Accumulation and aggregation of the amyloid-β (Aβ) peptide is associated with Alzheimer&a... more Accumulation and aggregation of the amyloid-β (Aβ) peptide is associated with Alzheimer's disease (AD). Aβ is generated from the amyloid precursor protein by the successive action of two membrane-associated processing enzymes: β-secretase or β-site of amyloid precursor protein cleaving enzyme 1 (BACE1) and γ-secretase. Inhibition of one or both of these enzymes prevents Aβ generation and the accompanying Aβ accumulation. Antigen binding fragments from camelid heavy chain only antibodies (VHHs) were found to exert excellent enzyme inhibition activity. In the present study, we generated VHHs against BACE1 by active immunization of Lama glama with the recombinant BACE1 protein. Two classes of VHHs were selected from a VHH-phage display library by competitive elution with a peptide encoding the Swedish mutation variant of the BACE1 processing site. One VHH was found to inhibit the enzyme activity of BACE1 in vitro and in cell culture, whereas two other VHHs were found to stimulate BACE1 activity under the same conditions in vitro. Furthermore, an in vivo study with a transgenic AD mouse model, using intracisternal injection of the inhibitory VHH, led to acute reduction of the Aβ load in the blood and brain. This inhibitory VHH may be considered as a candidate molecule for a therapy directed towards reduction of Aβ load and prevention of AD progression. Both the inhibitory and stimulatory VHH may be useful for improving our understanding of the structure-function relationship of BACE1, as well as its role in AD progression. The GenBank sequence accession numbers are KR363186 for VHH B1a; KR363187 for VHH B3a; and KR363188 for VHH B5a.
Journal of the American Society of Nephrology : JASN, Jan 31, 2014
In total, 1 in 1000 individuals carries a germline mutation in the PKD1 or PKD2 gene, which leads... more In total, 1 in 1000 individuals carries a germline mutation in the PKD1 or PKD2 gene, which leads to autosomal dominant polycystic kidney disease (ADPKD). Cysts can form early in life and progressively increase in number and size during adulthood. Extensive research has led to the presumption that somatic inactivation of the remaining allele initiates the formation of cysts, and the progression is further accelerated by renal injury. However, this hypothesis is primarily on the basis of animal studies, in which the gene is inactivated simultaneously in large percentages of kidney cells. To mimic human ADPKD in mice more precisely, we reduced the percentage of Pkd1-deficient kidney cells to 8%. Notably, no pathologic changes occurred for 6 months after Pkd1 deletion, and additional renal injury increased the likelihood of cyst formation but never triggered rapid PKD. In mildly affected mice, cysts were not randomly distributed throughout the kidney but formed in clusters, which could...
The effect of osmotic stress (-0.35 MPa) on the cell water balance and apical growth was studied ... more The effect of osmotic stress (-0.35 MPa) on the cell water balance and apical growth was studied non-invasively for maize (Zea mays L., cv. LG 11) and pearl millet (Pennisetum americanum L., cv. MH 179) by (1)H NMR microscopy in combination with water uptake measurements. Single parameter images of the water content and the transverse relaxation time (T(2)) were used to discriminate between the different tissues and to follow the water status of the apical region during osmotic stress. The T(2) values of non-stressed stem tissue turned out to be correlated to the cell dimensions as determined by optical microscopy. Growth was found to be strongly inhibited by mild stress in both species, whereas the water uptake was far less affected. During the experiment hardly any changes in water content or T(2) in the stem region of maize were observed. In contrast, the apical tissue of pearl millet showed a decrease in T(2) within 48 h of stress. This decrease in T(2) is interpreted as an increase in the membrane permeability for water.
Journal of magnetic resonance (San Diego, Calif. : 1997), 2002
Multicompartment characteristics of relaxation and diffusion in a model for (plant) cells and tis... more Multicompartment characteristics of relaxation and diffusion in a model for (plant) cells and tissues have been simulated as a means to test separating the signal into a set of these compartments. A numerical model of restricted diffusion and magnetization relaxation behavior in PFG-CPMG NMR experiments, based on Fick's second law of diffusion, has been extended for two-dimensional diffusion in systems with concentric cylindrical compartments separated by permeable walls. This model is applicable to a wide range of (cellular) systems and allows the exploration of temporal and spatial behavior of the magnetization with and without the influence of gradient pulses. Numerical simulations have been performed to show the correspondence between the obtained results and previously reported studies and to investigate the behavior of the apparent diffusion coefficients for the multicompartment systems with planar and cylindrical geometry. The results clearly demonstrate the importance of...
