1,778 research outputs found
Anti-apoptotic gene therapy in Parkinson's disease
No full textApoptosis, whether caspase-dependent or caspase-independent, has been implicated as one of the important mechanisms leading to the death of dopaminergic neurons in the substantia nigra of Parkinson's disease patients. Major advances of our understanding of apoptosis have been achieved in studies of 1-methyl-4-phenyl-1,2,3,6-tetra-hydropyridine (MPTP) toxicity in mice and monkeys and 6-hydroxydopamine (6-OHDA) toxicity in rats and monkeys. The use of viral vectors to either express anti-apoptotic proteins or to downregulate pro-apoptotic proteins has the major advantage of addressing selective molecular targets, bypassing the blood-brain-barrier to specifically target the nigrostriatal pathway by their stereotaxic application and by the choice of the appropriate virus and promotor. Used thus far have been virus-mediated overexpression of inhibitor of apoptosis proteins, inhibitors of the c-jun-N-terminal kinase (JNK) pathway, inhibitors of calpains and dominant negative inhibitors of the protease activating factor (APAF)-1 and cdk5. Most studies implicate the endogenous, mitochondrial pathway in the apoptosis of dopaminergic neurons. The results suggest that only an inhibition of this pathway upstream of caspase activation will also result in the protection of nigrostriatal dopaminergic terminals and behavioral benefit, whereas an inhibition of caspases alone may not be sufficient to prevent the degeneration of terminals, although it may promote the survival of neuronal cell bodies for some time
Anti-apoptotic gene therapy in Parkinson's disease
No full textApoptosis, whether caspase-dependent or caspase-independent, has been implicated as one of the important mechanisms leading to the death of dopaminergic neurons in the substantia nigra of Parkinson's disease patients. Major advances of our understanding of apoptosis have been achieved in studies of 1-methyl-4-phenyl-1,2,3,6-tetra-hydropyridine (MPTP) toxicity in mice and monkeys and 6-hydroxydopamine (6-OHDA) toxicity in rats and monkeys. The use of viral vectors to either express anti-apoptotic proteins or to downregulate pro-apoptotic proteins has the major advantage of addressing selective molecular targets, bypassing the blood-brain-barrier to specifically target the nigrostriatal pathway by their stereotaxic application and by the choice of the appropriate virus and promotor. Used thus far have been virus-mediated overexpression of inhibitor of apoptosis proteins, inhibitors of the c-jun-N-terminal kinase (JNK) pathway, inhibitors of calpains and dominant negative inhibitors of the protease activating factor (APAF)-1 and cdk5. Most studies implicate the endogenous, mitochondrial pathway in the apoptosis of dopaminergic neurons. The results suggest that only an inhibition of this pathway upstream of caspase activation will also result in the protection of nigrostriatal dopaminergic terminals and behavioral benefit, whereas an inhibition of caspases alone may not be sufficient to prevent the degeneration of terminals, although it may promote the survival of neuronal cell bodies for some time
Limitations of cellular models in Parkinson's disease research
No full textCell cultures for Parkinson's disease research have the advantage of virtually unlimited access, they allow rapid screening for disease pathogenesis and drug candidates, and they restrict the necessary number of animal experiments. Limitations of cell cultures, include that the survival of neurons is dependent upon the culture conditions; that the cells do not develop their natural neuronal networks. In most cases, neurons are deprived from the physiological afferent and efferent connections. In Parkinson's disease research, mesencephalic slice cultures, primary immature doparninergic neurons and immortalized cell lines - either in a proliferating state or in a differentiated state - are used. Neuronal cultures may be plated in the presence or absence of glial cells and serum. These different culture conditions as well as the selection of outcome parameters (morphological evaluation, viability assays, biochemical assays, metabolic assays) have a strong influence on the results of the experiments and the conclusions drawn from them. A primary example is the question of whether L-Dopa is toxic to doparninergic neurons or whether it provides neurotrophic effects: In pure, neuronal-like cultures, L-Dopa provides toxicity, whereas in the presence of glial cells, it provides trophic effects when applied. The multitude of factors that influence the data generated from cell culture experiments indicates that in order to obtain clear-cut and unambiguous results, investigators need to choose their model carefully and are encouraged to verify their main results with different models
