Rates of mortality in populations of Caenorhabditis elegans.
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Animals↗
Biomedical subjects
H G Müller
Publications and source records attributed to H G Müller.
Hazard rate estimation under random censoring with varying kernels and bandwidths.
We discuss the estimation of hazard rates under random censoring with the kernel method. Two practically relevant problems that occur when applying unmodified kernel estimators are boundary effects near the endpoints of the support of the hazard rate, and a substantial increase in the variance from left to right over the range of abscissae where the hazard rate is estimated. A new class of boundary kernels is proposed for the first problem. Explicit formulas for these kernels are developed, and it is shown that this boundary correction works well in practice. A data-adaptive varying bandwidth selection procedure is proposed for the second problem. This procedure generally will lead to increasing bandwidths near the left endpoint and toward the right endpoint, and will lead to smaller integrated mean squared error of the hazard rate estimator as compared to a fixed bandwidth method. A practically feasible method incorporating the new boundary kernels and local bandwidth choices is implemented and illustrated with survival data from a leukemia study.
Algorithms↗
A depletion-repletion folate bioassay based on growth and tissue folate concentrations of rats.
To improve standardization of a folate bioassay, folate-depleted rats were repleted with a folate-free amino acid-based diet supplemented with 29 levels of folic acid. Growth was the main response variable and body tissue folate concentrations were also assessed. Because a positive correlation was observed between low levels of dietary folic acid and growth and little or no correlation was observed between high levels and growth, six regression models with a steep slope for low levels and a shallow or zero slope for high levels of dietary folic acid were evaluated. The model referred to as the "two-phase regression" or "change-point" model best described the relationship. Depleted rats needed 674 +/- 71 nmol folic acid/kg diet to reach their full growth potential. This value is biologically sensible, and this regression model is well established in the statistical literature. The change-point model is highly recommended to characterize the growth response, because growth is a functional response and, in the range of 226 to 680 nmol folic acid/kg, this response is linear, which is an additional advantage. Linear responses are easier to interpret because of complicated issues of interpretation and confidence intervals with nonlinearities. Linear regressions described serum and liver folate responses, whereas exponentials described whole blood and carcass folate responses. Depleted rats needed 5920 and 5780 nmol folic acid/kg diet to maximize their whole blood and carcass folates, respectively.
Animals↗
Quality control in routine chromosome analysis: prediction of total number of bands for the individual case analyzed.
In routine diagnosis it is of importance for each single analysis to provide information about the level of quality at which the chromosomal analysis has been performed. The number of bands counted can be used as a direct criterion for the level of quality. Statistical prediction methods via linear regression were employed in order to predict the total number of bands of a haploid set of the metaphase (TNB) from those of single chromosomes or pairs of chromosomes. It was demonstrated that TNB can be predicted successfully by counting bands on just one chromosome, where chromosomes C2, C4, C5 or C7 were found suitable for prediction. If pairs of chromosomes are used to predict TNB, we would recommend C4/C7, C5/C6, and C2/C9.
Chromosome Banding↗
Immunocytochemical localization of alkane-inducible cytochrome P-450 and its NADPH-dependent reductase in the yeast Candida maltosa.
Antibodies directed against cytochrome P-450Cm1 and the NADPH-cytochrome P-450 reductase were used to study the induction and intracellular localization of these components of the alkane monooxygenase system in the yeast Candida maltosa. Transition from glucose to n-hexadecane utilization resulted in an about 100-fold increase of the immunodetectable P-450 form whereas the reductase was only moderately induced by a factor of about 5. P-450 but not the reductase was further increased by oxygen limitation during cultivation on n-hexadecane. Using an immunogold technique on ultrathin cryosections, P-450 was found to be concentrated in the nuclear envelope during the early phase of the induction process. However, after maximal induction, the highest labeling was observed in membranes of the endoplasmic reticulum closely associated with the peroxisomes and the plasma membrane. Double-labeling experiments revealed that P-450 and its reductase were distributed in the same regions of the endoplasmic reticulum.
Alkanes↗
Evidence that more than one gene encodes n-alkane-inducible cytochrome P-450s in Candida maltosa, found by two-step gene disruption.
