Van Dorp Research Articles

Microtubule Binding and Clustering of Human Tau-4R and Tau-P301L Proteins Isolated from Yeast Deficient in Orthologues of Glycogen Synthase Kinase-3β or cdk5

Phosphorylation of Tau protein and binding to microtubules is complex in neurons and was therefore studied in the less complicated model of humanized yeast. Human Tau was readily phosphorylated at pathological epitopes, but in opposite directions regulated by kinases Mds1 and Pho85, orthologues of glycogen synthase kinase-3beta and cdk5, respectively (1). We isolated recombinant Tau-4R and mutant Tau-P301L from wild type, Delta mds1 and Delta pho85 yeast strains and measured binding to Taxol-stabilized mammalian microtubules in relation to their phosphorylation patterns. Tau-4R isolated from yeast lacking mds1 was less phosphorylated and bound more to microtubules than Tau-4R isolated from wild type yeast. Paradoxically, phosphorylation of Tau-4R isolated from kinase Pho85-deficient yeast was dramatically increased resulting in very poor binding to microtubules. Dephosphorylation promoted binding to microtubules to uniform high levels, excluding other modifications. Isolated hyperphosphorylated, conformationally altered Tau-4R completely failed to bind microtubules. In parallel to Tau-4R, we expressed, isolated, and analyzed mutant Tau-P301L. Total dephosphorylated Tau-4R and Tau-P301L bound to microtubules very similarly. Surprisingly, Tau-P301L isolated from all yeast strains bound to microtubules more extensively than Tau-4R. Atomic force microscopy demonstrated, however, that the high apparent binding of Tau-P301L was due to aggregation on the microtubules, causing their deformation and bundling. Our data explain the pathological presence of granular Tau aggregates in neuronal processes in tauopathies.

On the two-sided power distribution

This paper concerns a two-parameter two-sided power distribution introduced by van Dorp and Kotz on the interval [0,1]. We introduce a reformulated two-sided power distribution (with the same number of parameters) and provide evidence to prove that it is more flexible than the one suggested by van Dorp and Kotz. We derive various properties of the new distribution as well as provide several hitherto unknown properties of the distribution due to van Dorp and Kotz. We also discuss estimation by the method of moments and the method of maximum likelihood.

On the General Class of Two-Sided Power Distribution

Van Dorp and Kotz (2003) introduced a general class of two-sided power distribution. We provide several examples of this distribution by considering a non negative, non decreasing differentiable function g on [0, 1] satisfying g(1) − g(0) = 1. For the considered distributions the maximum likelihood estimation and moment estimation of parameters are obtained. Moments, moment generating functions, and relative entropy are also derived.

Prosurvival and Prodeath Effects of Hypoxia-inducible Factor-1α Stabilization in a Murine Hippocampal Cell Line

Hypoxia-inducible factor-1 (HIF-1) is a transcriptional activator involved in adaptation to hypoxic stress. Previous studies from our laboratory demonstrated that pharmacological activators of HIF-1 (e.g. deferoxamine, cobalt chloride) could also protect cultured primary neurons or an immortalized hippocampal neuroblast line (HT22) from oxidative stress-induced death. However, whether HIF-1 activation is sufficient to abrogate neuronal death resulting from oxidative stress or other hypoxia-independent death inducers remains unclear. To address this question we utilized a HIF-1alpha fusion protein that partially lacks the domain required for oxygen-dependent degradation of HIF-1alpha and that has a VP16 transcriptional activation domain from herpes simplex virus. HT22 cells were infected with a retrovirus encoding either the HIF-1alpha-VP16 fusion protein or the activation domain of the VP16 protein alone as a control. Expression of HIF-1alpha-VP16, but not VP16 alone, increased luciferase activity driven by a canonical hypoxia response element, increased mRNA of established HIF-1 target genes, and increased activity of one of these HIF-1 target genes. Unexpectedly, enhanced HIF-1 activity in HT22 cells enhanced sensitivity to oxidative death induced by glutathione depletion. Accordingly, suppression of HIF-1alpha expression using RNA interference prevented oxidative death. By contrast, HIF-1alpha-VP16-expressing HT22 cells were more resistant to DNA damage (induced by camptothecin) or endoplasmic reticulum stress (induced by thapsigargin and tunicamycin) than were VP16-expressing cells, and suppression of HIF-1alpha expression using RNA interference rendered HT22 cells more sensitive to death induced by DNA damage or endoplasmic reticulum stress. Together, these data demonstrate that HIF-1 can mediate prodeath or prosurvival responses in the same cell type depending on the injury stimulus.

