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Biomedical subjects

H J Müller

Publications and source records attributed to H J Müller.

At least 55 records · Page 3Linked to original sources
PubMed1998

Disinhibition of return: unnecessary and unlikely.

Recently, from data obtained with a temporal order judgment (TOJ) task, Gibson and Egeth (1994) concluded that inhibition of return (IOR; a response time effect that reveals slower responding to targets at previously cued versus uncued locations) reflects impaired perceptual processing. By replotting their data, we demonstrate that the perception of temporal order is influenced only by the facilitatory effect of a cue at short stimulus onset asynchronies (SOAs) and is unaffected by IOR at long SOAs. The target paper proposed that, when extra stimuli are presented at task-relevant locations (i.e., in the TOJ task), IOR is prevented by a hypothetical process that is known as disinhibition of return (DOR). We argue that the assumptions that IOR affects perceptual processing and that DOR exists are unnecessary, as a more parsimonious response-based interpretation of IOR is consistent with their data. Further, we summarize recent results and present new data that demonstrate that DOR is unlikely.

Humans↗
PubMed1997

Phosphorylation of protein kinase Cdelta (PKCdelta) at threonine 505 is not a prerequisite for enzymatic activity. Expression of rat PKCdelta and an alanine 505 mutant in bacteria in a functional form.

A structural feature shared by many protein kinases is the requirement for phosphorylation of threonine or tyrosine in the so-called activation loop for full enzyme activity. Previous studies by several groups have indicated that the isotypes alpha, betaI, and betaII of protein kinase C (PKC) are synthesized as inactive precursors and require phosphorylation by a putative "PKC kinase" for permissive activation. Expression of PKCalpha in bacteria resulted in a nonfunctional enzyme, apparently due to lack of this kinase. The phosphorylation sites for the PKC kinase in the activation loop of PKCalpha and PKCbetaII could be identified as Thr497 and Thr500, respectively. We report here that PKCdelta, contrary to PKCalpha, can be expressed in bacteria in a functional form. The activity of the recombinant enzyme regarding substrate phosphorylation, autophosphorylation, and dependence on activation by 12-O-tetradecanoylphorbol-13-acetate as well as the Km values for two substrates are comparable to those of recombinant PKCdelta expressed in baculovirus-infected insect cells. By site-directed mutagenesis we were able to show that Thr505, corresponding to Thr497 and Thr500 of PKCalpha and PKCbetaII, respectively, is not essential for obtaining a catalytically competent conformation of PKCdelta. The mutant Ala505 can be activated and does not differ from the wild type regarding activity and several other features. Ser504 can not take over the role of Thr505 and is not prerequisite for the kinase to become activated, as proven by the unaffected enzyme activity of respective mutants (Ala504 and Ala504/Ala505). These results indicate that phosphorylation of Thr505 is not required for the formation of functional PKCdelta and that at least this PKC isoenzyme differs from the isotypes alpha, betaI, and betaII regarding the permissive activation by a PKC kinase.

Alanine↗
PubMed1997

Reporter gene analysis of four DNaseI hypersensitive sites in the plasminogen/apolipoprotein(a) intergenic region.

We have previously described four DNaseI hypersensitive sites (DH 1 to DH4) in the 40-kb intergenic region between the plasminogen gene and the apo(a) gene. Here, we wanted to analyse whether any of these sites, located 4, 21, 28 and 34 kb upstream of the apo(a) transcriptional start site, would act as an enhancer on a minimal apo(a) promoter. Starting from a cloned, highly expressed apo(a) allele, we obtained four fragments comprising the DHI to DH4 sites, respectively. These fragments were cloned in both orientations into a luciferase reporter gene plasmid comprising a minimal apo(a) promoter (-100 to +141 with respect to the transcriptional start site). Our results from transfection studies with the resulting series of reporter gene plasmids into liver (HepG2) and non-liver (HeLa) cells suggest that the four DH sites from the selected apo(a) allele do not provide a strong, liver-specific enhancer activity.

Apolipoproteins A↗
PubMed1997

Right ventricular dysfunction in patients with obstructive sleep apnoea syndrome.

