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At least 127 records · Page 7Linked to original sources
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↗
PubMed2000

A systematic analysis of factors which may impact upon tomographic perfusion imaging measurements: implications for the use of Tc-99m sestamibi in acute myocardial infarction.

BACKGROUND: The use of acute Tc-99m sestamibi imaging has provided a valuable methodology to assess myocardium at risk and collateral blood flow. OBJECTIVE: The purpose of this study was to determine the impact of physical, physiologic, and reconstruction factors on the extent and severity of Tc-99m sestamibi images in a porcine model of coronary occlusion and reperfusion. METHODS AND RESULTS: Eleven pigs underwent 40 min of coronary occlusion using a balloon catheter followed by reperfusion. Radiolabeled microspheres were injected during occlusion for blood flow determination and 20-30 mCi of Tc-99m sestamibi was injected intravenously for cardiac imaging. Each animal underwent four modes of gamma camera imaging: a cardiac and respiratory gated SPECT study, an ungated SPECT study, a post-mortem SPECT study and an ex-situ study where the heart was sliced into five short axis slices and directly imaged. All animals had extensive wall motion abnormalities at the time of imaging. Myocardial risk area by ex-situ imaging was 32 +/- 9% LV and did not significantly change with the addition of a chest cavity and tomographic reconstruction (post-mortem and gated imaging) or cardiac and respiratory motion (ungated imaging). Defect severity was significantly underestimated with the addition of a chest cavity and tomographic reconstruction but was unaltered by cardiac and respiratory motion. CONCLUSIONS: The assessment of risk area acutely by SPECT Tc-99m sestamibi imaging is unaffected by cardiac motion obviating the necessity for gated imaging. Estimated defect severity (which has been used as a measure of collateral flow) is significantly reduced by the chest wall and tomographic acquisition and reconstruction suggesting a role for scatter and attenuation algorithms for this measure.

Animals↗
PubMed2002

Functional organization of the yeast proteome by systematic analysis of protein complexes.

Most cellular processes are carried out by multiprotein complexes. The identification and analysis of their components provides insight into how the ensemble of expressed proteins (proteome) is organized into functional units. We used tandem-affinity purification (TAP) and mass spectrometry in a large-scale approach to characterize multiprotein complexes in Saccharomyces cerevisiae. We processed 1,739 genes, including 1,143 human orthologues of relevance to human biology, and purified 589 protein assemblies. Bioinformatic analysis of these assemblies defined 232 distinct multiprotein complexes and proposed new cellular roles for 344 proteins, including 231 proteins with no previous functional annotation. Comparison of yeast and human complexes showed that conservation across species extends from single proteins to their molecular environment. Our analysis provides an outline of the eukaryotic proteome as a network of protein complexes at a level of organization beyond binary interactions. This higher-order map contains fundamental biological information and offers the context for a more reasoned and informed approach to drug discovery.

Cells, Cultured↗
PubMed2003

Systematic analysis of the TGF-beta/Smad signalling pathway in the rhabdomyosarcoma cell line RD.

Transforming growth factor-beta (TGF-beta) is a multifunctional regulator of cell growth and differentiation, whose actions are highly cell type specific. To study the role of the TGF-beta1 autocrine loop in regulating growth and myogenic differentiation in the human rhabdomyosarcoma cell line, RD, an attempt was made to establish a framework for the expression of several components of TGF-beta1/Smad signalling pathway at the mRNA and protein levels by reverse transcription-polymerase chain reaction (RT-PCR) and Western blot analysis in RD cells compared with the normal myoblasts. Higher exogenous concentration of TGF-beta1 was necessary to reach a growth-inhibition effect, whereas TGF-beta1 downregulated the expression of myosin heavy-chain mRNA at lower concentrations than that was required for growth inhibition. Treatment with TGF-beta1 significantly decreased the number of sarcomeric actin and myosin-expressing cells. In this study, we have shown that RD cells displayed higher expression of TbetaRI, TbetaRII, Smad2 and Smad4 at both the mRNA and protein levels than myoblasts. Smad3 and Smad7 mRNA were expressed at higher level in RD cells than in myoblasts. The staining patterns of TbetaR and Smads suggest that they may transduce different TGF-beta1 signalling in RD cells than in myoblasts. TGF-beta1 signalling induced a rapid relocation of Smad2 to the nucleus; in contrast, Smad4 remained localized to the cytoplasm unless it was coexpressed with Smad2. These studies suggest that signalling from the cell surface to the nucleus through Smad proteins is a required component of TGF-beta1-induced cell response in RD cells. The RD cell line is a suitable model to study the TGF-beta autocrine loop involved in growth and differentiation of RMS.

