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Biomedical subjects

R Jansen

Publications and source records attributed to R Jansen.

At least 37 records · Page 2Linked to original sources

Interrelating different types of genomic data, from proteome to secretome: 'oming in on function.

With the completion of genome sequences, the current challenge for biology is to determine the functions of all gene products and to understand how they contribute in making an organism viable. For the first time, biological systems can be viewed as being finite, with a limited set of molecular parts. However, the full range of biological processes controlled by these parts is extremely complex. Thus, a key approach in genomic research is to divide the cellular contents into distinct sub-populations, which are often given an "-omic" term. For example, the proteome is the full complement of proteins encoded by the genome, and the secretome is the part of it secreted from the cell. Carrying this further, we suggest the term "translatome" to describe the members of the proteome weighted by their abundance, and the "functome" to describe all the functions carried out by these. Once the individual sub-populations are defined and analyzed, we can then try to reconstruct the full organism by interrelating them, eventually allowing for a full and dynamic view of the cell. All this is, of course, made possible because of the increasing amount of large-scale data resulting from functional genomics experiments. However, there are still many difficulties resulting from the noisiness and complexity of the information. To some degree, these can be overcome through averaging with broad proteomic categories such as those implicit in functional and structural classifications. For illustration, we discuss one example in detail, interrelating transcript and cellular protein populations (transcriptome and translatome). Further information is available at http://bioinfo.mbb.yale.edu/what-is-it.

Bacillus subtilis↗

Cost effectiveness of continuous terbinafine compared with intermittent itraconazole in the treatment of dermatophyte toenail onychomycosis: an analysis of based on results from the L.I.ON. study. Lamisil versus Itraconazole in Onychomycosis.

OBJECTIVE: To compare the costs and effectiveness of 2 oral antifungal treatment regimens in patients with dermatophyte toenail onychomycosis. DESIGN AND METHODS: A cost-effectiveness analysis using a model based on data from the Lamisil versus Itraconazole in Onychomycosis (L.I.ON.) study, a randomised controlled trial comparing continuous terbinafine with intermittent itraconazole. The trial included 4 treatment arms: terbinafine 250 mg/day for 12 or 16 weeks (T12, T16) and itraconazole 400 mg/day for 1 week in every 4 weeks for 12 or 16 weeks (I3, I4). Cost calculations for 6 countries (Finland, Germany, Iceland, Italy, The Netherlands, UK) included costs for medication, physician visits, laboratory tests, management of adverse events and management of relapse. Effectiveness was based on complete cure rates (mycological cure plus 100% toenail clearing). Costs per complete cure were determined and both average and incremental cost-effectiveness ratios were calculated. PERSPECTIVE: Healthcare system. MAIN OUTCOME MEASURES AND RESULTS: In the L.I.ON. study, terbinafine was seen to be more effective than itraconazole (cure rates, 45.8 vs 23.4%). In most comparisons (5 of the 6 countries), the costs of T12 were statistically significantly lower than those of I3 [range: -37 to -173 euros (EUR); 1998 values; 1.172 US dollars = EUR1], indicating that T12 was the dominant strategy (i.e. less expensive and more effective). One exception (Finland) showed an incremental cost-effectiveness ratio of EUR524 per additional cure. In the other 5 countries, T16 and 14 were essentially equal in cost, but the greater effectiveness of T16 (cure rates, 55.1 vs 25.9%) resulted in a situation of extended dominance. CONCLUSION: From a healthcare system perspective, continuous terbinafine is less costly and more effective than intermittent itraconazole in the treatment of dermatophyte toenail onychomycosis.

Antifungal Agents↗

Predicting the sound power and impact of a wastewater treatment plant.

Several process units at a wastewater treatment plant (WWTP) can produce a significant level of sound and thus induce sound nuisance for nearby residents. The risk for sound nuisance should be considered by making a prognosis of sound impact in an early project phase (planning, design). A prognosis requires information with respect to the sound characteristics of the different process units. This paper reports the development of empirical models for the sound power of relevant process units in the water line at Aquafin WWTPs. The used methodology for model derivation and validation allowed us to minimize the required number of measurements. Besides the methodology, the paper describes in detail the derivation and validation of the empirical model for the splashing water of screw pumps. Also the use of all the derived empirical models to determine the sound impact of a wastewater treatment plant at close distance is illustrated with a case-study.

Consumer Behavior↗

Thermal spin-wave scattering in hot-electron magnetotransport across a spin valve.