An n-alkane-assimilating yeast, Candida maltosa, has a diploid genome. Probed with the previously isolated gene of n-alkane-inducible cytochrome P-450 (P-450alk), its allelic gene had been isolated, its nucleotides sequenced, and the interallelic divergence examined. Using one of the allelic genes, we disrupted the two alleles of the cytochrome P-450alk gene by a two-step gene disruption system. Surprisingly, the disruptant still assimilated n-alkane and contained n-alkane-inducible cytochrome P-450. This result indicates that, other than the disrupted two alleles, there is at least one other gene that encodes an n-alkane-inducible cytochrome P-450.
Alkanes↗
Comparison of two cytochromes P-450 from Candida maltosa: primary structures, substrate specificities and effects of their expression in Saccharomyces cerevisiae on the proliferation of the endoplasmic reticulum.
cDNAs were cloned, sequenced and expressed which encode two different cytochrome P-450 forms of the alkane-assimilating yeast Candida maltosa, designated as P-450Cm1 and P-450Cm2. The amino acid sequences deduced were about 55% identical. Expression in Saccharomyces cerevisiae resulted in the formation of intact microsomal P-450 systems catalyzing the hydroxylation of n-hexadecane and lauric acid with significantly different substrate preferences. A massive proliferation of the endoplasmic reticulum was observed in the S. cerevisiae cells which produced P-450. Depending on the P-450 form expressed, distinctly organized stacks of paired membranes appeared and occupied considerable areas of the cytoplasm. As shown by immunoelectron microscopy for P-450Cm1, the protein expressed was highly concentrated within these newly formed membrane structures.
Amino Acid Sequence↗
A hypothesis on the abnormal seasonality of schizophrenic births.
The hypothesis is proposed that the abnormal seasonality of schizophrenic births is partly a consequence of seasonal variation of conception and of an associated seasonal variation of risk of premature delivery.
Cross-Sectional Studies↗
Tissue distribution and prediction of total body folate of rats.
To clarify relationships between dietary folic acid intake, blood levels and body stores of folate, rats were fed an amino acid-based diet supplemented with 0, 0.125, 0.5, 1, 2 or 4 mg folic acid/kg diet for 25 d. Folate concentrations of carcass, liver, gastrointestinal (GI) tract, kidney, spleen, testes, heart and lung from rats fed the folate-free diet were 0.06 +/- 0.01, 0.73 +/- 0.08, 0.05 +/- 0.01, 0.39 +/- 0.01, 0.05 +/- 0.01, 0.17 +/- 0.01, 0.02 +/- 0.01 and 0.02 +/- 0.01 micrograms/g, respectively. Serum and erythrocyte concentrations and total body stores were 0.88 +/- 0.16 ng/mL, 0.30 +/- 0.01 micrograms/mL and 13.9 +/- 0.7 micrograms, respectively. Body folate distribution was carcass, 55.6 +/- 1.4%; liver, 26.0 +/- 1.9%; erythrocytes, 7.7 +/- 0.4%; kidney, 4.8 +/- 0.2%; GI tract, 3.0 +/- 0.2%; and testes, 2.5 +/- 0.2%. Carcass content dropped to 38% whereas liver content increased to 44% in rats fed the highest dietary level. Tissue concentrations were correlated with one another and with dietary folate levels. Under these experimental conditions total body folate could be predicted from serum folate, but the general applicability of this relationship requires further study.
Animals↗
[Electronic measurements of the masticatory muscles. 2: Interpretation of activity changes in the masticatory muscles].
In part II, a method is described which reduced the variations of the three determinants of the voltage/tension curves to the fluctuation of only one three dimensional variable. A way to estimate three dimensional regions for the fluctuations is shown. For a given level of significance, limits can be calculated that allow us to decide whether differences between post- and pre-treatment measurements are random or due to treatment.
Electromyography↗
[Morphometric analysis of age-dependent changes of the human ciliary body].
