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PubMed1995

Systematic analysis of the Saccharomyces cerevisiae alpha-factor containing lactam constraints of different ring size.

Eight cyclic analogs and corresponding linear homologs of the alpha-factor mating pheromone (WHWLQLKPGQPMY) of Saccharomyces cerevisiae were synthesized using solid-phase procedures on a phenylacetamidomethyl support. On-resin lactamization of the side chains of residues 7 and 10 to form rings containing from 14 to 18 atoms was effected by the BOP reagent. All peptides were highly homogeneous and gave expected molecular ions by FAB mass spectrometry. The constrained analogs had biological activities varying from 10% to less than 0.1% of that of [Nle12]-alpha-factor. In all cases, cyclic analogs with Glu in position 10 were more active than the homolog with Asp at this position. This trend was also found with the corresponding linear pheromones, suggesting that a gamma-carbonyl in position 10 is an important determinant of pheromone potency. The cyclic peptides had from 50- to 20000-fold lower affinities for the alpha-factor receptor than for [Nle12]-alpha-factor, as judged using a competition binding assay. Circular dichroism studies indicate that the cyclic lactam-containing region of cyclo7.10[Orn7, Glu10,Nle12]-alpha-factor retains a beta-turn-like structure similar to that found in the corresponding model tetrapeptide. The results show that covalently constrained analogs of the linear pheromone can maintain biological activity, despite binding poorly to the receptor, and indicate that a beta-turn-like structure in the center of the pheromone allows signal transduction.

Binding, Competitive↗
PubMed1988

Mapping the binding site of aflatoxin B1 in DNA: systematic analysis of the reactivity of aflatoxin B1 with guanines in different DNA sequences.

The mutagenic and carcinogenic chemical aflatoxin B1 (AFB1) reacts almost exclusively at the N(7)-position of guanine following activation to its reactive form, the 8,9-epoxide (AFB1 oxide). In general N(7)-guanine adducts yield DNA strand breaks when heated in base, a property that serves as the basis for the Maxam-Gilbert DNA sequencing reaction specific for guanine. Using DNA sequencing methods, other workers have shown that AFB1 oxide gives strand breaks at positions of guanines; however, the guanine bands varied in intensity. This phenomenon has been used to infer that AFB1 oxide prefers to react with guanines in some sequence contexts more than in others and has been referred to as "sequence specificity of binding". Herein, data on the reaction of AFB1 oxide with several synthetic DNA polymers with different sequences are presented, and (following hydrolysis) adduct levels are determined by high-pressure liquid chromatography. These results reveal that for AFB1 oxide (1) the N(7)-guanine adduct is the major adduct found in all of the DNA polymers, (2) adduct levels vary in different sequences, and, thus, sequence specificity is also observed by this more direct method, and (3) the intensity of bands in DNA sequencing gels is likely to reflect adduct levels formed at the N(7)-position of guanine. Knowing this, a reinvestigation of the reactivity of guanines in different DNA sequences using DNA sequencing methods was undertaken. The reactivities of 190 guanines were determined quantitatively and considered in a pentanucleotide context, 5'-WXGYZ-3', where the central, underlined G represents the reactive guanine and W, X, Y, and Z can be any of the nucleotide bases. Methods are developed to determine that the X (5'-side) base and the Y (3'-side) base are most influential in determining guanine reactivity. The influence of the bases in the 5'-position (X) is 5'-G (1.0) greater than C (0.8) greater than A (0.3) greater than T (0.2), while the influence of the bases in the 3'-position (Y) is 3'-G (1.0) greater than T (0.8) greater than C (0.4) greater than A (0.3). These rules in conjunction with molecular modeling studies (to be published elsewhere) were used to assess the binding sites that might be utilized by AFB1 oxide in its reaction with DNA.

Aflatoxin B1↗
PubMed1980

Quantitative structure-activity relationships by distance geometry: systematic analysis of dihydrofolate reductase inhibitors.