There is conclusive evidence that obstructive sleep apnoea syndrome (OSAS) influences right heart haemodynamics and can also induce pulmonary hypertension. It is not known, however, whether right ventricular dysfunction can occur in patients with OSAS in the absence of lung disease. We studied 107 patients (94 males, 13 females, mean age 55 +/- 11 yrs) with polysomnographically verified OSAS in whom clinically significant lung disease was excluded. Right ventricular ejection fraction (RVEF) was determined by radionuclide ventriculography. In addition, pulmonary function tests, arterial blood gas analysis and right heart catheterization were performed. RVEF was impaired in 19 patients (18%). Eighteen (95%) had signs or symptoms consistent with mild right ventricular failure. Patients with or without impaired RVEF did not differ with respect to body mass index, age or lung function. Stepwise multiple logistic regression analysis revealed that RVEF was significantly associated with the apnoea/hypopnoea index (r = -0.68; p = 0.0009) and the extent of nocturnal oxyhaemoglobin saturation (r = 0.42; p = 0.035), but not with age, body mass index, blood gas analysis, gender, lung function, pulmonary artery pressure and left ventricular ejection fraction. We conclude that in patients with otherwise unexplained right ventricular failure, obstructive sleep apnoea syndrome may underlie the right ventricular dysfunction.

Adult↗
PubMed1997

Local and global orientation in visual search.

Six experiments investigated the role of global (shape) and local (contour) orientation in visual search for an orientation target. Experiment 1 demonstrated that search for a conjunction of local contours with a distinct global orientation was less efficient than search for a target featurally distinct in terms of both global and local contour orientation. However, Experiments 2 and 4 demonstrated that the presence of a unique line contour was neither sufficient nor necessary to allow efficient search. Experiment 5 found that search for a local orientation difference was strongly impeded by irrelevant variation in global orientation, arguing for a preeminent role for global orientation. Finally, Experiment 6 demonstrated that the orientation search asymmetry holds for the global orientation of stimuli. Taken together, the results are consistent with visual search processes guided predominantly by a representation of global orientation.

Adult↗
PubMed1996

The number of identical kringle IV repeats in apolipoprotein(a) affects its processing and secretion by HepG2 cells.

A variable number of 5.6-kilobase kringle IV repeats in the human apolipoprotein(a) (apo(a)) gene results in a size polymorphism of the protein and correlates inversely with the plasma levels of the atherogenic lipoprotein(a) (Lp(a)). In order to analyze whether this association reflects a direct effect of kringle IV repeat number on Lp(a) plasma concentration, we have studied the expression of recombinant apo(a) (r-apo(a)) isoforms in the human hepatocarcinoma cell line HepG2. Following transient transfection of apo(a) cDNA expression plasmids that differed only in the number of kringle IV repeats, we observed a gradual decrease of Lp(a) in the medium of the cells with an increasing number of kringle IV repeats, mimicking the relationship present in humans in vivo. The analysis of apo(a) protein in the lysate and in the medium of cells that were transfected with a plasmid encoding an apo(a) isoform with 22 kringles revealed a predominant intracellular precursor with little secretion of the mature apo(a) protein. In contrast, transfection of a plasmid encoding an isoform with 11 kringles led to effective secretion of the mature peptide into the medium, indicating differential processing rates of apo(a) isoforms in the secretory path way. The intracellular accumulation of an apo(a) precursor in the endoplasmic reticulum was demonstrated by cell fractionation and [35S]Met metabolic labeling/temperature block experiments using HepG2 cells stably transfected with recombinant apo(a). The direct and causal effect of kringle IV repeat number on the expression of recombinant apo(a) in HepG2 cells, and presumably liver cells, provides a novel mechanism for the genetic regulation of the concentration of a protein.

Apolipoproteins A↗
PubMed1996

Visual search for conjunctions of motion and form: display density and asymmetry reversal.

In visual search for motion-form conjunctions, search rates have been reported to be faster for moving than for stationary targets if the target-nontarget discrimination is easy (45 degrees target line tilt from vertical), but this asymmetry is reversed if the discrimination is difficult (9 degrees tilt) (J. Driver & P. McLeod, 1992). Driver and McLeod proposed that gross aspects of form discrimination are performed within a motion filter that represents only the moving items, whereas fine discriminations rely on a stationary form system that is poor at filtering by motion. However, H. J. Müller and J. Maxwell (1994) failed to observe the asymmetry reversal, possibly because they used lower density displays. The study reported in this article also did not yield an effect due to varying display density. This lends support to the notion of a unitary form system, with the role of the motion filter being limited to guiding the search to the moving items or, if required by the task, the stationary items.