Theoretical study of triplet state properties of free-base porphin

Abstract This paper presents results and analysis of various properties of the triplet state of free-base porphin (FBP) as calculated by density-functional theory. The radiative lifetime of phosphorescence lines and microwave signals in optical detection of magnetic resonance (ODMR) spectra are obtained using the B3LYP hybrid density-functional and the quadratic response method. The zero-field splitting (ZFS) in the lowest triplet state, a 3 B 2u , of FBP is calculated as an expectation value of spin–spin coupling operator using the self-consistent field wavefunction. The second-order contribution to ZFS from the spin–orbit coupling operator is found to be almost negligible. The interpretation of the ODMR spectrum is completed by computing the hyperfine tensors of the 14 N, 13 C and hydrogen atoms in the lowest triplet state. The most intense phosphorescence emission corresponds to the T z -spin-sublevel of the a 3 B 2u state, where the z -axis lies in the N–H direction of the FBP molecule in a qualitative agreement with ODMR data. The results indicate that the observed decay of the lowest triplet state of FBP molecule is determined by non-radiative deactivation. The calculated radiative rate constant for the T z -spin-sublevel k z = 2.65 × 10 −3 s −1 is in agreement with the value k z ≃ 2 × 10 −3 s −1 , estimated by van Dorp et al. [W. van Dorp, W. Schoemaker, M. Soma, J. van der Waals, Mol. Phys. 30 (1975) 1701] from kinetic analysis of microwave-induced fluorescent signals. The correct prediction of the spin quantization axis of the most active spin sublevel and of its radiative lifetime in the lowest triplet state of the FBP molecule is taken as a proof of capability of the quadratic response time-dependent density-functional theory.

Glycogen Synthase Kinase 3β Induces Caspase-cleaved Tau Aggregation in Situ

Tau is a substrate of caspases, and caspase-cleaved tau has been detected in Alzheimer's disease brain but not in control brain. Furthermore, in vitro studies have revealed that caspase-cleaved tau is more fibrillogenic than full-length tau. Considering these previous findings, the purpose of this study was to determine how the caspase cleavage of tau affected tau function and aggregation in a cell model system. The effects of glycogen synthase kinase 3 beta (GSK3 beta), a well established tau kinase, on these processes also were examined. Tau or tau that had been truncated at Asp-421 to mimic caspase cleavage (Tau-D421) was transfected into cells with or without GSK3 beta, and phosphorylation, microtubule binding, and tau aggregation were examined. Tau-D421 was not as efficiently phosphorylated by GSK3 beta as full-length tau. Tau-D421 efficiently bound microtubules, and in contrast to the full-length tau, co-expression with GSK3 beta did not result in a reduction in the ability of Tau-D421 to bind microtubules. In the absence of GSK3 beta, neither Tau-D421 nor full-length tau formed Sarkosyl-insoluble inclusions. However, in the presence of GSK3 beta, Tau-D421, but not full-length tau, was present in the Sarkosyl-insoluble fraction and formed thioflavin-S-positive inclusions in the cell. Nonetheless, co-expression of GSK3 beta and Tau-D421 did not result in an enhancement of cell death. These data suggest that a combination of phosphorylation events and caspase activation contribute to the tau oligomerization process in Alzheimer's disease, with GSK3 beta-mediated tau phosphorylation preceding caspase cleavage.