The role of thermal scattering in spin-dependent transport of hot electrons at 0.9 eV is studied using a spin-valve transistor with a soft Ni(80)Fe(20)/Au/Co base. Spin-dependent scattering makes the collected electron current depend sensitively on the magnetic state of the base. The magnetocurrent reaches 560% at 100 K, decays with increasing temperature, and a huge effect of 350% still remains at room temperature. The results demonstrate that thermal spin waves produce quasielastic spin-flip scattering of hot electrons, resulting in mixing of the two spin channels.

Journal Article↗

Mex67p mediates nuclear export of a variety of RNA polymerase II transcripts.

Mex67p is essential for nuclear poly(A)(+) RNA export in yeast, but which specific transcripts are transported by Mex67p is not known. We observed that thermosensitive mex67-5 cells do not produce a heat shock response at 37 degrees C but will induce heat shock proteins (Hsp) (e.g. Hsp104p and Hsp70p) when shifted back from the restrictive to permissive temperature (30 degrees C). This memory of a previous heat stress in mex67-5 cells could be explained if HSP mRNAs accumulated inside the nucleus during heat shock and were exported and translated in the cytoplasm on return to the permissive temperature. To test this hypothesis, nuclear export of heat shock mRNAs was directly analyzed by in situ hybridization using fluorescent-labeled oligonucleotide probes specific for SSA transcripts. This revealed that Mex67p is required for nuclear export of heat shock mRNAs. Furthermore, other polymerase II transcripts encoding the transcriptional repressor ASH1 and the glycolytic enzyme PGK1 are shown to require Mex67p for their export into the cytoplasm. Thus, Mex67p is an mRNA export factor for a broad range of polymerase II transcripts.

Adenosine Triphosphatases↗

Analysis of the yeast transcriptome with structural and functional categories: characterizing highly expressed proteins.

We analyzed 10 genome expression data sets by large-scale cross-referencing against broad structural and functional categories. The data sets, generated by different techniques (e.g. SAGE and gene chips), provide various representations of the yeast transcriptome (the set of all yeast genes, weighted by transcript abundance). Our analysis enabled us to determine features more prevalent in the transcriptome than the genome: i.e. those that are common to highly expressed proteins. Starting with simplest categories, we find that, relative to the genome, the transcriptome is enriched in Ala and Gly and depleted in Asn and very long proteins. We find, furthermore, that protein length and maximum expression level have a roughly inverse relationship. To relate expression level and protein structure, we assigned transmembrane helices and known folds (using PSI-blast) to each protein in the genome; this allowed us to determine that the transcriptome is enriched in mixed alpha-beta structures and depleted in membrane proteins relative to the genome. In particular, some enzymatic folds, such as the TIM barrel and the G3P dehydrogenase fold, are much more prevalent in the transcriptome than the genome, whereas others, such as the protein-kinase and leucine-zipper folds, are depleted. The TIM barrel, in fact, is overwhelmingly the 'top fold' in the transcriptome, while it only ranks fifth in the genome. The most highly enriched functional categories in the transcriptome (based on the MIPS system) are energy production and protein synthesis, while categories such as transcription, transport and signaling are depleted. Furthermore, for a given functional category, transcriptome enrichment varies quite substantially between the different expression data sets, with a variation an order of magnitude larger than for the other categories cross-referenced (e.g. amino acids). One can readily see how the enrichment and depletion of the various functional categories relates directly to that of particular folds.

Amino Acids↗

[Workload and health of older employees in service occupations].

Presented are the results of a representative survey of the German work force (N = 34,343) regarding work load and work-related diseases. The study comprises females and males aged 45 years and older, who are occupied in the service sector (N = 8310). The findings show that older workers in this economic sector have to bear considerable physical and mental work loads that are often higher than those for the total labor force. The results presented point to the need to encourage and practice a more comprehensive health promotion for older workers in the service sector.

Aged↗

[Continuous bone distraction with the help of a microhydraulic cylinder].

Distraction osteogenesis of the mandible is one treatment option in mandibular hypoplasia. Usually, a non-continuous distraction mode is applied. The aim of the present study was to establish continuous bone distraction using a microhydraulic cylinder. Using a submandibular approach, the mandible was dissected subperiostally on one side in four mini-pigs; corticotomy was performed and the microhydraulic cylinder fixed with two bicortical screws. The hydraulic tube was connected with an automatic hydropneumatic injector system. Following 7 days at rest, a continuous distraction of 1.5 mm per day was performed for 14 days. After 2 and 4 weeks postoperatively, the animals were killed and X-rays taken. The mandible was then removed en bloc and microscopic evaluation of the sections was performed. The microhydraulic cylinder was easy to apply and to handle. The continuous stimulus did induce direct mineralisation of longitudinal oriented collagenous fibre bundles. Bony regeneration seems to be accelerated, which might reduce the postoperatively stabilizing phase.

