PubMed Health⌕ Search

Biomedical subjects

G Wulf

Publications and source records attributed to G Wulf.

At least 19 recordsLinked to original sources
PubMed2007

Asthenoteratozoospermia in mice lacking testis expressed gene 18 (Tex18).

Testis expressed gene 18 (Tex18) is a small gene with one exon of 240 bp, which is specifically expressed in male germ cells. The gene encodes for a protein of 80 amino acids with unknown domain. To investigate the function of (Tex18) gene, we generated mice with targeted disruption of the (Tex18) gene by homologous recombination. Homozygous mutant males on a mixed genetic background (C57BL/6J x 129/Sv) are fertile, while they are subfertile on the 129/Sv background, although mating is normal. We showed that Tex18(-/-) males are subfertile because of abnormal sperm morphology and reduced motility, which is called asthenoteratozoospermia, suggesting that (Tex18) affects sperm characteristics. Maturation of spermatids is unsynchronized and partially impaired in seminiferous tubules of Tex18(-/-) mice. Electron microscopical examination demonstrated abnormal structures of sperm head. In vivo experiments with sperm of Tex18(-/-) 129/Sv mice revealed that the migration of spermatozoa from the uterus into the oviduct is reduced. This result is supported by the observation that sperm motility, as determined by the computer-assisted semen analysis system, is significantly affected, compared to wild-type spermatozoa. Generation of transgenic mice containing Tex18-EGFP fusion construct revealed a high transcriptional activity of (Tex18) during spermiogenesis, a process with morphological changes of haploid germ cells and development to mature spermatozoa. These results indicate that (Tex18) is expressed predominantly during spermatid differentiation and subfertility of the male Tex18(-/-) mice on the 129/Sv background is due to the differentiation arrest, abnormal sperm morphology and reduced sperm motility.

Acrosome Reaction↗
PubMed2006

Resistance against natural killer cell cytotoxicity: analysis of mechanisms.

Target cell resistance against natural killer (NK) cell-mediated cytotoxicity obstructs NK cell-based immunotherapy of leukaemia. Several mechanisms of resistance have been described. Because of lack of simple assays for analysing these mechanisms, their relative impact on a given effector-target pair is mostly unknown. We here analysed the combination of the Granzyme B (GrB) enzyme-linked immunospot assay (ELISPOT) for the assessment of NK cell reactivity and cytotoxicity assays to estimate target cell escape mechanisms. Target cell recognition failure leads to negative GrB ELISPOT results, whereas target cell resistance shows positive GrB ELISPOT results in the absence of cytotoxicity. We confronted NK cells with the sensitive target cell line K562, and with the resistant cell lines ML2, SupB15 and Raji. ML2 cells sufficiently activated GrB-release whilst being resistant against cytotoxic granules of NK cells. Partial resistance of Raji results from the interaction of HLA class I with inhibitory killer immunglobulin-like receptors (KIR) on the NK cells. Failure of target recognition by HLA class I-KIR interaction, lacking ligands to stimulatory NK cell receptors and partial resistance to cytotoxic granules all contributed to resistance of SupB15. In conclusion, revealing the mechanisms of resistance against NK cell-mediated cytotoxicity may allow improving the results of NK-based immunotherapy.

Cell Line, Tumor↗
PubMed2004

Reduced-intensity conditioning prior to allogeneic transplantation of hematopoietic stem cells: the need for T cells early after transplantation to induce a graft-versus-lymphoma effect.

In patients with poor-risk relapse of aggressive lymphoma, reduced-intensity conditioning followed by allogeneic PBSCT may have its limitations because of rapid regrowth of the tumor. We tried to address this problem by intermediate-intensity conditioning followed by allogeneic SCT. A total of 21 patients received fludarabine, busulfan and cyclophosphamide prior to allogeneic SCT. In the first 10 patients, GVHD prophylaxis by CD34+ selection of the grafts was employed (group I). The next 11 patients received nonmanipulated grafts and mycophenolat mofetil plus cyclosporinA (group II). In group I, no GVHD was observed. In contrast, patients in group II had a significant risk of acute GVHD (aGVHD) (six patients with grade II-IV acute GVHD). However, in group I, all surviving patients progressed within 9 months. In contrast, eight of nine surviving patients of group II remain in remission after a median observation time of 10.5 months (range 4-22 months). Survival differed significantly between the groups (P=0.004). Multivariate analysis identified intensive GVHD prophylaxis as important risk factor for survival. These results support the existence of a clinically relevant GVL effect in aggressive lymphoma. T-cell depletion (or CD34 selection) of grafts is not recommended in patients with poor-risk aggressive NHL.