14-3-3 Binds to and Mediates Phosphorylation of Microtubule-associated Tau Protein by Ser9-phosphorylated Glycogen Synthase Kinase 3β in the Brain

In mammalian brain, tau, glycogen synthase kinase 3beta (GSK3beta), and 14-3-3, a phosphoserine-binding protein, are parts of a multiprotein tau phosphorylation complex. Within the complex, 14-3-3 simultaneously binds to tau and GSK3beta (Agarwal-Mawal, A., Qureshi, H. Y., Cafferty, P. W., Yuan, Z., Han, D., Lin, R., and Paudel, H. K. (2003) J. Biol. Chem. 278, 12722-12728). The molecular mechanism by which 14-3-3 connects GSK3beta to tau within the complex is not clear. In this study, we find that GSK3beta within the tau phosphorylation complex is phosphorylated on Ser(9). From extracts of rat brain and rat primary cultured neurons, Ser(9)-phosphorylated GSK3beta precipitates with glutathione-agarose beads coated with glutathione S-transferase-14-3-3. Similarly, from rat brain extract, Ser(9)-phosphorylated GSK3beta co-immunoprecipitates with tau. In vitro, 14-3-3 binds to GSK3beta only when the kinase is phosphorylated on Ser(9). In transfected HEK-293 cells, 14-3-3 binds to Ser(9)-phosphorylated GSK3beta and does not bind to GSK3beta (S9A). Tau, on the other hand, binds to both GSK3beta (WT) and GSK3beta (S9A). Moreover, 14-3-3 enhances the binding of tau with Ser(9)-phosphorylated GSK3beta by approximately 3-fold but not with GSK3beta (S9A). Similarly, 14-3-3 stimulates phosphorylation of tau by Ser(9)-phosphorylated GSK3beta but not by GSK3beta (S9A). In transfected HEK-293 cells, Ser(9) phosphorylation suppresses GSK3beta-catalyzed tau phosphorylation in the absence of 14-3-3. In the presence of 14-3-3, however, Ser(9)-phosphorylated GSK3beta remains active and phosphorylates tau. Our data indicate that within the tau phosphorylation complex, 14-3-3 connects Ser(9)-phosphorylated GSK3beta to tau and Ser(9)-phosphorylated GSK3beta phosphorylates tau.

Transient Cerebral Ischemia Induces Aberrant Neuronal Cell Cycle Re-entry and Alzheimer's Disease-like Tauopathy in Female Rats

Aberrant mitosis occurs in many tauopathy-related neurodegenerative diseases and is believed to precede the formation of neurofibrillary tangles. In this study, we report for the first time that transient cerebral ischemia induces aberrant mitotic proteins and hyperphosphorylation of tau protein with neurofibrillary tangle-like conformational epitopes in adult female rat cortex. Following transient cerebral ischemia in rats, initiation of apoptosis precedes and is potentially integrated with subsequent aberrant mitosis and tau hyperphosphorylation. Furthermore, inhibition of mitosis-related cyclin-dependent kinases (Cdks) by roscovitine significantly reduced the hyperphosphorylation of tau. Administration of the female sex steroid and potent neuroprotective agent, 17beta-estradiol, reduced ischemia-reperfusion-induced cerebral damage and the subsequent aberrant mitosis and tauopathies. These results provide a neuropathological basis for the higher prevalence of dementia in stroke patients and support the hypothesis that apoptosis and aberrant mitosis are integrated pathological events in neurons that may play a critical role in the development of Alzheimer's disease and other tauopathy-related neuropathology.