Adolescent↗
PubMed1996

Searching for unknown feature targets on more than one dimension: investigating a "dimension-weighting" account.

Search for odd-one-out feature targets takes longer when the target can be present in one of several dimensions as opposed to only one dimension (Müller, Heller, & Ziegler, 1995; Treisman, 1988). Müller et al. attributed this cost to the need to discern the target dimension. They proposed a dimension-weighting account, in which master map units compute, in parallel, the weighted sum of dimension-specific saliency signals. If the target dimension is known in advance, signals from that dimension are amplified. But if the target dimension is unknown, it is determined in a process that shifts weight from the nontarget to the target dimension. The weight pattern thus generated persists across trials, producing intertrial facilitation for a target (trial n + 1) dimensionally identical to the preceding target (trial n). In the present study, we employed a set of new tasks in order to reexamine and extend this account. Targets were defined along two possible dimensions (color or orientation) and could take on one of two feature values (e.g., red or blue). Experiments 1 and 2 required absent/present and color/orientation discrimination of a single target, respectively. They showed that (1) both tasks involve weight shifting, though (explicitly) discerning the dimension of a target requires some process additional to simply detecting its presence; and (2) the intertrial facilitation is indeed (largely) dimension specific rather than feature specific in nature. In Experiment 3, the task was to count the number of targets in a display (either three or four), which could be either dimensionally the same (all color or all orientation) or mixed (some color and some orientation). As predicted by the dimension-weighting account, enumerating four targets all defined within the same dimension was faster than counting three such targets or mixed targets defined in two dimensions.

Adult↗
PubMed1996

Attentional tracking and inhibition of return in dynamic displays.

Seven experiments were conducted to replicate, and extend, a finding by Tipper, Driver, and Weaver (1991). They reported evidence for dynamic, object-centered inhibition of return (IOR)--that is, coding of inhibition following a peripheral cue in coordinates that move with the previously cued object, providing a dynamic bias against reattending to that object. The present experiments used a variation of Posner and Cohen's (1984) spatial cuing paradigm. Subjects responded manually (simple reaction time) to a luminance increment in one of two peripheral boxes, one of which had previously been cued (brightened). Experiments 1, 2, and 5 replicated the standard (environmental) IOR effect when the display was stationary. IOR was more marked for right-side targets than for left-side targets and tended to be affected by the compatibility between response hand and (cued) target position. However, when the boxes moved around the display center (Experiments 1, 2, 3, 4, 6, and 7), contrary to Tipper et al., there was no evidence of dynamic, object-centered IOR. Rather, there was strong evidence of attentive tracking of whatever box happened to move from left to right, irrespective of the direction of its motion (clockwise or counterclockwise) and whether it was more likely to contain the target than the other (right-to-left moving) box. There was a tendency for left-to-right tracking to be more marked with right-hand responses, pointing to the existence of a dynamic stimulus-response compatibility effect. The implications of the present findings for the role of attentive tracking and IOR in dynamic scenes are discussed.

Adolescent↗
PubMed1995

Protein kinase C delta-specific phosphorylation of the elongation factor eEF-alpha and an eEF-1 alpha peptide at threonine 431.

Two cytosolic proteins of murine epidermis or porcine spleen with molecular masses of 37 kDa (p37) and 50 kDa (p50) are differentially phosphorylated in vitro by the purified protein kinase C (PKC) isoenzymes alpha, beta, gamma (cPKC) and PKC delta. p37, identified as annexin I, is preferentially phosphorylated by cPKC, whereas p50, identified as elongation factor eEF-1 alpha, is phosphorylated with much greater efficacy by PKC delta than by cPKC. Using the recombinant PKC isoenzymes alpha, beta, gamma, delta, epsilon, eta, and zeta, we could show that purified eEF-1 alpha is indeed a specific substrate of PKC delta. It is not significantly phosphorylated by PKC epsilon, -eta, and -zeta and only slightly by PKC alpha, -beta, and -gamma. PKC delta phosphorylates eEF-1 alpha at Thr-431 (based on the murine amino acid sequence). The peptide RFAVRDMRQTVAVGVIKAVDKK with a sequence corresponding to that of 422-443 from murine eEF-1 alpha and containing Thr-431 is an absolutely specific substrate for the delta-type of PKC. The single basic amino acid close to Thr-431 (Arg-429) is essential for recognition of the peptide as a substrate by PKC delta and for the selectivity of this recognition. Substitution of Arg-429 by alanine abolishes the ability of PKC delta to phosphorylate the peptide, and insertion of additional basic amino acids in the vicinity of Thr-431 causes a complete loss of selectivity.