Adolescent↗
PubMed2001

Telomeric protein Pin2/TRF1 induces mitotic entry and apoptosis in cells with short telomeres and is down-regulated in human breast tumors.

Telomeres are essential for cell survival and have been implicated in the mitotic control. The telomeric protein Pin2/TRF1 controls telomere elongation and its expression is tightly regulated during cell cycle. We previously reported that overexpression of Pin2/TRF1 affects mitotic progression. However, the role of Pin2/TRF1 at the interface between cell division and cell survival remains to be determined. Here we show that overexpression of Pin2 induced apoptosis in cells containing short telomeres, but not in cells with long telomeres. Furthermore, before entering apoptosis, Pin2-expressing cells first accumulated in mitosis and strongly stained with the mitosis-specific MPM2 antibody. Moreover, Pin2-induced apoptosis is potentiated by arresting cells in mitosis, but suppressed by accumulating cells in G1. In addition, overexpression of Pin2 also resulted in activation of caspase-3, and its proapoptotic activity was significantly reduced by inhibition of caspase-3. These results indicate that up-regulation of Pin2/TRF1 can specifically induce entry into mitosis and apoptosis, likely via a mechanism related to activation of caspase-3. Significantly, we also found that, out of 51 human breast cancer tissues and 10 normal controls examined, protein levels of Pin2/TRF1 in tumors were significantly lower than in normal tissues, as detected by immunoblotting analysis and immunocytochemistry. Since down-regulation of Pin2/TRF1 allows cells to maintain long telomeres, these results suggest that down-regulation of Pin2/TRF1 may be important for cancer cells to extend their proliferative potential.

Adaptor Proteins, Signal Transducing↗
PubMed2001

Pin1 regulates turnover and subcellular localization of beta-catenin by inhibiting its interaction with APC.

Phosphorylation on a serine or threonine residue preceding proline (Ser/Thr-Pro) is a key regulatory mechanism, and the conformation of certain phosphorylated Ser/Thr-Pro bonds is regulated specifically by the prolyl isomerase Pin1. Whereas the inhibition of Pin1 induces apoptosis, Pin1 is strikingly overexpressed in a subset of human tumours. Here we show that Pin1 regulates beta-catenin turnover and subcellular localization by interfering with its interaction with adenomatous polyposis coli protein (APC). A differential-display screen reveals that Pin1 increases the transcription of several beta-catenin target genes, including those encoding cyclin D1 and c-Myc. Manipulation of Pin1 levels affects the stability of beta-catenin in vitro. Furthermore, beta-catenin levels are decreased in Pin1-deficient mice but are increased and correlated with Pin1 overexpression in human breast cancer. Pin1 directly binds a phosphorylated Ser-Pro motif next to the APC-binding site in beta-catenin, inhibits its interaction with APC and increases its translocation into the nucleus. Thus, Pin1 is a novel regulator of beta-catenin signalling and its overexpression might contribute to the upregulation of beta-catenin in tumours such as breast cancer, in which APC or beta-catenin mutations are not common.

Adenomatous Polyposis Coli↗
PubMed2001

Effects of an auditory model on the learning of relative and absolute timing.

The effects of an auditory model on the learning of relative and absolute timing were examined. In 2 experiments, participants attempted to learn to produce a 1,000- or 1,600-ms sequence of 5 key presses with a specific relative-timing pattern. In each experiment, participants were, or were not, provided an auditory model that consisted of a series of tones that were temporally spaced according to the criterion relative-timing pattern. In Experiment 1, participants (n = 14) given the auditory template exhibited better relative- and absolute-timing performance than participants (n = 14) not given the auditory template. In Experiment 2, auditory and no-auditory template groups again were tested, but in that experiment each physical practice participant (n = 16) was paired during acquisition with an observer (n = 16). The observer was privy to all instructions as well as auditory and visual information that was provided the physical practice participant. The results replicated the results of Experiment 1: Relative-timing information was enhanced by the auditory template for both the physical and observation practice participants. Absolute timing was improved only when the auditory model was coupled with physical practice. Consistent with the proposal of D. M. Scully and K. M. Newell (1985), modeled timing information in physical and observational practice benefited the learning of the relative-timing features of the task, but physical practice was required to enhance absolute timing.

Auditory Perception↗
PubMed2001

Attention and motor performance: preferences for and advantages of an external focus.