Online_Supplements_(Tables) – Supplemental material for Fertility Intentions and Their Realization in Couples: How the Division of Household Chores Matters
No full textSupplemental material, Online_Supplements_(Tables) for Fertility Intentions and Their Realization in Couples: How the Division of Household Chores Matters by Bernhard Riederer, Isabella Buber-Ennser and Zuzanna Brzozowska in Journal of Family Issues</p
Limitations of cellular models in Parkinson's disease research
No full textCell cultures for Parkinson's disease research have the advantage of virtually unlimited access, they allow rapid screening for disease pathogenesis and drug candidates, and they restrict the necessary number of animal experiments. Limitations of cell cultures, include that the survival of neurons is dependent upon the culture conditions; that the cells do not develop their natural neuronal networks. In most cases, neurons are deprived from the physiological afferent and efferent connections. In Parkinson's disease research, mesencephalic slice cultures, primary immature doparninergic neurons and immortalized cell lines - either in a proliferating state or in a differentiated state - are used. Neuronal cultures may be plated in the presence or absence of glial cells and serum. These different culture conditions as well as the selection of outcome parameters (morphological evaluation, viability assays, biochemical assays, metabolic assays) have a strong influence on the results of the experiments and the conclusions drawn from them. A primary example is the question of whether L-Dopa is toxic to doparninergic neurons or whether it provides neurotrophic effects: In pure, neuronal-like cultures, L-Dopa provides toxicity, whereas in the presence of glial cells, it provides trophic effects when applied. The multitude of factors that influence the data generated from cell culture experiments indicates that in order to obtain clear-cut and unambiguous results, investigators need to choose their model carefully and are encouraged to verify their main results with different models
A novel screen for nuclear mitochondrial gene associations with Parkinson's disease
No full textGenetic factors play an important role in the aetiology of Parkinson's disease (PD). We have screened nuclear genes encoding subunits of mitochondrial complex I for associations between single nucleotide polymorphisms (SNPs) and PD. Abnormal functioning of complex I is well documented in human PD. Moreover, toxicological inhibition of complex I can lead to parkinsonism in animals. Thus, commonly occurring variants in these genes could potentially influence complex I function and the risk of developing PD. A sub-set of 70 potential SNPs in 31 nuclear complex I genes were selected and association analysis was performed on 306 PD patients plus 321 unaffected control subjects. Genotyping was performed using the DASH method. There was no evidence that the examined SNPs were significant genetic risk factors for PD, although this initial screen could not exclude the possibility that other disease-influencing variations exist within these genes
The glucocorticoid receptor gene exon 1-F promoter is not methylated at the NGFI-A binding site in human hippocampus
No full textRecent research has demonstrated that early life experience, such as variation in maternal care, can have a profound impact on the physiological and endocrine stress response of Rattus norvegicus. Low maternal care resulted in increased methylation of the nerve growth
factor-inducible protein A (NGFI-A, EGR1) binding site located in the hippocampal glucocorticoid receptor gene (Nr3c1) exon 17 promoter, leading to decreased Nr3c1 expression, which results in a reduced efficiency of glucocorticoid-mediated negative feedback on hypothalamus-pituitary-adrenal axis activity. The human glucocorticoid receptor gene (NR3C1) has a highly similar 5’ structure compared to the rat, and the human alternative exon 1-F is the orthologue to the rat exon 17. Based upon the evidence from rats, and the high sequence identity of the regulatory sequences, we examined the methylation pattern of the corresponding NGFI-A binding site in the human glucocorticoid receptor
exon 1-F specific promoter in post-mortem hippocampal tissue.