Amino Acid Sequence↗
PubMed1995

Identification of two functionally distinct lysine-binding sites in kringle 37 and in kringles 32-36 of human apolipoprotein(a).

The well documented association between high plasma levels of lipoprotein(a) (Lp(a)) and cardiovascular disease might be mediated by the lysine binding of apolipoprotein(a) (apo(a)), the plasminogen-like, multikringle glycoprotein in Lp(a). We employed a mutational analysis to localize the lysine-binding domains within human apo(a). Recombinant apo(a) (r-apo(a)) with 17 plasminogen kringle IV-like domains, one plasminogen kringle V-like domain, and a protease domain or mutants thereof were expressed in the human hepatocarcinoma cell line HepG2. The lysine binding of plasma Lp(a) and r-apo(a) in the culture supernatants of transfected HepG2 cells was analyzed by lysine-Sepharose affinity chromatography. Wild type recombinant Lp(a) (r-Lp(a)) revealed lysine binding in the range observed for human plasma Lp(a). A single accessible lysine binding site in Lp(a) is indicated by a complete loss of lysine binding observed for r-Lp(a) species that contain either a truncated r-apo(a) lacking kringle IV-37, kringle V, and the protease or a point-mutated r-apo(a) with a Trp-4174-->Arg substitution in the putative lysine-binding pocket of kringle IV-37. Evidence is also presented for additional lysine-binding sites within kringles 32-36 of apo(a) that are masked in Lp(a) as indicated by an increased lysine binding for the point mutant (Cys-4057-->Ser), which is unable to assemble into particles. An important role of these lysine-binding site(s) for Lp(a) assembly is suggested by a decreased assembly efficiency for deletion mutants lacking either kringle 32 or kringles 32-35.

Amino Acid Sequence↗
PubMed1995

[Ethical aspects in gene therapy].

Gene technology including gene therapy represents the most controversial subject in natural sciences or medicine and is discussed quite emotionally not only by the general public but also by persons within the medical profession. The ethical concerns with respect to gene therapy are complex and multifaceted. Besides categorical arguments, purely pragmatic ones are raised against this new medical procedure. Ethical aspects, primarily related to somatic gene therapy, will be evaluated in this paper from the point of view of a physician.

Biotechnology↗
PubMed1995

Sequence polymorphism in kringle IV 37 in linkage disequilibrium with the apolipoprotein (a) size polymorphism.

Apolipoprotein(a) [apo(a)] contains a variable number of identical (K-IV A/B) or nearly identical (K-IV 1, K-IV 30-37) kringle repeats that are homologous to K-IV from plasminogen. The sizes of 414 apo(a) alleles were determined by pulsed-field gel electrophoresis (PFGE) of KpnI-digested DNA. Furthermore, sequence variation in the apo(a) K-IV 30-37 domain was analysed. Reverse transcription/polymerase chain reaction (RT-PCR) cloning of human liver poly A+ RNA followed by sequencing revealed a single nucleotide exchange in the ultimate K-IV (K-IV 37) of apo(a) (codon 4168); this results in an ATG (Met) to ACG (Thr) substitution. A PCR-based restriction assay of genomic DNA demonstrated that this substitution represents a common polymorphism. In 231 unrelated Tyroleans, the frequencies for the K-IV 37 Thr and K-IV 37 Met alleles were 0.66 and 0.34, respectively. The phase between the K-IV 37 Met/Thr and the KpnI size polymorphism was determined for 224 alleles. A significant linkage disequilibrium was detected between the sequence and size polymorphisms of apo(a). K-IV 37 Met was significantly associated with KpnI allele no. 18 (DAB = 0.0267 +/- 0.0101; chi 2 = 10.09, df = 1). The Met/Thr polymorphism was further used to test whether deletions or duplications of K-IV 37 occur frequently in the apo(a) gene. Some 40 apo(a) alleles, 22 of which were from subjects that appeared to be double heterozygotes for K-IV repeat number and the Met/Thr variation were separated by PFGE and analysed for the 4168 Met/Thr polymorphism. The Met and Thr sequences were always present on different size alleles and no evidence for a duplication or deletion of K-IV 37 was obtained. This suggests that the copy number of K-IV 37 is invariable, in contrast to the highly variable K-IV A/B domain of the gene. The 4168 Met/Thr polymorphism had no effect on Lp(a) concentration, neither did it influence the lysine-binding property of the Lp(a) particle.