This study examined individuad differences in the preference for and effectiveness of the type of attentional focus for motor learning. In two experiments, participants practicing a balance task (stabilometer) were asked to find out whether focusing on their feet (internal focus) or on two markets in front of their feet (external focus) was more effective. In Experiment 1, participants switched their attentional focus from trial to trial on Day 1 and used their preferred attentional focus on Day 2. In Experiment 2, participants were free to switch their attentional focus any time during 2 days of practice. Retention tests were performed on Day 3. Most participants chose an external focus. Also, they were more effective in retention than participants who preferred an internal focus.

Attention↗
PubMed2001

Surfing the implicit wave.

Implicit learning was investigated in two experiments involving a complex motor task. Participants were required to balance on a stabilometer and to move the platform on which they were standing to match a constantly changing target position. Experiment 1 examined whether a segment (middle third) that was repeated on each trial would be learned without participants becoming aware of the repetitions (i.e., implicitly). The purpose of Experiment 2 was to determine the relative effectiveness of explicit versus implicit learning. Here, two identical segments were presented on each trial (first and last thirds), with participants only being informed that one segment (either first or last) was repeated. The acquisition results from both experiments indicated large improvements in performance across 4 days of practice, with performance on the repeated segments being generally superior to that on the non-repeated segment. On the retention tests on Day 5, errors on the repeated segment(s) were smaller than those on the random segment(s). Furthermore, in Experiment 2, the errors on the repeated-known segment, although smaller than those on the random segment, were larger than those on the repeated-unknown segment. Interview results indicated that participants were not consciously aware that a segment was repeated unless they were informed. These results suggest that implicit learning can occur for relatively complex motor tasks and that withholding information concerning the regularities is more beneficial than providing this information.

Humans↗
PubMed2001

The automaticity of complex motor skill learning as a function of attentional focus.

The present experiment was designed to test the predictions of the constrained-action hypothesis. This hypothesis proposes that when performers utilize an internal focus of attention (focus on their movements) they may actually constrain or interfere with automatic control processes that would normally regulate the movement, whereas an external focus of attention (focus on the movement effect) allows the motor system to more naturally self-organize. To test this hypothesis, a dynamic balance task (stabilometer) was used with participants instructed to adopt either an internal or external focus of attention. Consistent with earlier experiments, the external focus group produced generally smaller balance errors than did the internal focus group and responded at a higher frequency indicating higher confluence between voluntary and reflexive mechanisms. In addition, probe reaction times (RTs) were taken as a measure of the attention demands required under the two attentional focus conditions. Consistent with the hypothesis, the external focus participants demonstrated lower probe RTs than did the internal focus participants, indicating a higher degree of automaticity and less conscious interference in the control processes associated with the balance task.

Attention↗
PubMed2001

Directing attention to movement effects enhances learning: a review.

Studies investigating the influence of the learner's focus of attention, induced by instructions or feedback, on motor skill learning are reviewed. In general, directing performers' attention to the effects of their movements (external focus of attention) appears to be more beneficial than directing their attention to their own movements (internal focus of attention). Preliminary evidence is presented indicating that an internal attentional focus constrains the motor system by interfering with natural control processes, whereas an external focus seems to allow automatic control processes to regulate the movements. Support for the view that actions are controlled by their anticipated effects comes from research demonstrating functional variability in motor control, as well as the benefits of purposeful activity in occupational therapy. We explain these results in terms of the ideomotor principle of human actions (James, 1890) and its more modern derivatives (Hommel, 1996; Prinz, 1990, 1997).

Attention↗
PubMed2000

Physical and observational practice afford unique learning opportunities.

In 2 experiments, the authors studied the effectiveness of physical and observational practice on learning and the effect on learning of combining physical practice and observation, as compared with providing physical practice alone. In Experiment 1, retention and transfer performance of 30 university students after physical, observational, or no practice were contrasted. Consistent with findings from other studies, the retention results indicated that observational practice is inferior to physical practice. The transfer data indicated no differences between observation and physical practice groups. In Experiment 2, retention and transfer performance of 30 participants in physical and combined (alternating physical and observational) practice groups were contrasted. The retention results showed no differences between the combined and physical practice groups, but the combined group performed significantly better than the physical practice group on the transfer test. Those findings suggest that a combination of observation and physical practice permits unique opportunities for learning beyond those available via either practice regimen alone.

Analysis of Variance↗
PubMed2000

Optimizing generalized motor program and parameter learning.