Morphometric and stereologic techniques have been applied to human ciliary epithelium and bordering stroma of 31 (respectively 16) normal donor eyes aged 15 to 86, providing quantitative information on the age-related structural changes of ciliary body tissue. Aging appeared to result in a generalized widening of the stromal layer from 19.3 +/- 2.4 microns (10-20 years; n = 4) to 60.0 +/- 11.5 microns (80-90 years; n = 3) in ciliary processes and from 53.0 +/- 6.8 microns to 107.6 +/- 15.2 microns in the ground plate between ciliary valleys and ciliary muscle, a density increase of collagenous fibers from 39.3 +/- 4.9 to 83.5 +/- 14.6 fibers/microns 2 and a concomitant decrease in mean fiber diameter from 62.8 +/- 3.4 nm to 55.7 +/- 1.5 nm, a decline of stromal cell density from 31.4 +/- 1.8 to 9.6 +/- 1.0 cells/0.014 mm2, a progressive thickening of the inner and outer limiting membranes from 0.8 +/- 0.4 micron to 8.1 +/- 1.5 microns and 2.1 +/- 0.6 microns to 4.5 +/- 0.5 microns respectively as well as the endothelial basement membrane from 0.13 +/- 0.004 micron to 0.25 +/- 0.03 micron, a gradual widening of the perivascular space between capillaries and overlying pigment epithelium from 6.2 +/- 1.5 microns to 11.3 +/- 2.9 microns, an increase in number of fenestrations in the capillary endothelium from 39.0 +/- 8.5 to 69.0 +/- 7.0 pores/100 microns, and finally a continuous augmentation of degenerative elements including lipids, lipofuscin granules, and lysosomes from 1.5 +/- 0.06% to 7.2 +/- 0.6% within the non-pigmented epithelium (NPE) over the 71-year period studied. Regression analysis yielded a highly significant impact of age on these morphometric parameters, while the relative volumes of the remaining cell compartments of the NPE-cells revealed no statistically significant correlation with age. Rather, the variations in volume densities of Golgi bodies (0.34 +/- 0.25%; n = 16) and pigment granules (0.36 +/- 0.27%; n = 16) seemed to be random with respect to age, whereas the relative volumes of mitochondria (21.7 +/- 1.8%; n = 16) and RER (5.9 +/- 0.7%; n = 16) remained fairly constant indicating that the NPE-cells maintain their functional capacity with advancing age. Age-related reduction of aqueous humor formation therefore appears to be rather due to impaired fluid passage from vasculature to ciliary epithelium than to functional incompetency of the NPE.
Adolescent↗
Desmosomal-mitochondrial complexes in human nonpigmented ciliary and retinal pigment epithelia.
In the normal human nonpigmented ciliary epithelium structural associations between mitochondria and desmosomes are described electron-microscopically: either a single desmosome or a linear array of several desmosomes joined by filamentous bundles is associated with one or two mitochondria (19.6 +/- 5.4%; n = 29). The frequency of occurrence of these complexes was studied in five different regions of the ciliary body; analysis of covariance revealed a significantly increased number of associations in the ciliary processes. Further, the age dependence of their occurrence was examined in 29 different age classes (15 to 86 years); correlation analysis revealed no correlation between age and number of associations. Similar complexes occur, in addition, in the retinal pigment epithelium, but have not been observed in ciliary pigmented, lens, iris and corneal epithelia. Desmosomal-mitochondrial complexes are considered to be a characteristic feature of basic physiological significance of certain epithelia only. The cytochemical demonstration of calcium in the associated mitochondria provides support for the hypothesis that the mitochondria may serve as buffers for intracellular calcium by controlling the local calcium concentration, thus increasing the stability and functional integrity of desmosomal junctions in secretory or actively transporting epithelia with high endogenous calcium levels.
Ciliary Body↗
Choice of number of doses for maximum likelihood estimation of the ED50 for quantal dose-response data.
We address the question of how to choose the number of doses when estimating the median effective dose (ED50) of a symmetric dose-response curve by the maximum likelihood method. One criterion for this choice here is the asymptotic mean squared error (determined by the asymptotic variance) of the estimated ED50 of a dose-response relationship with qualitative responses. The choice is based on an analysis of the inverse of the information matrix. We find that in many cases, assuming various symmetric dose-response curves and various design densities, choice of as many doses as possible, i.e., the allocation of one subject per dose, is optimal. The theoretical and numerical results are supported by simulations and by an example concerning choice of design in an adolescence study.
Animals↗
Molecular cloning and characterization of the primary structure of the alkane hydroxylating cytochrome P-450 from the yeast Candida maltosa.
