results for linear tapers are compared with the analogous expressions for parabolic tapers. Parabolic tapers may provide lower loss, but linear tapers with moderate values of a2/a1 may be attractive because of their simplicity of fabrication.

The synthesis, structure-activity, and structure-side effect relationships of a series of 8-alkoxy- and 5-amino-8-alkoxyquinolone antibacterial agents.

A series of 1-cyclopropyl-6-fluoro-8-alkoxy (8-methyoxy and 8-ethoxy)-quionoline-3-carboxylic acids and 1-cyclopropyl-5-amino-6-fluoro-8-alkoxyquinoline-3-carboxylic acids has been prepared and evaluated for antibacterial activity. In addition, they were also compared to quinolones with classic substitution at C8 (H, F, Cl) and the naphthyridine nucleus in a phototoxicity and mammalian cell cytotoxicity assay. The series of 8-methoxyquinolones had antibacterial activity against Gram-positive, Gram-negative, and anaerobic bacteria equivalent to the most active 8-substituted compounds (8-F and 8-Cl). There was also a concomitant reduction in several of the potential side effects (i.e., phototoxicity and clonogenicity) compared to the most active quinolones with classic substitution at C-8. The 8-ethoxy derivatives had an even better safety profile but were significantly less active (2-3 dilutions) in the antibacterial assay.

Structure-activity relationships of the quinolone antibacterials against mycobacteria: effect of structural changes at N-1 and C-7.

The re-emergence of tuberculosis infections which are resistant to conventional drug therapy has demonstrated the need for alternative chemotherapy against Mycobacterium tuberculosis. As part of a study to optimize the quinolone antibacterials against M. tuberculosis, we have prepared a series of N-1- and C-7-substituted quinolones to examine specific structure-activity relationships between modifications of the quinolone at these two positions and activity against mycobacteria. The compounds, synthesized by literature procedures, were evaluated for activity against Mycobacterium fortuitum and Mycobacterium smegmatis as well as Gram-negative and Gram-positive bacteria. The activity of the compounds against M. fortuitum was used as a barometer of M. tuberculosis activity. The results demonstrate that (i) the activity against mycobacteria was related more to antibacterial activity than to changes in the lipophilicity of the compounds, (ii) the antimycobacterial activity imparted by the N-1 substituent was in the order tert-butyl > or = cyclopropyl > 2,4-difluorophenyl > ethyl approximately cyclobutyl > isopropyl, and (iii) substitution with either piperazine or pyrrolidine heterocycles at C-7 afforded similar activity against mycobacteria.

Effect of lipophilicity at N-1 on activity of fluoroquinolones against mycobacteria.

The dramatic increase in drug resistant Mycobacterium tuberculosis has caused a resurgence in research targeted toward these organisms. As part of a systematic study to optimize the quinolone antibacterials against mycobacteria, we have prepared a series of N-1-phenyl-substituted derivatives to explore the effect of increasing lipophilicity on potency at this position. The compounds, synthesized by the modification of a literature procedure, were evaluated for activity against Gram-negative and Gram-positive bacteria, Mycobacterium fortuitum and Mycobacterium smegmatis, and the results correlated with log P, pKa, and other attributes. The activity of the compounds against the rapidly growing, less hazardous organism M. fortuitum was used as a measure of M. tuberculosis activity. The results demonstrate that increasing lipophilic character by itself does not correlate with increased potency against mycobacteria. Rather, intrinsic activity against Gram-negative and/or Gram-positive bacteria is the governing factor for corresponding activity against mycobacteria.

Quinolone antibacterials containing the new 7-[3-(1-aminoethyl)-1- pyrrolidinyl] side chain: the effects of the 1-aminoethyl moiety and its stereochemical configurations on potency and in vivo efficacy.

A series of stereochemically pure 7-[3-(1-aminoethyl)-1-pyrrolidinyl]-1, 4-dihydro-4-oxoquinoline and 1,8-naphthyridine-3-carboxylic acids, with varied substituents at the 1-, 5-, and 8-positions, were synthesized to study the effects of the 7-[3-(1-aminoethyl)-1- pyrrolidinyl] moiety on potency and in vivo efficacy relative to the known 7-[3-(aminomethyl)-1- pyrrolidinyl] derivatives. The antibacterial efficacies of the target compounds and their relevant reference agents were determined in vitro using an assortment of Gram-negative and Gram-positive organisms and in vivo using Escherichia coli and Streptococcus pyogenes mouse infection models. The effects of the 7-[3-(1-aminoethyl)-1-pyrrolidinyl] moiety were also examined at the level of the target enzyme by employing a DNA-gyrase supercoiling inhibition assay. Selected compounds were further evaluated for potential phototoxic and clastogenic liabilities using a phototoxicity mouse model and an in vitro mammalian cell cytotoxicity assay. It was found that the differences in in vitro antibacterial activity between the stereoisomers were significantly greater than previously reported for other optically pure 3-substituted pyrrolidinyl side chains. Relative to their 7-[3-(aminomethyl)-1-pyrrolidinyl] analogs, the (3R,1S)-3-(1-aminoethyl)pyrrolidines generally conferred a 2-4-fold increase in Gram-positive in vitro activity and an average of 10-fold improvement in oral efficacy. The level of phototoxicity and cytotoxicity of the product quinolones was ultimately determined by the combined influence of the 7-[3-(1-aminoethyl)-1-pyrrolidinyl] side chains and the other quinolone substituents. From this study, several compounds were identified with outstanding antibacterial activity and low degrees of phototoxicity and mammalian cell cytotoxicity. One such agent, 34F-R,S (PD 140248), showed the best overall blend of safety and efficacy.