Two experiments examined generalized motor program (GMP) and parameter learning. Experiment 1 examined the effects of bandwidth knowledge of results (KR) about relative timing in constant and variable practice. The purpose was to determine if movement stability created by the bandwidth manipulation is associated with increased GMP learning and if bandwidth KR interacts with constant and variable practice. Participants were asked to depress four keys sequentially, using the same relative timing structure. Constant practice had one absolute timing requirement, whereas variable practice had three different absolute timing requirements. The results indicated that GMP learning was enhanced by constant practice (independent of the bandwidth KR condition) and by bandwidth KR, when variable practice was used. The findings suggest practice conditions (bandwidth KR, constant practice) that increase movement stability during practice enhance GMP learning. Parameter learning (during transfer), however, was enhanced by variable practice. Experiment 2 attempted to determine how constant and variable practice conditions could be combined to enhance both GMP and parameter learning. The results indicated that developing a stable GMP early in practice--by providing learners with constant practice early in practice--and refining parameter learning later in practice--by providing them with variable practice late in practice--were effective for both GMP and parameter learning. This suggests a hierarchy in the development of programmed actions with a stable GMP being a requisite for developing an effective and stable parameter rule.

Adult↗
PubMed2000

Attentional focus in complex skill learning.

Experiment 1 examined whether it is more advantageous to direct learners' attention to the external effects of their movements relative to other external cues. Two groups of participants hit tennis balls at a target, with one group focusing on the ball coming toward them (antecedent) and the other group focusing on the ball leaving the racket (effect). The effect group demonstrated more effective learning. Experiment 2 examined whether it is more beneficial if the movement effect is related to the movement technique, relative to other movement effects (e.g., outcome). Two groups of participants hit golf balls at a target. The attention of these groups was directed to the club or the ball trajectory, respectively. The club group showed more effective learning than the target group, suggesting that focusing on technique-related effects is more effective.

Adolescent↗
PubMed2000

Effects of attentional focus, self-control, and dyad training on motor learning: implications for physical rehabilitation.

In this article, the authors review recent studies on 3 factors that have been shown to affect the learning of motor skills-the performer's attentional focus, self-control, and practice in dyads-and discuss their implications for rehabilitation. Research has shown that directing learners' attention to the effects of their movements can be more beneficial for learning than directing their attention to the details of their own actions. Furthermore, giving learners some control over the training regimen has been found to enhance learning, unlike prescriptive training protocols that dictate when feedback will be delivered, how often, and the order that tasks will be practiced. Finally, not only can practice in dyads (or larger groups) reduce the costs of training, but it can also result in more effective learning than individual practice sessions. The incorporation of these factors into rehabilitation practice can potentially enhance the effectiveness and efficiency of rehabilitation.

Attention↗
PubMed1999

Phosphorylation-dependent prolyl isomerization: a novel signaling regulatory mechanism.

Protein phosphorylation on serine or threonine residues preceding proline (Ser/Thr-Pro) plays an essential role for regulating various cellular processes, including cell cycle progression. Although phosphorylation has been proposed to regulate the function of a protein by inducing conformational changes, much less is known about what phosphate additions actually do and how the functions of phosphoproteins are coordinated. Proline is important for determining protein structure because it exists in cis or trans conformation and can put kinks into a polypeptide chain. We have shown that phosphorylation on Ser/Thr-Pro motifs reduces the cis/trans isomerization rate of Ser/Thr-Pro bonds. At the same time, proteins containing phosphorylated Ser/Thr-Pro motifs are substrates for the prolyl isomerase Pin1. The WW domain of Pin1 acts as a phosphoserine/threonine-binding module binding a defined subset of mitosis-specific phosphoproteins, such as Cdc25 and tau. These interactions target the enzymatic activity of Pin1 close to its substrates. In contrast to other prolyl isomerases (peptidyl-prolyl isomerases, PPlases), Pin1 has an extremely high degree of substrate specificity, specifically isomerizing phosphorylated Ser/Thr-Pro bonds. Therefore, Pin1 binds and regulates the function of a defined subset of phosphoproteins. Furthermore, inhibiting Pin1 function is lethal for dividing cells. Interestingly, Pin1, which can restore the biological function of phosphorylated tau, is sequestered in the neurofibrillary tangles in Alzheimer's brains. Thus, we have proposed a novel signaling regulatory mechanism, where protein phosphorylation creates binding sites for Pin1, which can then latch on to and isomerize the phosphorylated Ser/Thr-Pro peptide bond. In turn, this may change the shape of the protein, regulating its activity, dephosphorylation, degradation or location in the cell. This new post-phosphorylation regulatory mechanism appears to play an important role in normal cell function, such as mitotic progression, and in the pathogenesis of some human pathologies, such as Alzheimer's disease.

Alzheimer Disease↗