Extensions are presented for the distance geometry approach to rationalizing ligand binding data. These are algorithms to (i) detect when homologues are not binding with the same orientation in the binding site although they are chemically similar; (ii) deduce what the binding site's size and shape must be; and (iii) calculate the optimal set of interaction energies between parts of the site and parts of the ligand molecules. This improved methodology is tested on a set of 68 quinazoline inhibitors of S. faecium dihydrofolate reductase. Results are discussed and compared with the Hansch method of QSAR, and an improved inhibitor is predicted.

Binding Sites↗
PubMed1996

Psychopharmacological drugs as represented in the press: results of systematic analysis of newspapers and popular magazines.

The representation of mental diseases and psychopharmacological drugs in the media, especially in the press, is thought to be of great impact on people's opinions on the subject. During the course of one year, all articles about psychopharmacological drugs and cardiac drugs published in nineteen German newspapers were collected. All statements, together with related aspects, reasons for prescription, individual details of the patient, effects and side-effects, were registered and classified according to a key. The results show that, in contrast to 13% of the articles about cardiac drugs, half of the reports about psychopharmacological drugs deal primarily with the problems of side-effects and dependence the drugs may produce. There was much more critical comment and emotional emphasis used to characterize the psychopharmacological drugs. Only in 9% of articles was their therapeutic efficacy mentioned. Cardiac drugs are generally discussed objectively in a medical context and in 53% efficacy is emphasized. Psychopharmacological drugs are often mentioned in stories about prominent persons having a life crisis, taking drugs, turning to alcoholism, or in the context of social decline. Only in 3% of all articles about psychopharmacological drugs was it possible to identify a serious mental disease as the reason for prescription. The reasons for and implications of these findings, which mainly reflect the negatively biased image of psychopharmacological drugs in women's magazines (while they are treated relatively fairly in general newspapers) are discussed.

Cardiovascular Agents↗
PubMed1996

[Systematic analysis of cervical lymph node metastasis of larynx and hypopharynx carcinomas--a clinical computerized tomography study with special reference to extension of the primary tumor].

PURPOSE: To assess the incidence and patterns of cervical lymph node metastases in laryngeal and hypopharyngeal carcinomas according to the location, extension, and relation of the primary tumor to the parapharyngeal compartments and tissues arising from different embryological structures as branchial arches and somites. PATIENTS AND METHODS: The findings of clinical and CT examinations of 230 patients with histological evidence of laryngeal and hypopharyngeal carcinoma (44 T1-, 33 T2-, 41 T3-, 112 T4-carcinomas with lymph node involvement in 116 cases) were evaluated retrospectively. Local tumor spread and relation of the primary to the parapharyngeal compartments and to tissues arising from different embryological structures such as branchial arches and somites were analysed and related to cervical lymph node involvement. RESULTS: The pattern of cervical lymph node involvement depends upon location and extension of the primary tumor in the adjacent tissues of the larynx and hypopharynx. The density of the lymphatic vessels in these areas determines the likelihood of lymph node involvement. The frequency of NO cases in carcinomas strictly located in the vocal cord (n = 31) was 100%; in the glottic-supraglottic, supraglottic, and transglottic cancer (n = 106) 85%; in larynx-hypopharynx carcinomas (n = 54) 26%; in hypopharynx carcinomas (n = 12) 17%; and in larynx-hypo-oropharynx carcinomas (n = 46) 9%. Tumors in tissues arising from branchial arches 4, 5, and 6 are glottic-supraglottic, transglottic laryngeal, and laryngeal-hypopharyngeal carcinomas. Metastases of these tumors were frequently found in the jugular lymph node chains, particularly if the developed tissue of the "primitive glottis" was invaded by the primary. Upper jugular nodes ipsilateral to a supraglottic or hypopharyngeal primary were usually involved. The frequency of metastases in the jugular lymph node chains decreased in craniocaudal direction. If the tumor invaded the posterior wall of the hypopharynx or tissues.

Adult↗
PubMed1995

[Systematic analysis of local growth behavior and cervical lymph node metastasis of nasopharyngeal carcinoma--a clinical and computerized tomography examination].