Information processing in medical imaging : proceedings of the ... conference, 2009
Non-rigid registration of MR images to a common reference image results in deformation fields, fr... more Non-rigid registration of MR images to a common reference image results in deformation fields, from which anatomical differences can be statistically assessed, within and between populations. Without further assumptions, nonparametric tests are required and currently the analysis of deformation fields is performed by permutation tests. For deformation fields, often the vector magnitude is chosen as test statistic, resulting in a loss of information. In this paper, we consider the three dimensional Moore-Rayleigh test as an alternative for permutation tests. This nonparametric test offers two novel features: first, it incorporates both the directions and magnitude of the deformation vectors. Second, as its distribution function is available in closed form, this test statistic can be used in a clinical setting. Using synthetic data that represents variations as commonly encountered in clinical data, we show that the Moore-Rayleigh test outperforms the classical permutation test.
Arteriosclerosis, thrombosis, and vascular biology, Jan 10, 2013
Recent advances in molecular resonance imaging of atherosclerosis enable to visualize atheroscler... more Recent advances in molecular resonance imaging of atherosclerosis enable to visualize atherosclerotic plaques in vivo using molecular targeted contrast agents. This offers opportunities to study atherosclerosis development and plaque vulnerability noninvasively. In this review, we discuss MRI contrast agents targeted toward atherosclerotic plaques and illustrate how these new imaging platforms could assist in our understanding of atherogenesis and atheroprogression. In particular, we highlight the challenges and limitations of the different contrast agents and hurdles for clinical application. We describe the most promising existing compounds to detect atherosclerosis and plaque vulnerability. Of particular interest are the fibrin-targeted compounds that detect thrombi and, furthermore, the contrast agents targeted to integrins that allow to visualize plaque neovascularization. Moreover, vascular cell adhesion molecule 1-targeted iron oxides seem promising for early detection of ath...
Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism, 2010
Heat shock protein 27 (HSP27) has a major role in mediating survival responses to a range of cent... more Heat shock protein 27 (HSP27) has a major role in mediating survival responses to a range of central nervous system insults, functioning as a protein chaperone, an antioxidant, and through inhibition of cell death pathways. We have used transgenic mice overexpressing HSP27 (HSP27tg) to examine the role of HSP27 in cerebral ischemia, using model of permanent middle cerebral artery occlusion (MCAO). Infarct size was evaluated using multislice T(2)-weighted anatomical magnetic resonance imaging (MRI) after 24 h. A significant reduction of 30% in infarct size was detected in HSP27tg animals compared with wild-type (WT) littermates. To gain some insight into the mechanisms contributing to cell death and its attenuation by HSP27, we monitored the effect of induction of c-jun and ATF3 on tissue survival in MCAO and their effects on the expression of endogenous mouse HSP25 and HSP70. It is important that, the c-jun induction seen at 4 h tended to be localized to regions that were salvageabl...
... tracers and places no restriction of the number of repeat measurements that can be made in a ... more ... tracers and places no restriction of the number of repeat measurements that can be made in a single study. ... 3 s) saturating off-resonance RF pulse, followed by a second image (S 0 ) withouta presaturation pulse. The magnetization transfer ratio (MTR) is then quantified as: 4. ...