Adult↗
PubMed1995

Increased phagocytic capacity of the blood, but decreased phagocytic activity per individual circulating neutrophil after an ultradistance run.

The effect of a long strenuous endurance exercise on the phagocytic function of neutrophils was examined. 9 athletes [7 males, 2 females, age: 36-68 years, body mass: 64 (SD 10) kg, height: 175 (SD 10) cm] completed a competetive 100 km run in 8:07 (median value; range: 7:29-9:50 hours). In a whole blood assay the phagocytosis of opsonized E. coli, the receptor density of the Fc gamma receptor 3 (CD16) and the complement receptor 3 (CD11b, direct immunofluorescence) of neutrophils were measured on a per cell basis by flow cytometry before and up to 3 hours after the race. The phagocytic rate (percentage of neutrophils incorporating bacteria) was unchanged after exercise, whereas the phagocytic activity (number of incorporated bacteria per cell) was significantly reduced by -34 (SD 8) % (Wilcoxon test, P < 0.001). The total phagocytic capacity of the blood increased 2-3fold post exercise. The surface antigen expressions of CD11b and CD16 were unaffected by the ultradistance run. The results indicate either a reduced phagocytic function of neutrophils on a single cell basis or the mobilization of neutrophils of the marginal pool with a lower phagocytic activity. However, after a long endurance exercise the phagocytotic capacity of the blood was enhanced due to increased cell concentrations.

Adult↗
PubMed1995

The value of family investigations in newly detected Charcot-Marie-Tooth disease in children.

Charcot-Marie-Tooth disease (CMT) was diagnosed by nerve conduction velocity and histology of the sural nerve in two boys aged 3 and 6 years with clinical signs of a severe neuromuscular disease. DNA analysis revealed the typical duplication on chromosome 17p11.2 (2.7 kb allele) for CMT 1A. Although none of their family members reported symptoms of neuromuscular disease, the nerve conduction velocity was reduced in three members (father and two aunts). They were homozygous for the 2.7 kb allele and were assumed to carry three copies of this allele. The very differing clinical picture from one generation to the next in patients with identical neurophysiological and genetic results is discussed.

Autoradiography↗
PubMed1995

Sequence polymorphisms in the apo(a) gene associated with specific levels of Lp(a) in plasma.

Most of the interindividual variations in plasma levels of lipoprotein(a) [Lp(a)] can be attributed to sequence differences linked to the apolipoprotein(a) [apo(a)] locus. Plasma levels of Lp(a) tend to be inversely related to the number of kringle 4 (K4)-encoding sequences in the apo(a) gene, but there are several exceptions to this general trend. Other aspects of the apo(a) gene, in addition to the number of K4 repeats, affect plasma levels of Lp(a). To identify sequences in the apo(a) gene that contribute to plasma Lp(a) levels, we characterized the relationship between a length polymorphism [(TTTTA)n] located 1.3 kb 5' of the first exon of the apo(a) gene, the number of K4 repeats in the gene, and the plasma levels of Lp(a). There was significant linkage disequilibrium between the number of TTTTA repeats and the number of K4 repeats. All of the apo(a) alleles with 11 TTTTA repeats contained fewer than 24 K4 repeats and were paradoxically associated with low plasma Lp(a) levels (< or = mg/dl). To determine whether this association was due to the effect of the 11 TTTTA copies on apo(a) gene transcription, we measured the ability of fragments containing 11 or eight TTTTA repeats to promote transcription when introduced into cultured human hepatocarcinoma cells. No difference was found in the transcriptional activity of the two fragments. The TTTTA repeat constitutes the first sequence polymorphism at the apo(a) locus, other than the number of K4 repeats, which is associated with plasma concentrations of Lp(a).

Alleles↗