A cDNA library was established starting from poly(A) RNA of n-alkane-grown Candida maltosa cells and cDNA clones were isolated containing the entire coding sequence for the alkane hydroxylating cytochrome P-450. The deduced protein consists of 521 amino acids, contains two putative transmembrane segments in the N-terminal region and has a characteristic heme-binding sequence in the C-terminal part. Sequence alignments with members of 11 reported cytochrome P-450 families revealed a strong homology to an alkane-inducible cytochrome P-450 from Candida tropicalis.
Amino Acid Sequence↗
A novel L-glutamate oxidase from Streptomyces endus. Purification and properties.
A new flavoenzyme using molecular oxygen to oxidize L-glutamic acid has been purified to homogeneity, as judged by polyacrylamide gel electrophoresis, from the culture medium of Streptomyces endus. Hydrogen peroxide, 2-oxoglutaric acid and ammonia are formed as products. Among 25 amino acids tested including D-glutamic acid, L-glutamine and L-aspartic acid, only L-glutamic acid is converted. The molecular mass of the enzyme was estimated to be about 90 kDa by gel chromatography and 50 kDa by SDS/PAGE. The subunit contains 1 molecule noncovalently bound FAD. The absorption spectrum shows maxima at 273, 355 and 457 nm and the isoelectric point is at pH 6.2. The Km value for L-glutamic acid in air-saturated phosphate pH 7.0 was estimated to be 1.1 mM, the Km for oxygen was calculated to be 1.86 mM at saturating concentration of L-glutamic acid. The enzymic reaction is inhibited by Ag+ and Hg2+ ions. The enzyme described here distinctly differs from two microbial L-glutamate oxidases purified hitherto, with regard to extremely high substrate specificity and to the subunit structure.
Amino Acid Oxidoreductases↗
Evaluation of prognostic factors in cerebral arteriovenous malformations.
In a retrospective study of 48 patients who underwent elective surgery for cerebral arteriovenous malformations, a statistical analysis of demographic, clinical, and neuroradiological data was undertaken in order to discover the best predictors of operative morbidity. In addition, the predictive value of different clinical grading systems as applied to this series was compared. All patients had a computed tomographic scan and a positive angiogram before surgery. Complete resection was proven angiographically. The univariate Mann-Whitney-Wilcoxon rank sum test, the Fisher exact test, Spearman's rank correlation coefficient analysis, and multivariate logistic regression were used as statistical methods. Duration of surgery, the development, of either new deficits or an increase in the preoperative neurological signs immediately after surgery, and rehabilitation (as measured by the Karnofsky index) were taken as target variables for the difficulty of operation and for postoperative morbidity, respectively. The largest diameter of the nidus of the arteriovenous malformation, eloquence of the adjacent brain, and deep venous drainage showed the most consistent correlation with these target variables. Intracerebral hematoma and other single factors, such as the age of the patient or localization of the arteriovenous malformation did not affect the outcome. The clinical grading scale of Spetzler and Martin provided better prediction of surgical risks than other proposed systems.
Adult↗
Oxygen limitation induces indirectly the synthesis of cytochrome P-450 mRNA in alkane-growing Candida maltosa.
Candida maltosa cells grown on hexadecane under oxygen limitation have an up to 6-fold higher cytochrome P-450 content in comparison to cells cultivated at oxygen saturation. We show by mRNA quantification using an in vitro translation system and subsequent specific immunoprecipitation that the cytochrome P-450 induction occurs mainly on the transcriptional level. The signal for induction may be the enhanced intracellular hexadecane concentration owing to a reduced hydroxylation capacity of the cytochrome P-450 at oxygen limitation.
Aerobiosis↗
Post-translational transport of proteins into microsomal membranes of Candida maltosa.
We have isolated from the yeast Candida maltosa microsomal membranes that are active in the translocation of proteins synthesized in cell-free systems derived from C. maltosa, Saccharomyces cerevisiae or wheat germ. Translocation and core glycosylation of prepro-alpha-factor, a secretory protein, were observed with yeast microsomes added during or after translation. The signal peptide is cleaved off. Cytochrome P-450 from C. maltosa, the first integral membrane protein studied in a yeast system, is also inserted both co- and post-translationally into Candida microsomal membranes. Its insertion into canine microsomes occurs efficiently only in a co-translational manner and is dependent on the function of the signal recognition particle.
Candida↗