BACKGROUND: Assessment of the incidence and patterns of cervical lymph node involvement according to the location, extension, and histological subtype of nasopharyngeal carcinoma. PATIENTS AND METHODS: The findings of the clinical and CT examinations of 80 patients with histological evidence of nasopharyngeal carcinoma (9T1-, 20 T2-, 17 T3-, 34 T4-carcinomas, lymph node involvement in 59 cases) were evaluated retrospectively. The histological subtype, local tumor spread, relation of the primary to the parapharyngeal fascias, compartments, and skull base structures were analysed and related to the cervical lymph node involvement. RESULTS: Two main types of nasopharyngeal carcinomas with different patterns of cervical lymph node involvement were identified: the posterior wall type, which spreads into the retropharyngeal and spinal accessorial neck node chains and the ventral type, which is located which is located at the roof, anterior, and lateral walls of the nasopharynx and spreads into the jugular neck node chains, preferring the neck side in which the main part of the primary is located. The border of lymph drainage via retropharyngeal-spinal accessorial or via jugular neck node chains is localised ventral of the origin of the m. capitus longus at the skull base. If the primary involves the prestyloidal compartment, the tumor may spread into the ipsilateral submaxillary lymph nodes. Combinations of the different types are frequently found with the neck node spread following the described directions. CONCLUSIONS: Knowledge of the regular patterns of spread of nasopharyngeal carcinoma is important for treatment procedures, especially for planning 3-dimensional radiotherapy.

Adult↗
PubMed1993

Systematic analysis of antisense RNA inhibition of myosin II heavy-chain gene expression in Dictyostelium discoideum.

The powerful potential of antisense nucleotide inhibition of gene expression is presently being exploited in many biological systems. Although use of the technique is widespread, little is known about the variables that contribute to experimental success. We sought to define those variables that affect inhibition of myosin II heavy-chain (MIIHC) gene expression by stable nuclear-derived antisense RNAs in Dictyostelium discoideum. Different fragments of the MIIHC gene cloned in the antisense orientation into several transformation vectors were introduced into cells, and the accumulation of MIIHC protein and mRNA was examined. Inhibition of expression ranged from slight to virtually complete, and depended only on the specific gene fragment used to generate the antisense RNA. Fragments of the 3' end of the gene were the most effective and resulted in almost complete inhibition, whereas 5' fragments gave very little reduction. The severity of the morphological phenotypes associated with MIIHC depletion reflected the different levels of MIIHC in the transformants. Important implications for the design of antisense vectors suggested by these results are discussed.

Animals↗
PubMed1996

Systematic analysis of repeated gene delivery into animal lungs with a recombinant adenovirus vector.

Adenovirus-based vectors are promising candidates for genetic therapy of cystic fibrosis (CF). Because adenoviruses naturally infect airway cells, they grow to very high titers, and the transgenes carried by the adenoviruses are expressed at high levels. In addition, adenoviruses are relatively safe because the disease caused by the wild-type virus is self-limiting. One disadvantage of adenovirual vectors is that the transgene expression would be transient because adenoviruses do not integrate their DNA into the genome of the host cells. Adenoviral gene delivery into the lungs is also complicated by the anatomy of the airways and the defense mechanisms of the recipient. To assess the feasibility of adenovirus-mediated gene therapy for CF, a recombinant adenovirus carrying a lacZ gene was delivered into animal lungs to study the efficiency and cellular distribution of gene transfer, the duration of gene expression, the possible histopathology of the lungs after gene transfer, and the efficacy of repeated administrations of the viral agent. The results of these studies demonstrate that (i) efficient gene transfer into animal lungs can be achieved; (ii) a near-homogenous delivery of the vectors can be achieved by airway instillation, although the pattern of transduction varies among individual animals; (iii) pathological effects are generally mild in CD1 mice; (iv) gene expression is transient; (v) repetitive gene transfer is achievable, but becomes progressively less efficient, and (vi) immune responses are induced against both the viral and transgene products.

Adenoviridae↗
PubMedDate not supplied

Systematic analysis of solvents and other volatile substances by gas chromatography.

Four column packings for screening volatiles in biological material by gas chromatography are evaluated. Retention data are standardized by the calculation of retention indices, and packing materials are compared by discriminating power and identification power. A combination of 5% Carbowax 20M on Carbopack B and 0.3% Carbowax 20M on Carbopack C appears to be best suited for screening. Hydroxy-n-alkanes are used as reference substances for the calculation of retention indices.