Autocrine Communication↗
PubMed2003

Systematic analysis of the ABO gene diversity within exons 6 and 7 by PCR screening reveals new ABO alleles.

BACKGROUND: Mutations critical for ABO blood group phenotypes have predominantly been found in exons 6 and 7 of the ABO gene, both of which encode the catalytic domain of ABO glycosyltransferase. To design rapid and reliable ABO genotyping assays, a profound knowledge of the prevalent alleles is required and a reliable sequence database needs to be established. STUDY DESIGN AND METHODS: A PCR screening system was established consisting of 102 different PCRs, each specific for a single nucleotide (nt) variation. The primer mixes were developed to walk from the 5' to the 3' end of exons 6 and 7 of the ABO gene to screen for nt mutations at 50 known polymorphic sites. A total of 109 unrelated individuals with common and rare ABO characteristics were screened. All blood samples in which the PCR results were inconclusive or inconsistent with the ABO phenotypes were subjected to sequence analysis of exons 6 and 7. RESULTS: The results of PCR screening were conclusive and consistent with the ABO phenotypes in 90 cases. In the remaining 19 cases, PCR screening revealed unusual allele combinations or amplification results that were incompatible with known ABO allele combinations or subgroups predicted by serologic analysis. In these 19 cases, sequencing revealed new ABO alleles (one ABO*Ael allele, one ABO*B(A) allele and two ABO*O alleles) in two individuals with common and seven individuals with variant ABO phenotypes. CONCLUSION: This PCR screening strategy is an effective tool for obtaining deeper insight into the ABO gene diversity and diversification and may be useful to increase the quality of the ABO sequence database.

ABO Blood-Group System↗
PubMed2001

[Approaches to systematic analysis of addiction management].

The aim to calculate the functions of health care also considers the care system for addicts. The scientific basis of these intentions are organizational analyses, health economy and systems analysis. Those approaches however do not fit well into quality assessments of care systems for people with psychic problems. Especially the functions and the structure of the health care system for addicts are of considerable heterogeneity and complexity. These features represent a great methodological challenge for systems analysis. Already the causal analysis of essential parameters like the number of drug deaths depends on so many variables, so that it cannot be ascertained that any particular intervention has a specific definite effect on drug mortality. Besides, the waiting period for withdrawal facilities is determined by many factors. Hence, unique measures of addiction policies probably do not have essential effects. On the contrary, waiting periods of few days lead to a higher occurrence of drop-outs at detoxification programmes. For the future, in order to obtain quantitative functional analysis of the addiction care system research projects have to be designed based on a unification of the documentary systems which help to better understand the flow of patients.

Cause of Death↗
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↗
PubMed2001

Genes linked by fusion events are generally of the same functional category: a systematic analysis of 30 microbial genomes.

Recent work in computational genomics has shown that a functional association between two genes can be derived from the existence of a fusion of the two as one continuous sequence in another genome. For each of 30 completely sequenced microbial genomes, we established all such fusion links among its genes and determined the distribution of links within and among 15 broad functional categories. We found that 72% of all fusion links related genes of the same functional category. A comparison of the distribution of links to simulations on the basis of a random model further confirmed the significance of intracategory fusion links. Where a gene of annotated function is linked to an unclassified gene, the fusion link suggests that the two genes belong to the same functional category. The predictions based on fusion links are shown here for Methanobacterium thermoautotrophicum, and another 661 predictions are available at http://fusion.bu.edu.

Gene Expression Regulation, Bacterial↗
PubMed2001

Structural compensation for the deficit of rRNA with proteins in the mammalian mitochondrial ribosome. Systematic analysis of protein components of the large ribosomal subunit from mammalian mitochondria.