Animals↗

The current excitement in bioinformatics-analysis of whole-genome expression data: how does it relate to protein structure and function?

Whole-genome expression profiles provide a rich new data-trove for bioinformatics. Initial analyses of the profiles have included clustering and cross-referencing to 'external' information on protein structure and function. Expression profile clusters do relate to protein function, but the correlation is not perfect, with the discrepancies partially resulting from the difficulty in consistently defining function. Other attributes of proteins can also be related to expression-in particular, structure and localization-and sometimes show a clearer relationship than function.

Computational Biology↗

Genetic variation and evolutionary origin of the direct repeat locus of Mycobacterium tuberculosis complex bacteria.

The direct repeat region in Mycobacterium tuberculosis complex strains is composed of multiple direct variant repeats (DVRs), each of which is composed of a 36-bp direct repeat (DR) plus a nonrepetitive spacer sequence of similar size. It has been shown previously that clinical isolates show extensive polymorphism in the DR region by the variable presence of DVRs, and this polymorphism has been used in the epidemiology of tuberculosis. In an attempt to better understand the evolutionary scenario leading to polymorphic DR loci and to improve strain differentiation by spoligotyping, we characterized and compared the DNA sequences of the complete DR region and its flanking DNA of M. tuberculosis complex strains. We identified 94 different spacer sequences among 26 M. tuberculosis complex strains. No sequence homology was found between any of these spacers and M. tuberculosis DNA outside of the DR region or with any other known bacterial sequence. Although strains differed extensively in the presence or absence of DVRs, the order of the spacers in the DR locus was found to be well conserved. The data strongly suggest that the polymorphism in clinical isolates is the result of successive deletions of single discrete DVRs or of multiple contiguous DVRs from a primordial DR region containing many more DVRs than seen in present day isolates and that virtually no scrambling of DVRs took place during evolution. Because the majority of the novel spacer sequences identified in this study were confined to isolates of the rare Mycobacterium canettii taxon, the use of the novel spacers in spoligotyping led only to a slight improvement of strain differentiation by spoligotyping.

Animals↗

Factors influencing efficacy of nitrate therapy for stable angina pectoris: a multiple linear regression analysis.

In an open-label self-controlled study of 1,350 patients with stable angina pectoris (SAP), we previously demonstrated that 50 mg of isosorbide mononitrate (ISMN) slow release formulation once daily not only provided a better antianginal effect but also a better quality of life (QOL) than did the daily administration of multiple small doses of the compound. It is unknown whether certain patient characteristics contribute to this benefit. The objective of this article was to determine what independent factors contribute to this benefit. Multiple linear regression analysis was performed on the data from these 1,350 patients. Quality of life was assessed by the Marquis QOL-questionnaire for patients with angina and included the domains of immobility, pain, and psychological distress. For the purpose of this study, overall QOL was calculated as the pooled sums of the domain scores and expressed as mean scores on an ordinal scale of 10. Age did not influence the beneficial effect of nitrate therapy on QOL. Neither did gender, rhythmic disturbances, peripheral artery disease, or the concomitant use of calcium channel blockers or beta blockers. New York Heart Association (NYHA) angina classification was an independent variable: patients with a NYHA class I or II benefited less than did patients with NYHA III or IV (p = 0.02). Obese patients as well as hypertensive patients benefited less (p = 0.04 and 0.02), and smokers tended to benefit less also (p = 0.08). In contrast, hypercholesterolemia and diabetes mellitus improved the beneficial effect of nitrates on QOL (p = 0.03 and 0.05). The authors conclude that patients with coronary artery disease (CAD) and concomitant diabetes mellitus or hypercholesterolemia, a category particularly prone to early endothelial dysfunction and thus dysfunctional endogenous nitric oxide (NO) production, may benefit more from NO-donor therapy than patients without such concomitant conditions.

Angina Pectoris↗

Independent determinants of the efficacy of nitrate therapy.