To determine biventricular cardiac function in pneumovirus-induced acute lung injury in spontaneo... more To determine biventricular cardiac function in pneumovirus-induced acute lung injury in spontaneously breathing mice. Experimental animal study. Animal laboratory. C57Bl/6 mice. Mice were inoculated with the rodent pneumovirus, pneumonia virus of mice. Pneumonia virus of mice-infected mice were studied for right and left ventricular function variables by high-field strength (7 Tesla) cardiac MRI at specific time points during the course of disease compared with baseline. One day before and at peak disease severity, pneumonia virus of mice-infected mice showed significant right and left ventricular systolic and diastolic volume changes, with a progressive decrease in stroke volume and ejection fraction. No evidence for viral myocarditis or viral presence in heart tissue was found. These findings show adverse pulmonary-cardiac interaction in pneumovirus-induced acute lung injury, unrelated to direct virus-mediated effects on the heart.
The visualization of activity in mouse brain using inversion recovery spin echo (IR-SE) manganese... more The visualization of activity in mouse brain using inversion recovery spin echo (IR-SE) manganese-enhanced MRI (MEMRI) provides unique contrast, but suffers from poor resolution in the slice-encoding direction. Super-resolution reconstruction (SRR) is a resolution-enhancing post-processing technique in which multiple low-resolution slice stacks are combined into a single volume of high isotropic resolution using computational methods. In this study, we investigated, first, whether SRR can improve the three-dimensional resolution of IR-SE MEMRI in the slice selection direction, whilst maintaining or improving the contrast-to-noise ratio of the two-dimensional slice stacks. Second, the contrast-to-noise ratio of SRR IR-SE MEMRI was compared with a conventional three-dimensional gradient echo (GE) acquisition. Quantitative experiments were performed on a phantom containing compartments of various manganese concentrations. The results showed that, with comparable scan times, the signal-to-noise ratio of three-dimensional GE acquisition is higher than that of SRR IR-SE MEMRI. However, the contrast-to-noise ratio between different compartments can be superior with SRR IR-SE MEMRI, depending on the chosen inversion time. In vivo experiments were performed in mice receiving manganese using an implanted osmotic pump. The results showed that SRR works well as a resolution-enhancing technique in IR-SE MEMRI experiments. In addition, the SRR image also shows a number of brain structures that are more clearly discernible from the surrounding tissues than in three-dimensional GE acquisition, including a number of nuclei with specific higher brain functions, such as memory, stress, anxiety and reward behavior.
Accumulation and aggregation of the amyloid-β (Aβ) peptide is associated with Alzheimer&a... more Accumulation and aggregation of the amyloid-β (Aβ) peptide is associated with Alzheimer's disease (AD). Aβ is generated from the amyloid precursor protein by the successive action of two membrane-associated processing enzymes: β-secretase or β-site of amyloid precursor protein cleaving enzyme 1 (BACE1) and γ-secretase. Inhibition of one or both of these enzymes prevents Aβ generation and the accompanying Aβ accumulation. Antigen binding fragments from camelid heavy chain only antibodies (VHHs) were found to exert excellent enzyme inhibition activity. In the present study, we generated VHHs against BACE1 by active immunization of Lama glama with the recombinant BACE1 protein. Two classes of VHHs were selected from a VHH-phage display library by competitive elution with a peptide encoding the Swedish mutation variant of the BACE1 processing site. One VHH was found to inhibit the enzyme activity of BACE1 in vitro and in cell culture, whereas two other VHHs were found to stimulate BACE1 activity under the same conditions in vitro. Furthermore, an in vivo study with a transgenic AD mouse model, using intracisternal injection of the inhibitory VHH, led to acute reduction of the Aβ load in the blood and brain. This inhibitory VHH may be considered as a candidate molecule for a therapy directed towards reduction of Aβ load and prevention of AD progression. Both the inhibitory and stimulatory VHH may be useful for improving our understanding of the structure-function relationship of BACE1, as well as its role in AD progression. The GenBank sequence accession numbers are KR363186 for VHH B1a; KR363187 for VHH B3a; and KR363188 for VHH B5a.