In contrast to the findings in rats, neither of the two CpG motifs within the NGFI-A binding site was methylated in the 32 subjects investigated. These observations might reflect different promoter methylation patterns in humans and rats
Dolostones used in Middle Age in Friuli (Ne Italy)
No full textIl contributo riferisce di una ricerca sul campo svolta per l’individuazione dell’area di provenienza del materiale lapideo utilizzato per la realizzazione del Portale trecentesco del Duomo di Udine, oggetto di un intervento di restauro a cura di T. Perusini e dello studio litologico a cura di P. Spadea. Prendendo avvio da un approfondimento storico di carattere generale sull’utilizzo della pietra in elementi scultorei coevi, ripetuti sopralluoghi in località della fascia pedemontana del Friuli Occidentale (Ragogna, Pinzano, Travesio, Oltrerugo, Paludea, Castelnovo), luogo di residenza dei lapicidi lombardi del Rinascimento friulano, a cura di A. Frangipane,hanno permesso il campionamento di elementi architettonici dell’edilizia spontanea, visivamente individuati dalla cromia giallo–pallida, consentendo un riscontro delle caratteristiche petrografiche del materiale con quello cercato e la formulazione di un’ipotesi originale sull’area di approvvigionamento. | The paper reports on a field study carried out for the identification of the origin of the stone material used for the construction of the fourteenth-century portal of the Duomo of Udine, the subject of a restoration edited by T. Perusini and a lithological study by P. Spadea. Taking as its starting from a historical study of a general nature on the use of stone in contemporary sculptural elements, repeated surveys in the area of the foothills of the Western Friuli (Ragogna, Pinzano, Travesio, Oltrerugo, Paludea, Castelnovo), place of residence of the Lombard masons Renaissance Friuli, carried out by A. Frangipane, have allowed the sampling of the architectural elements of the building spontaneous, visually identified by the pale-yellow color scheme, allowing a comparison of the petrographic characteristics of the material with the tried and the formulation of a hypothesis on the site of the original supply
Behavior of nuclear matrix proteins during camptothecin-induced apoptosis in HL-60 human leukemia cells.
No full textIn this study we focused our attention on the behavior of four nuclear matrix proteins during the various stages of apoptosis in the HL-60 cell line exposed to the DNA topoisomerase I inhibitor, camptothecin. We have examined the following antigens by immunocytochemical techniques: (i) the 180-kDa nucleolar isoform of DNA topoisomerase II; (ii) a 126-kDa polypeptide of nuclear bodies; (iii) a 125-kDa protein; and (iv) a 160-kDa polypeptide which are known to be components of the matrix inner network. Indirect immunofluorescence experiments were performed to follow these nuclear matrix antigens during apoptosis. Moreover, the ultrastructural localization of both 125- and 160-kDa proteins was investigated by electron microscope immunocytochemistry with gold-conjugated secondary antibodies. While the antibody to the nucleolar isoform of DNA topoisomerase II gave a fluorescent pattern that was well-maintained until the late phases of apoptosis, the other three nuclear antigens showed marked modifications in their distribution. A common feature, particularly evident for 125- and 160-kDa proteins, was their absence from cap-shaped chromatin marginations, whereas they were present in the areas of remaining decondensed chromatin. The 126-kDa polypeptide concentrated progressively in an irregular mass at the opposite side of the crescentic caps and then broke up in fine spots. The 125- and 160-kDa proteins localized in the nucleolus and precisely within certain granules which are known to appear in the nucleolar area after camptothecin administration. These results show that, in addition to the well-known chromatin changes, nuclear organization undergoes other rearrangements during the apoptotic process
Indoor Thermal Comfort Analysis for Developing Energy- Saving Strategies in Buildings
No full textHumans spend most of their time indoors, whether in their place of residence or work, with large amounts of energy consumed to create comfortable living conditions. Buildings are, therefore, accountable for a considerable proportion of global energy demand; within them, heating, ventilation, and air-conditioning systems constitute major energy drains. Traditionally, these systems are controlled by conventional, mainly static set points, but research has shown that substantial energy savings can be achieved by applying adaptive ones. This work aims to showcase the lower energy consumption achievable when employing adaptive over static approaches, using empirical data from a non-residential living lab. Assessments of rational and adaptive thermal comfort indices over the energy used in HVAC systems are provided, and the energy-saving potential of adaptive thermal comfort models in the design of HVAC control algorithms is estimated. The findings of this work highlight that controlling indoor setpoint temperature according to the adaptive comfort model can achieve energy savings from 15% up to 33%, compared to the rational one, while providing a satisfactory thermal environmen
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