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21.
The roles of duplicate genes and their contribution to the phenomenon of enzyme dispensability are a central issue in molecular and genome evolution. A comprehensive classification of the mechanisms that may have led to their preservation, however, is currently lacking. In a systems biology approach, we classify here back-up, regulatory, and gene dosage functions for the 105 duplicate gene families of Saccharomyces cerevisiae metabolism. The key tool was the reconciled genome-scale metabolic model iLL672, which was based on the older iFF708. Computational predictions of all metabolic gene knockouts were validated with the experimentally determined phenotypes of the entire singleton yeast library of 4658 mutants under five environmental conditions. iLL672 correctly identified 96%-98% and 73%-80% of the viable and lethal singleton phenotypes, respectively. Functional roles for each duplicate family were identified by integrating the iLL672-predicted in silico duplicate knockout phenotypes, genome-scale carbon-flux distributions, singleton mutant phenotypes, and network topology analysis. The results provide no evidence for a particular dominant function that maintains duplicate genes in the genome. In particular, the back-up function is not favored by evolutionary selection because duplicates do not occur more frequently in essential reactions than singleton genes. Instead of a prevailing role, multigene-encoded enzymes cover different functions. Thus, at least for metabolism, persistence of the paralog fraction in the genome can be better explained with an array of different, often overlapping functional roles. 相似文献
22.
Uwe Beginn Gabriela Zipp Martin Mller Gary Johansson Virgil Percec 《Macromolecular chemistry and physics.》1997,198(9):2839-2852
Crystallization and supramolecular aggregation of 1,4,7,10,13-pentaoxacyclopentadecane-2-ylmethyl 3,4-bis[4-(dodecyl-1-oxy)benzyloxy]-5-(11-methacryloyloxyundecyl-1-oxy)benzoate ( 1 ) and its complexes with sodium triflate are described in solutions of the methacrylate monomers. Formation of a gel was observed covering a rather wide concentration range in the pseudo-binary phase diagram. In the low concentration regime and at low temperatures, gel formation by elongated crystals of 1 was observed. It was demonstrated that the formation of a crystalline network and the shape of the crystals strongly depend on the cooling rate. 相似文献
23.
The trisomy 16 mouse model of Down syndrome has been used to compare calcium (Ca)-homeostasis and Ca-signaling in astrocytes from trisomic mice and from diploid littermates. Ratio calcium-imaging of Fura-2/AM loaded primary astroglial cultures prepared from the hippocampus shows that resting Ca levels are on average significantly higher in trisomic than in the control astrocytes (280 vs. 120 nM). Serotonin (3 μM) and glutamate (30–300 μM) evoked transient Ca-increases from 400 to 600 nM in euploid but from only 20 to 150 nM in trisomic astrocytes. Imaging of ATP-driven Ca-accumulation in cellular organelles revealed a significantly stronger uptake of Ca in trisomic astrocytes that might buffer cytosolic Ca-increases. Our results demonstrate major disturbances in Ca-signaling in trisomic astrocytes that are likely to be of pathophysiological relevance. 相似文献
24.
25.
Virgil Percec Gabriela Zipp Gary Johansson Uwe Beginn Martin Mller 《Macromolecular chemistry and physics.》1997,198(2):265-277
Synthesis and characterization of methacrylate-monofunctionalized crown ether compounds based on derivatives of 2-hydroxymethyl-1,4,7,10,13-pentaoxacyclopentadecane and 4′-hydroxymethyl-1,4,7,10,13-pentaoxabenzocyclopentadecane is described. By differential scanning calorimetry (DSC) and thermooptical analysis (TOA) it is shown that the synthesized compounds and their sodium triflate complexes exhibit columnar mesophases. 相似文献
26.
27.
Notfall + Rettungsmedizin - Das akute Koronarsyndrom ist der häufigste Grund für einen Rettungsdiensteinsatz in Deutschland. So resultieren in etwa 20–25 % aller Einsätze... 相似文献
28.