New 8-(trifluoromethyl)-substituted quinolones. The benefits of the 8-fluoro group with reduced phototoxic risk.

A series of 8-(trifluoromethyl)-substituted quinolones has been prepared and evaluated for in vitro and in vivo antibacterial activity, and phototolerance in a mouse phototolerance assay. These analogues were compared to the corresponding series of 6,8-difluoro- and 6-fluoro-8H-quinolones (ciprofloxacin type). Although their in vitro antibacterial activities are less than the 6,8-difluoro analogues, the 8-(trifluoromethyl)quinolones are generally equivalent to their 8H analogues. In vivo, they are comparable to the 6,8-difluoro series and show up to 10-fold improvement in efficacy when compared to their ciprofloxacin counterparts vs Streptococcus pyogenes and Streptococcus pneumonia. In the phototolerance model, the 8-(trifluoromethyl)quinolones are comparable to the 8H-quinolones. Both of these series display much higher no effect doses (greater tolerance) than the corresponding 6,8-difluoroquinolones.

In vitro evaluation of cefdinir (FK482), a new oral cephalosporin with enhanced antistaphylococcal activity and beta-lactamase stability.

Cefdinir (FK482), a new oral cephalosporin with enhanced beta-lactamase stability, was tested by microbroth dilution against respiratory, urogenital, and skin and skin-structure bacterial pathogens. Included were beta-lactamase (beta LAC)-producing and -nonproducing isolates. Activity was compared with that of other orally administered beta-lactams. Cefdinir minimum inhibitory concentrations for 90% of isolates MIC90s (microgram/ml) were < or = 0.5 versus beta LAC+/oxacillin-susceptible Staphylococcus, aureus, S. epidermidis, and S. saprophyticus; < or = 0.06 versus Streptococcus groups A and B, and Neisseria gonorrhoeae beta LAC+; 0.125 versus S. pneumoniae penicillin-susceptible and Proteus mirabilis beta LAC+; 0.25 versus beta LAC+ versus strains of Moraxella catarrhalis, Escherichia coli, Klebsiella pneumoniae, and K. oxytoca; 0.5 versus Haemophilus influenzae beta LAC-; 1 versus H. influenzae beta LAC+; 4 versus Legionella pneumophila beta LAC+; and 8 versus Enterococcus faecalis beta LAC-strains. Cefdinir was equally effective against both standard and high inocula of S. aureus strains producing A, B, C, or D beta LAC types. MICs were also generated versus quality-control reference strains.

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.

A novel rapid throughput phototolerance screen in mice.

A relatively simple, rapid throughput phototolerance screen in small animals would be very useful in early drug development. It could prioritize or select potential lead compounds from among a number of analogs with similar biological activities. This study describes an in vivo mouse phototolerance screen established for that purpose. It also reports phototolerance data with standard reference drugs obtained using this screen.

Smooth vs. rough: an 8-year survey of mammary prostheses.

One-hundred and seventy patients (124 augmentations and 46 reconstructions) were followed for 8 post-operative years. Ninety patients received the "standard" smooth silicone mammary prosthesis, and 80 patients received a polyurethane-covered prosthesis. The longest follow-up was 4 years and the shortest was 1 year, with the average just over 2 years. Six types of complications were registered, with three attributed to implant design (wrinkles, draping, capsules) and three to the operator or surgery (infection, hematoma, extrusion). Firm capsule formation was considered a complication only if another intervention (reoperation, closed capsulotomy, etc.) was recommended by the surgeon or requested by the patient. Ninety-six percent of the patients with polyurethane prostheses had a satisfactory (grade II) or better than satisfactory (grade IA or IB) result, whereas 72 percent of the patients with a standard silicone-gel prosthesis achieved a satisfactory (grade II) or better than satisfactory (grade IA or IB) result. Technical details for use of polyurethane prostheses are given, as well as complications inherent to the polyurethane-covered implant.