Chromatography, Gas↗
PubMedDate not supplied

Systematic analysis of stimulants and narcotic analgesics by gas chromatography with nitrogen specific detection and mass spectrometry.

The recovery data of 40 doping agents from human urine were evaluated. Retention data were standardized by the calculation of relative retention times using N,N-diisopropyl-n-dodecane as the internal standard. The relative standard deviations of retention times were less than 0.5% for the within batch analyses and less than 0.8% for the day-to-day analyses. Good recoveries (greater than 70%) were observed for most of the drugs.

Analgesics, Opioid↗
PubMedDate not supplied

Systematic analysis of diuretic doping agents by HPLC screening and GC/MS confirmation.

The simultaneous analysis of diuretic agents by reversed-phase liquid chromatography with a diode-array detector (DAD) was performed by using a gradient elution with acetonitrile and phosphate buffer on a Hypersil-ODS column. For the spiked urine the extraction recovery of solid-phase extraction (SPE) using Sep-Pak C18 cartridge was compared with that of liquid-liquid extraction (LLE) with diethyl ether at various pH. The standard calibration curves were linear from 0.20-20.0 micrograms/mL for all diuretic agents except amiloride, 1.0-20.0 micrograms/mL, and the detection limit was about 0.2 micrograms/mL for 3 mL of urine, except that of amiloride, which was 1.0 micrograms/mL. The confirmation analysis was performed by gas chromatography/mass spectrometry (GC/MS) following methylation. The characteristic mass fragment ions obtained by electron-impact (EI) ionization (70 eV) provided identification of each diuretic agent.

Adult↗
PubMed1991

Construction of an ordered clone bank and systematic analysis of the whole transcripts of chromosome VI of Saccharomyces cerevisiae.

By comparing sequences of restriction enzyme cleavage sites and their distance data, we sorted 384 lambda phage clones containing segments of chromosome VI of S. cerevisiae and constructed an ordered clone bank for this chromosome. The physical length of this bank is 269.7 kb. The bank contains the entire chromosome including the left telomere, but it is not certain whether it contains the right telomere as well. To estimate the number of genes present on this chromosome, we performed a series of Northern hybridization experiments using 157 restriction enzyme fragments prepared from the bank as hybridization probes and total poly(A)+ RNA from vegetatively growing cells. Thus, 97 distinct transcripts were identified. The relative abundance levels of individual transcripts were measured by comparing their band intensity with that of the RPO41 transcript. It was found that the transcripts from the genes located in the telomeric and centromeric regions are less abundant as compared to those from the genes in the central regions of both arms.

Blotting, Northern↗
PubMed1997

A systematic analysis of how medical school characteristics relate to graduates' choices of primary care specialties.

PURPOSE: To examine medical school characteristics, in particular federal funding for biomedical research, as they relate to the graduates' choices of family medicine, general internal medicine, general pediatrics, or all three specialties. METHOD: Data were collected for 121 U.S. medical schools, including information on funding, faculty, curricula, and other school characteristics. In addition, a questionnaire was mailed to the schools requesting information about non-federal funding for primary care, primary care department characteristics, and primary care representation on the admission, curriculum, and promotion and tenure committees. Analyses were carried out separately for each specialty and for all three combined. The first multiple regression analysis was done to predict specialty choice (proximate predictors), the second to predict the predictors of specialty choice (intermediate predictors), and the third to predict those predictors (distal predictors). RESULTS: Prediction was best for family medicine practice. Interest at matriculation and required third-year and fourth-year time in primary care were the two best proximate predictors. The best predictors of initial interest were the percentage of rural students and special programs for primary care, while the best predictors of required time in primary care were funding for family medicine and the percentage of faculty in family medicine (intermediate predictors). The best predictor of the percentage of faculty in family medicine was funding for family medicine (distal predictor). CONCLUSION: The results suggest that the most effective way to increase the number of physicians with generalist practices is to increase the number of students interested in a family medicine career at matriculation.

Career Choice↗
PubMed1992

Evidence that the systematic analysis of bile cytology permits monitoring of hepatic allograft rejection.