The mammalian mitochondrial ribosome (mitoribosome) is a highly protein-rich particle in which almost half of the rRNA contained in the bacterial ribosome is replaced with proteins. It is known that mitochondrial translation factors can function on both mitochondrial and Escherichia coli ribosomes, indicating that protein components in the mitoribosome compensate the reduced rRNA chain to make a bacteria-type ribosome. To elucidate the molecular basis of this compensation, we analyzed bovine mitoribosomal large subunit proteins; 31 proteins were identified including 15 newly identified proteins with their cDNA sequences from human and mouse. The results showed that the proteins with binding sites on rRNA shortened or lost in the mitoribosome were enlarged when compared with the E. coli counterparts; this suggests the structural compensation of the rRNA deficit by the enlarged proteins in the mitoribosome.

Amino Acid Sequence↗
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↗
PubMed1998

A systematic analysis of the factors that determine the strength of pre-mRNA splicing enhancers.

We find that the strength of splicing enhancers is determined by the relative activities of the bound serine-arginine (SR)-rich splicing factors, the number of SR proteins within the enhancer complex and the distance between the enhancer and the intron. Remarkably, the splicing activity of the bound SR proteins is directly proportional to the number of RS tetrapeptide sequences within the RS domain. Quantitative analysis of the effects of varying the distance between the enhancer and the intron revealed that the splicing efficiency is directly proportional to the calculated probability of a direct interaction between the enhancer complex and the 3' splice site. These data are consistent with a model in which splicing enhancers function by increasing the local concentration of SR proteins in the vicinity of the nearby intron through RNA looping.

Base Sequence↗
PubMed2003

Systematic analysis of essential yeast TAFs in genome-wide transcription and preinitiation complex assembly.

The general transcription factor TFIID is composed of the TATA box binding protein (TBP) and a set of conserved TBP-associated factors (TAFs). Here we report the completion of genome-wide expression profiling analyses of yeast strains bearing temperature-sensitive mutations in each of the 13 essential TAFs. The percentage of the yeast genome dependent on each TAF ranges from 3% (TAF2) to 59-61% (TAF9). Approximately 84% of yeast genes are dependent upon one or more TAFs and 16% of yeast genes are TAF independent. In addition, this complete analysis defines three distinct classes of yeast promoters whose transcriptional requirements for TAFs differ substantially. Using this collection of temperature-sensitive mutants, we show that in all cases the transcriptional dependence for a TAF can be explained by a requirement for TBP recruitment and assembly of the preinitiation complex (PIC). Unexpectedly, these assembly experiments reveal that TAF11 and TAF13 appear to provide the critical functional contacts with TBP during PIC assembly. Collectively, our results confirm and extend the proposal that individual TAFs have selective transcriptional roles and distinct functions.

Base Sequence↗
PubMed1999

Artefactual increasing frequency of omphaloceles in the Northern Netherlands: lessons for systematic analysis of apparent epidemics.

BACKGROUND: While monitoring birth defects in a registry, statistically significant increases in prevalence occasionally occur. In the European Registration Of Congenital Anomalies (EUROCAT) in the Northern Netherlands 20000 births are monitored every year. For omphaloceles, a steady increase in the prevalence from 0.86 per 10000 live- and stillbirths in 1981-1983 to 3.11 per 10000 live- and stillbirths in 1994 was seen in the three northern provinces of The Netherlands. METHODS: A stepwise enquiry into this increase, which included checking for misclassification and change in coding and ascertainment when necessary, was done. All cases of omphalocele and associated or similar birth defects registered at the EUROCAT registry were retrieved and if necessary recoded. RESULTS: This study showed that the increase reported previously was not a true time trend. A few cases of e.g. diastasis recti and trisomy 18 were misclassified. The prevalence in more recent years is comparable with that in the rest of Europe, whereas it used to be lower. There was an increase in isolated omphalocele, but the numbers are small. CONCLUSIONS: The stepwise enquiry described should be a standard procedure after noticing an increasing prevalence in a registry. A better subdivision, e.g. in isolated cases versus children with multiple congenital anomalies, before monitoring can contribute to a lower number of false positive signals.

Congenital Abnormalities↗
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↗