Pharmacological Profiles of Peptide Drug Candidates for the Treatment of Alzheimer's Disease

Amyloid plaques in brain, composed of aggregates of amyloid-beta peptide, play a central role in the pathogenesis of Alzheimer's disease and represent a good target for treatment. We have shown previously that a 5-amino acid beta-sheet breaker peptide (iA beta 5p), end-protected, has the ability to induce a dramatic reduction in amyloid deposition in two different transgenic Alzheimer's models (Permanne, B., Adessi, C., Saborio, G. P., Fraga, S., Frossard, M.-J., Dewachter, I., Van Dorpe, J., Banks, W. A., Van Leuven, F., and Soto, C. (2002) FASEB J. 16, 860-862). The aim of this study was to evaluate the effect of chemical modifications of the peptide bonds at the metabolite cleavage sites on the pharmacological properties of iA beta 5p derivatives. Using a rational approach, peptide analogs were designed and tested for in vitro activity and enzymatic stability. One peptide analog containing a methyl group introduced at the nitrogen atom of one amide bond showed increased stability in vitro, a 10-fold higher in vivo half-life, and good brain uptake compared with iA beta 5p while maintaining a similar activity in vitro. Our results suggest that the pharmacological profile of beta-sheet breaker peptides can be improved to produce compounds with drug-like properties that might offer a new promise in the treatment of Alzheimer's disease.

Mutant Presenilins Disturb Neuronal Calcium Homeostasis in the Brain of Transgenic Mice, Decreasing the Threshold for Excitotoxicity and Facilitating Long-term Potentiation

Mutant human presenilin-1 (PS1) causes an Alzheimer's-related phenotype in the brain of transgenic mice in combination with mutant human amyloid precursor protein by means of increased production of amyloid peptides (Dewachter, I., Van Dorpe, J., Smeijers, L., Gilis, M., Kuiperi, C., Laenen, I., Caluwaerts, N., Moechars, D., Checler, F., Vanderstichele, H. & Van Leuven, F. (2000) J. Neurosci. 20, 6452-6458) that aggravate plaques and cerebrovascular amyloid (Van Dorpe, J., Smeijers, L., Dewachter, I., Nuyens, D., Spittaels, K., van den Haute, C., Mercken, M., Moechars, D., Laenen, I., Kuipéri, C., Bruynseels, K., Tesseur, I., Loos, R., Vanderstichele, H., Checler, F., Sciot, R. & Van Leuven, F. (2000) J. Am. Pathol. 157, 1283-1298). This gain of function of mutant PS1 is approached here in three paradigms that relate to glutamate neurotransmission. Mutant but not wild-type human PS1 (i) lowered the excitotoxic threshold for kainic acid in vivo, (ii) facilitated hippocampal long-term potentiation in brain slices, and (iii) increased glutamate-induced intracellular calcium levels in isolated neurons. Prominent higher calcium responses were triggered by thapsigargin and bradykinin, indicating that mutant PS modulates the dynamic release and storage of calcium ions in the endoplasmatic reticulum. In reaction to glutamate, overfilled Ca(2+) stores resulted in higher than normal cytosolic Ca(2+) levels, explaining the facilitated long-term potentiation and enhanced excitotoxicity. The lowered excitotoxic threshold for kainic acid was also observed in mice transgenic for mutant human PS2[N141I] and was prevented by dantrolene, an inhibitor of Ca(2+) release from the endoplasmic reticulum.

Glycogen Synthase Kinase-3β Phosphorylates Protein Tau and Rescues the Axonopathy in the Central Nervous System of Human Four-repeat Tau Transgenic Mice

Protein tau filaments in brain of patients suffering from Alzheimer's disease, frontotemporal dementia, and other tauopathies consist of protein tau that is hyperphosphorylated. The responsible kinases operating in vivo in neurons still need to be identified. Here we demonstrate that glycogen synthase kinase-3beta (GSK-3beta) is an effective kinase for protein tau in cerebral neurons in vivo in adult GSK-3beta and GSK-3beta x human tau40 transgenic mice. Phosphorylated protein tau migrates slower during electrophoretic separation and is revealed by phosphorylation-dependent anti-tau antibodies in Western blot analysis. In addition, its capacity to bind to re-assembled paclitaxel (Taxol((R)))-stabilized microtubules is reduced, compared with protein tau isolated from mice not overexpressing GSK-3beta. Co-expression of GSK-3beta reduces the number of axonal dilations and alleviates the motoric impairment that was typical for single htau40 transgenic animals (Spittaels, K., Van den Haute, C., Van Dorpe, J., Bruynseels, K., Vandezande, K., Laenen, I., Geerts, H., Mercken, M., Sciot, R., Van Lommel, A., Loos, R., and Van Leuven, F. (1999) Am. J. Pathol. 155, 2153-2165). Although more hyperphosphorylated protein tau is available, neither an increase in insoluble protein tau aggregates nor the presence of paired helical filaments or tangles was observed. These findings could have therapeutic implications in the field of neurodegeneration, as discussed.