Walther Seiler Hermann Wetzel Andreas Hillert Günter Schöllnhammer Michael Langer Uwe Barlage Christoph Hiemke 《Psychopharmacology》1994,116(4):457-463
Pharmacokinetics and bioavailability of benperidol were determined in 13 schizophrenic patients after acute administration of 6 mg benperidol as an intravenous (i.v.) bolus injection, orally as liquid, and orally as tablets using a partially randomized cross-over design. Drug plasma levels were determined by high performance liquid chromatography with electrochemical detection and subjected to model independent pharmacokinetic analyses. After i.v. dosing the geometric means (mean-g) were 3.2 min for the distribution half-life, 5.80 h for the elimination half-life (t
1/2), 4.21 l/kg for the distribution volume, 7.50 h for the mean residence time (MRT), and 0.50 l/(h*kg) for the clearance. After oral administration as liquid and as tablet mean-g data for the time lag until the first appearance of measurable plasma concentrations were 0.33 and 1.1 h, mean-g
t
1/2 values were 5.5 and 4.7 h, respectively, mean-g t
max data were 1.0 h and 2.7 h, mean-g MRT values were 8.44 and 8.84 h, and mean-g C
max
maxvalues were 10.2 and 7.3 ng/ml. Differences between liquid and tablet administration were statistically significant for time lag,t
max, andC
max. Mean-g absolute bioavailabilities were computed as 48.6% after liquid and 40.2% after tablet administration respectively. All parameters studied exhibited large intersubject variation. The plasma concentrations of the presumed metabolite reduced benperidol were found to be very low. 相似文献
29.
Robert M. Mader Harald Zilg Otto Schlappack Günther G. Steger Martina Baur Bertold Greifenberg Uwe Heberle Christian Dittrich 《Cancer chemotherapy and pharmacology》1995,37(1-2):91-96
Improved quality of life has gained importance over shortly lasting remissions in yet incurable metastatic breast cancer. Fractionation of drug administration is one of the possible approaches to reduce the concentration-dependent toxicity of anthracyclines. We evaluated the pharmacokinetics of 4-O-tetrahydropyranyladriamycin (THP-ADM) under weekly administration in patients with advanced breast cancer (dose escalation, from 20 to 27 mg/m2 THP-ADM). The concentration-time curves of THP-ADM in plasma were best described by an open three-compartment model [half-life of the first disposition phase (t1/2), 3.15 min; terminal elimination half-life (t
1/2), 13.9 h] with a mean area under the curve (AUC) of 12.2 ng h ml–1mg–1m–2, resulting in a mean plasma clearance of 86.91 h–1m–2. Metabolism included the formation of Adriamycin (ADM), Adriamycinol (ADM-OH), 13-dihydro-4-O-tetrahydropyranyladriamycin (THP-OH), 7-deoxyadriamycinone (7H-ADn), and 7-deoxy-13-dihydroadrimycinone (7H-ADn-OH), with maximal plasma concentrations ranging from 2.8 to 5.5 ng/ml. The mean total amount of cytotoxic anthracyclines excreted into urine, mainly as the parent drug, was 5% of the delivered dose. ADM and ADM-OH, but not the parent drug, were observed in urine at up to 4 weeks after the last therapeutic cycle. There was a significant correlation between the leukocyte nadir under therapy and the AUC of ADM-OH (r=0.800,P<0.05). Since no shift in the plasma kinetics was observed from the first to the sixth cycle, the favorable ratio of the AUCs of THP-ADM and ADM after fractionation of THP-ADM suggests lower toxic side effects attributable to ADM. This hypothesis was confirmed in a clinical study, where no severe cardiotoxicity and only mild alopecia were observed in 19 patients. Thus, pharmacokinetics studies might be helpful in both individualization of therapy with THP-ADM and optimization of the administration schedule. 相似文献
30.
MRI findings in Hirayama’s disease: flexion-induced cervical myelopathy or intrinsic motor neuron disease? 总被引:6,自引:0,他引:6
Schröder R Keller E Flacke S Schmidt S Pohl C Klockgether T Schlegel U 《Journal of neurology》1999,246(11):1069-1074
Hirayama’s disease is a benign juvenile form of focal amyotrophy affecting the upper limbs. Previous studies have suggested
that the disorder is a neck flexion induced cervical myelopathy. We report clinical and magnetic resonance imaging findings
in nine patients with Hirayama’s disease. Cervical imaging of seven patients revealed spinal cord changes consisting of focal
atrophy and foci of signal alterations. On neck flexion a forward movement and mild reduction in the anteroposterior diameter
of the lower cervical cord against the vertebral bodies was noted in affected individuals as well as in five normal controls.
In contrast to earlier reports, none of our patients showed complete obliteration of the posterior subarachnoid space. Measurement
of the anteroposterior spinal cord diameter in each vertebral segment (C4–C7) revealed no significant differences in the degree
of spinal cord flattening between the two groups. Furthermore, two of our patients had significant degenerative changes in
the cervical spine (disc herniation, retrospondylosis) contralateral to the clinically affected side. These degenerative changes
resulted in a marked cord compression on neck flexion but were not associated with ipsilateral clinical abnormalities or spinal
cord alterations. Our results argue against a flexion-induced cervical myelopathy and support the view that Hirayama’s disease
is an intrinsic motor neuron disease.
Received: 15 March 1999 Received in revised form: 25 May 1999 Accepted: 1 June 1999 相似文献