BACKGROUND: Asymmetric dosage regimens of isosorbide mononitrate provide better antianginal efficacy and quality of life in patients with stable angina pectoris than the daily administration of multiple small doses of the compound. It is not known whether certain patient characteristics contribute to this improved benefit. OBJECTIVE: To determine independent factors contributing to this improved benefit. Multiple linear regression analysis was performed with a self assessment study in 1350 patients with stable angina pectoris. Quality of life was assessed by the Marquis questionnaire for patients with angina and included the assessment of immobility, pain and psychological distress. Individual scores were calculated as the pooled sums of the assessment scores and were expressed on an ordinal scale of 10. RESULTS: Age did not influence the improvement in benefit. Gender, rhythmic disturbances, peripheral artery disease and the concomitant use of calcium channel blockers or beta-blockers were without effect. New York Heart Association angina classification was an independent variable: patients with a class I or II showed less benefit than did patients with class III or IV (p = 0.02). Obese patients as well as hypertensive patients (p = 0.04 and 0.02), and smokers also tended to benefit less (p = 0.08). In contrast, the presence of cholesterolemia and diabetes mellitus were associated with increase in the beneficial effect of nitrates on quality of life (p = 0.03 and 0.05). CONCLUSIONS: Patients with severe angina pectoris benefit better from nitrate therapy than do patients with New York Heart Association class I - II. Also, patients with coronary artery disease and concomitant diabetes mellitus or cholesterolemia may benefit better from nitric oxide donor therapy than patients without such condition. In contrast, patients with concomitant obesity, hypertension, or who are smokers may show less benefit.

Aged↗

Large-scale analysis of the yeast genome by transposon tagging and gene disruption.

Economical methods by which gene function may be analysed on a genomic scale are relatively scarce. To fill this need, we have developed a transposon-tagging strategy for the genome-wide analysis of disruption phenotypes, gene expression and protein localization, and have applied this method to the large-scale analysis of gene function in the budding yeast Saccharomyces cerevisiae. Here we present the largest collection of defined yeast mutants ever generated within a single genetic background--a collection of over 11,000 strains, each carrying a transposon inserted within a region of the genome expressed during vegetative growth and/or sporulation. These insertions affect nearly 2,000 annotated genes, representing about one-third of the 6,200 predicted genes in the yeast genome. We have used this collection to determine disruption phenotypes for nearly 8,000 strains using 20 different growth conditions; the resulting data sets were clustered to identify groups of functionally related genes. We have also identified over 300 previously non-annotated open reading frames and analysed by indirect immunofluorescence over 1,300 transposon-tagged proteins. In total, our study encompasses over 260,000 data points, constituting the largest functional analysis of the yeast genome ever undertaken.

Algorithms↗

Discovery and synthesis of (S)-3-[2-(3,4-dimethoxyphenyl)ethoxy]-2- (4,6-dimethylpyrimidin-2-yloxy)-3,3-diphenylpropionic acid (LU 302872), a novel orally active mixed ET(A)/ET(B) receptor antagonist.

Structural variation of the endothelin A-selective antagonist (S)-3-methoxy-2-(4,6-dimethoxypyrimidin-2-yloxy)-3, 3-diphenylpropionic acid (LU 135252) led to analogues which retain ET(A) affinity but exhibit substantial ET(B) affinity as well. The most active derivative obtained is (S)-3-[2-(3, 4-dimethoxyphenyl)ethoxy]-2-(4,6-dimethylpyrimidin-2-yloxy)- 3, 3-diphenylpropionic acid (LU 302872), which can be prepared in enantiomerically pure form in eight steps via an acid-catalyzed transetherification. It has a K(i) = 2.15 nM for binding to the ET(A) receptor and a K(i) = 4.75 nM for binding to the ET(B) receptor, is orally available, and antagonizes the big ET-induced blood pressure increase in rats and the big ET-induced bronchospasm in guinea pigs each time at a dose of 10 mg/kg.

Administration, Oral↗

Do alterations in the sex ratio occur at fertilization? A case report using fluorescent in situ hybridization.

PURPOSE: The mechanisms by which the sex ratio might be altered at fertilization were reviewed, following a case of preimplantation gender analysis revealing a significantly skewed proportion of male-to-female embryos. METHODS: The case of a known carrier of X-linked hydrocephalus with a history of three affected male pregnancies is presented. Her husband's family history consisted of a strong increase in the number of males relative to females. She had four cycles of stimulated in vitro fertilization, with sex chromosome analysis using fluorescent in situ hybridization (FISH) on suitable cleavage-stage embryos. The difference in the sex ratio of normal male-to-female embryos was compared using a significance probabilities test for sex ratio. The sex ratio of sperm from a semen sample from the male partner was determined by FISH. RESULTS: Fifty embryos were suitable for analysis. A significantly higher number of normal male (n = 20) than normal female (n = 8) embryos was obtained (P < 0.05). The FISH assessment of the husband's semen analysis revealed no alteration in the normal X:Y ratio. CONCLUSIONS: As the sperm analysis revealed a normal X:Y ratio, an alteration in the embryo sex ratio might be explained by the preferential binding of Y-bearing sperm to the oocyte, an oocyte-related "discouragement" of binding of X-bearing sperm, or a postfertilization event.

Adult↗