Ways to improve the analysis of multi-level accelerated life testing

Multi-level accelerated life tests (ALTs), MEOST (multiple extreme overstress testing) and traditional step-stress approaches (hereafter all called simply step-stress) have a number of worthwhile applications for the analysis of the projected reliability of components and systems. These test methods are considered for many common situations of accelerated life testing (ALT). Some of the main purposes of ALT are to measure projected system life and to identify product weaknesses in order to improve reliability. These methods may apply well when only a small number of systems are available, when extremely long, specialized test equipment is required, when limited environmental chamber capability and/or test fixtures are involved and, lastly, when very expensive support equipment represents a serious test limit. The accelerated testing methods mentioned have had some limited applications in the past. The limits have been sometimes due to poorly described degradation or accumulative fatigue and the subsequent difficulty with the analysis of the failure data themselves. A tight series of ground rules is proposed in this paper that may help solve, mitigate or prevent this possibility. This paper also presents methods to improve the analysis of these multi-level stress tests. While the methods shown are approximate, they easily lend themselves to analysis on a computer by standard software packages or through manual techniques. Additionally, the ground rules presented suggest that wider limits may often be taken for running this type of accelerated testing than has been suggested in the past. These ground rules aid the analysis by ensuring uniformity of results. As an aid to test set-up, neither the step intervals need be of the same length nor the stress steps uniform. A recent paper by van Dorp et al. (IEEE Trans. Reliab., REL-45, 491–497 (1996)) provides a theoretical basis for some of these suggestions. Another paper by Bhote (Trans. Am. Soc. Met., 237–243 (1985)) identifies many reasons to perform this type of reliability test and credits Dorian Shainin with the development of many of the early MEOST techniques. Clearly, step-stress approaches and applications have not been exhausted for measuring life and identifying design or manufacturing flaws. Copyright © 1998 John Wiley & Sons, Ltd.

Value of chromosome painting in determining the chromosomal outcome in offspring of a 12;16 translocation carrier.

We currently use direct and reverse chromosome painting in prenatal diagnosis. In a family with a subtle 12;16 translocation, adjacent 1 segregation was diagnosed in the first child, a boy, in whom symptoms compatible with partial trisomy 16p and partial monosomy 12q were seen. In the next pregnancy, a chorionic villus biopsy was tested using chromosome painting. Only by supplementing conventional cytogenetic methods with molecular cytogenetic techniques could the true karyotype be unequivocally determined. Reverse painting, using DOP-PCR amplified, flow sorted paternal derivative chromosomes as a DNA library to paint the chorionic villus cells, was especially informative.

Nucleophilic attacks on carbon-carbon double bonds. Part 38. Chloride ion exchange and E .dblharw. Z isomerization of an electrophilic vinyl chloride

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTNucleophilic attacks on carbon-carbon double bonds. Part 38. Chloride ion exchange and E .dblharw. Z isomerization of an electrophilic vinyl chlorideGerrit Lodder, Jan Willem J. Van Dorp, Bianca Avramovitch, and Zvi RappoportCite this: J. Org. Chem. 1989, 54, 11, 2574–2580Publication Date (Print):May 1, 1989Publication History Published online1 May 2002Published inissue 1 May 1989https://doi.org/10.1021/jo00272a022RIGHTS & PERMISSIONSArticle Views56Altmetric-Citations5LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InReddit PDF (869 KB) Get e-Alerts Get e-Alerts