Cytologic analysis was performed on 128 bile specimens collected by schedule from 12 liver transplant recipients over a 4-month period. Clinical diagnoses at the time of specimen collection were determined retrospectively, as follows: clinically stable, 75; acute rejection, 15; CMV hepatitis, 1; systemic infection, 8; ischemic injury, 24 (all within the first 4 days postop); nonclassifiable, 5. Bile analysis was done by a blinded investigator. Specimens contained ductal epithelial cells (EC) and inflammatory cells (IC), which were counted using Cytospin slide preparations. Greater than 10 cells/slide were seen in 93.3% of rejections, 91.7% of ischemic injuries, 100% of systemic infections, and 14.6% of stable patients. In samples collected after POD 4, IC were seen in 86.7% of rejections, yielding a specificity of 94.4% (P less than 0.001). If lymphoblastic cells were also seen, the specificity increased to 96.6%. Five specimens were obtained the day before the clinical diagnosis of rejection; all demonstrated IC. Seven specimens were obtained 3 days after beginning therapy for rejection. In 5 the bile contained no IC, and clinical improvement occurred; in the 2 in whom IC were found, further therapy was subsequently required. IC were seen in 5 of 8 specimens taken when systemic infection was present; the clinical setting allowed differentiation from rejection. Only 1 case of CMV hepatitis was included, thus no conclusions can be drawn for this entity. Cytoplasmic vacuolization of EC was observed in 30% of cases, in these, cyclosporine levels were significantly higher (989.9 +/- 356.9 vs. 672.8 +/- 421.2, P = 0.02). In summary, bile cytology analysis aides in the monitoring of the onset and duration of rejection. It may be an indicator of persistent rejection, and it may help prevent overimmunosuppression in those cases with normal cytological findings.

Antibodies, Monoclonal↗
PubMed1987

Systematic analysis of the long-chain components of Eubacterium lentum.

The cellular long-chain component patterns of 33 strains of Eubacterium lentum were determined by gas chromatography. Two main types of long-chain component patterns were distinguished. The first (26 strains) was characterized by saturated branched-chain fatty acids (br14:0, br15:0, br16:0 and br17:0). The second (7 strains) did not contain branched-chain fatty acids and was characterized by saturated straight-chain fatty acids (11:0, 12:0, 14:0 and 16:0). Both types contained fatty aldehydes and their respective dimethyl acetals (14ald and 14dma, 16ald and 16dma). br16dma was only found in the first type. The G + C content of the DNA (Tm) of the 33 strains varied between 63.7 and 69.1 mol %. Canonical correlation analysis distinguished three subtypes within the first main type.

Base Composition↗
PubMed1996

A systematic analysis of the mutations of the uroporphyrinogen III synthase gene in congenital erythropoietic porphyria.

Congenital erythropoietic porphyria (CEP) or Günther's disease is an inborn error of heme biosynthesis, transmitted as an autosomal recessive trait and characterized by a profound deficiency of uroporphyrinogen III synthase activity (UROIIIS). The molecular defects observed in CEP are mainly heterogeneous, except for one missense mutation, C73R (Cys to Arg substitution at codon 73) which represents nearly 40% of the disease alleles. A convenient strategy was designed to establish a rapid diagnosis at the genetic level in samples from patients with CEP. As a first step, the most frequent mutation is searched for by restriction analysis from genomic. DNA amplified by PCR. Next, the nine coding exons and intron-exon boundaries are sequenced from genomic DNA. As an alternative, the mutation can be determined by sequencing the UROIIIS cDNA of the patient, using the RT-PCR technique on RNAs when a lymphoblastoid cell line can be established. Finally, for each new mutation in UROIIIS coding sequence, the corresponding mutant protein is expressed in Escherichia coli, in order to demonstrate the pathological significance of the mutation. This work describes the analysis of UROIIIS gene mutations in 10 new families with CEP and summarizes the data from 20 unrelated families studied in our laboratory. Three new missense mutations of UROIIIS coding sequence (H173Y, Q187P and P248Q) have been observed together with 8 known mutations. The significance of three intronic base changes (476 -31 T-->C; 562 -4 A-->T; 562 -23 A-->G) is discussed. In 6 alleles out of 40 (15%), the mutation remains undetermined.

Adolescent↗