Journal of the American Society of Nephrology : JASN, Jan 31, 2014
In total, 1 in 1000 individuals carries a germline mutation in the PKD1 or PKD2 gene, which leads... more In total, 1 in 1000 individuals carries a germline mutation in the PKD1 or PKD2 gene, which leads to autosomal dominant polycystic kidney disease (ADPKD). Cysts can form early in life and progressively increase in number and size during adulthood. Extensive research has led to the presumption that somatic inactivation of the remaining allele initiates the formation of cysts, and the progression is further accelerated by renal injury. However, this hypothesis is primarily on the basis of animal studies, in which the gene is inactivated simultaneously in large percentages of kidney cells. To mimic human ADPKD in mice more precisely, we reduced the percentage of Pkd1-deficient kidney cells to 8%. Notably, no pathologic changes occurred for 6 months after Pkd1 deletion, and additional renal injury increased the likelihood of cyst formation but never triggered rapid PKD. In mildly affected mice, cysts were not randomly distributed throughout the kidney but formed in clusters, which could...
The effect of osmotic stress (-0.35 MPa) on the cell water balance and apical growth was studied ... more The effect of osmotic stress (-0.35 MPa) on the cell water balance and apical growth was studied non-invasively for maize (Zea mays L., cv. LG 11) and pearl millet (Pennisetum americanum L., cv. MH 179) by (1)H NMR microscopy in combination with water uptake measurements. Single parameter images of the water content and the transverse relaxation time (T(2)) were used to discriminate between the different tissues and to follow the water status of the apical region during osmotic stress. The T(2) values of non-stressed stem tissue turned out to be correlated to the cell dimensions as determined by optical microscopy. Growth was found to be strongly inhibited by mild stress in both species, whereas the water uptake was far less affected. During the experiment hardly any changes in water content or T(2) in the stem region of maize were observed. In contrast, the apical tissue of pearl millet showed a decrease in T(2) within 48 h of stress. This decrease in T(2) is interpreted as an increase in the membrane permeability for water.
Journal of magnetic resonance (San Diego, Calif. : 1997), 2002
Multicompartment characteristics of relaxation and diffusion in a model for (plant) cells and tis... more Multicompartment characteristics of relaxation and diffusion in a model for (plant) cells and tissues have been simulated as a means to test separating the signal into a set of these compartments. A numerical model of restricted diffusion and magnetization relaxation behavior in PFG-CPMG NMR experiments, based on Fick's second law of diffusion, has been extended for two-dimensional diffusion in systems with concentric cylindrical compartments separated by permeable walls. This model is applicable to a wide range of (cellular) systems and allows the exploration of temporal and spatial behavior of the magnetization with and without the influence of gradient pulses. Numerical simulations have been performed to show the correspondence between the obtained results and previously reported studies and to investigate the behavior of the apparent diffusion coefficients for the multicompartment systems with planar and cylindrical geometry. The results clearly demonstrate the importance of...
Information processing in medical imaging : proceedings of the ... conference, 2009
Non-rigid registration of MR images to a common reference image results in deformation fields, fr... more Non-rigid registration of MR images to a common reference image results in deformation fields, from which anatomical differences can be statistically assessed, within and between populations. Without further assumptions, nonparametric tests are required and currently the analysis of deformation fields is performed by permutation tests. For deformation fields, often the vector magnitude is chosen as test statistic, resulting in a loss of information. In this paper, we consider the three dimensional Moore-Rayleigh test as an alternative for permutation tests. This nonparametric test offers two novel features: first, it incorporates both the directions and magnitude of the deformation vectors. Second, as its distribution function is available in closed form, this test statistic can be used in a clinical setting. Using synthetic data that represents variations as commonly encountered in clinical data, we show that the Moore-Rayleigh test outperforms the classical permutation test.
Arteriosclerosis, thrombosis, and vascular biology, Jan 10, 2013
Recent advances in molecular resonance imaging of atherosclerosis enable to visualize atheroscler... more Recent advances in molecular resonance imaging of atherosclerosis enable to visualize atherosclerotic plaques in vivo using molecular targeted contrast agents. This offers opportunities to study atherosclerosis development and plaque vulnerability noninvasively. In this review, we discuss MRI contrast agents targeted toward atherosclerotic plaques and illustrate how these new imaging platforms could assist in our understanding of atherogenesis and atheroprogression. In particular, we highlight the challenges and limitations of the different contrast agents and hurdles for clinical application. We describe the most promising existing compounds to detect atherosclerosis and plaque vulnerability. Of particular interest are the fibrin-targeted compounds that detect thrombi and, furthermore, the contrast agents targeted to integrins that allow to visualize plaque neovascularization. Moreover, vascular cell adhesion molecule 1-targeted iron oxides seem promising for early detection of ath...
Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism, 2010
Heat shock protein 27 (HSP27) has a major role in mediating survival responses to a range of cent... more Heat shock protein 27 (HSP27) has a major role in mediating survival responses to a range of central nervous system insults, functioning as a protein chaperone, an antioxidant, and through inhibition of cell death pathways. We have used transgenic mice overexpressing HSP27 (HSP27tg) to examine the role of HSP27 in cerebral ischemia, using model of permanent middle cerebral artery occlusion (MCAO). Infarct size was evaluated using multislice T(2)-weighted anatomical magnetic resonance imaging (MRI) after 24 h. A significant reduction of 30% in infarct size was detected in HSP27tg animals compared with wild-type (WT) littermates. To gain some insight into the mechanisms contributing to cell death and its attenuation by HSP27, we monitored the effect of induction of c-jun and ATF3 on tissue survival in MCAO and their effects on the expression of endogenous mouse HSP25 and HSP70. It is important that, the c-jun induction seen at 4 h tended to be localized to regions that were salvageabl...
... tracers and places no restriction of the number of repeat measurements that can be made in a ... more ... tracers and places no restriction of the number of repeat measurements that can be made in a single study. ... 3 s) saturating off-resonance RF pulse, followed by a second image (S 0 ) withouta presaturation pulse. The magnetization transfer ratio (MTR) is then quantified as: 4. ...
To determine biventricular cardiac function in pneumovirus-induced acute lung injury in spontaneo... more To determine biventricular cardiac function in pneumovirus-induced acute lung injury in spontaneously breathing mice. Experimental animal study. Animal laboratory. C57Bl/6 mice. Mice were inoculated with the rodent pneumovirus, pneumonia virus of mice. Pneumonia virus of mice-infected mice were studied for right and left ventricular function variables by high-field strength (7 Tesla) cardiac MRI at specific time points during the course of disease compared with baseline. One day before and at peak disease severity, pneumonia virus of mice-infected mice showed significant right and left ventricular systolic and diastolic volume changes, with a progressive decrease in stroke volume and ejection fraction. No evidence for viral myocarditis or viral presence in heart tissue was found. These findings show adverse pulmonary-cardiac interaction in pneumovirus-induced acute lung injury, unrelated to direct virus-mediated effects on the heart.
The visualization of activity in mouse brain using inversion recovery spin echo (IR-SE) manganese... more The visualization of activity in mouse brain using inversion recovery spin echo (IR-SE) manganese-enhanced MRI (MEMRI) provides unique contrast, but suffers from poor resolution in the slice-encoding direction. Super-resolution reconstruction (SRR) is a resolution-enhancing post-processing technique in which multiple low-resolution slice stacks are combined into a single volume of high isotropic resolution using computational methods. In this study, we investigated, first, whether SRR can improve the three-dimensional resolution of IR-SE MEMRI in the slice selection direction, whilst maintaining or improving the contrast-to-noise ratio of the two-dimensional slice stacks. Second, the contrast-to-noise ratio of SRR IR-SE MEMRI was compared with a conventional three-dimensional gradient echo (GE) acquisition. Quantitative experiments were performed on a phantom containing compartments of various manganese concentrations. The results showed that, with comparable scan times, the signal-to-noise ratio of three-dimensional GE acquisition is higher than that of SRR IR-SE MEMRI. However, the contrast-to-noise ratio between different compartments can be superior with SRR IR-SE MEMRI, depending on the chosen inversion time. In vivo experiments were performed in mice receiving manganese using an implanted osmotic pump. The results showed that SRR works well as a resolution-enhancing technique in IR-SE MEMRI experiments. In addition, the SRR image also shows a number of brain structures that are more clearly discernible from the surrounding tissues than in three-dimensional GE acquisition, including a number of nuclei with specific higher brain functions, such as memory, stress, anxiety and reward behavior.
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