My years in lipid research

Journal of the American Oil Chemists' SocietyVolume 60, Issue 9 p. 1645-1648 Technical News Features My years in lipid research D. A. Van Dorp, D. A. Van DorpSearch for more papers by this author D. A. Van Dorp, D. A. Van DorpSearch for more papers by this author First published: 01 September 1983 https://doi.org/10.1007/BF02662423AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Volume60, Issue9September 1983Pages 1645-1648 RelatedInformation

Profile: David van Dorp

Journal of the American Oil Chemists' SocietyVolume 60, Issue 9 p. 1609-1610 Article Profile: David van Dorp First published: 01 September 1983 https://doi.org/10.1007/BF02662415AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat No abstract is available for this article. Volume60, Issue9September 1983Pages 1609-1610 RelatedInformation

Book Reviews

Book reviewed in this article:Atlas or Human Limb Joints, by Jacques Guyot. Illustrations by J. L. VannsonDifferential Diagnosis in Pediatric Echocardiography. Lintermans JP, van Dorp WGAn Atlas of Normal and Abnormal Mammograms. By Ted Nathan, 1982. 118 pages.Histopathology of Non‐Hodgkin's Lymphomas (Based on the Kiel Classification). By Karl Lennert.Tumours and Tumouriike Lesions of Bones and Joints. Fritz SchajowczThe Australian Radiation Laboratory. A Concise History 1929–1979. J. F. Richardson.Renal Sonography. By F. S. Weill, E. Bihr, P. Rohmer and F. ZeltnerEnvironmental Health Criteria 14: Ultraviolet Radiation.Basic Radiology for General Practitioners.Coronary Bypass Surgery ‐ A Five Year Follow‐Up. By Torbjorn IvertAtlas of Phlebography of the Lower Limbs including the Iliac Veins. By J. Chermet.A History of X‐Rays and Radium with a chapter on Radiation Units: 1895–1937.Pioneers in Angiography. The Portuguese School of Angiography. Edited by J. A. Veiga‐Pires and Ronald G. Grainger. M.T.P. Press Ltd.

Mediation of Ventilatory Adaptations.

Mediation of Ventilatory Adaptations.

More's Letter to Dorp: Remapping the Trivium

Thomas More's long letter to Martin van Dorp, Louvain humanist turned theologian, has begun to distinguish itself in the minds of many Renaissance scholars as something more than indifferent episode in the long and inconclusive history of Erasmus' personal differences with Dorp. In fact, More's letter is one of the first systematic defenses of humanist method, encompassing a critique of Scholastic grammar, dialectic, and theology, as well as a tightly argued defense of the new philological theology. More's debt to Valla, long obscured by More's strategic unwillingness in this letter to make much of a figure whom Dorp so detests, has finally begun to receive due attention.

The role of prostaglandins in inflammation.

The possible involvement of prostaglandins (PGs) in the inflammatory response has received a great deal of attention since the nonsteroidal anti-inflammatory drugs (NSAID) were found to inhibit PG synthesis (Vane, 1911; Smith and Willis, 1971; Ferreira et al., 1971). Almost all mammalian cells have the ability to synthesize PGs. In fact, the precursors of the PGs are polyunsaturated fatty acids in cell membranes, derived from the dietary essential fatty acids (EFAs). These fatty acids are mainly found in the phospholipids imparting important structural properties to the cell. In 1929, Burr and Burr studied the pathologic syndrome that appeared when rats were kept on a fat-free diet. Later, it was appreciated that linoleic acid caused the deficiency state. Fulco and Mead (1959) demonstrated in EFA deficient animals, that oleic acid substitutes for linoleic acid with the resultant production of eicosatrienoic acid, which can substitute for arachidonate in cell membranes, but apparently cannot prevent the deficiency. After von Euler in 1935 had studied the polar fatty acids extracted from seminal plasma and termed them prostaglandins, van Dorp (1964) and Bergström et al. (1964) simultaneously introduced the concept that PGs were derived from the 20-carbon essential fatty acids (Fig. 1). It is now generally accepted that the conversion of arachidonic acid to PGs accounts for some of the pathology when animals are restricted in their dietary fat.