174 research outputs found
Organotypic cultures as tools for functional screening in the CNS
No full textScreening gets more complex with organotypic culture systems.A major challenge for the pharmaceutical industry is the development of relevant model systems in which knowledge gained from high-throughput, genomic and proteomic approaches can be integrated to study function. Animal models are still the main choice for such studies but over the past few years powerful new in vitro systems have begun to emerge as useful tools to study function. Organotypic cultures made from slices of explanted tissue represent a complex multi-cellular in vitro environment with the potential to assess biological function and are uniquely placed to act as an important link between high-throughput approaches and animal models
Characterisation of a novel class of polyamine-based neuroprotective compounds
No full textProlonged cerebral ischaemia initiates complex intra- and inter-cellular signalling cascades ultimately resulting in neuronal death. Well-characterised mediators of ischaemic cell death are glutamate, free radicals and nitric oxide. Many drugs that block these mechanisms are neuroprotective in vitro, but have unfavourable side-effect profiles in man. We have recently demonstrated that the compound L-arginyl-3,4-spermidine (L-Arg3,4) is neuroprotective in vitro through an interaction with several of these mechanisms, and prevents ischaemic neurodegeneration in vivo with no gross side effects. In this study, we have used solid-phase combinatorial chemistry, to synthesise a number of analogues of L-Arg3,4, and investigate the structure-activity relationship using an in vitro, organotypic hippocampal slice culture model of cerebral ischaemia. A number of molecular features were identified which were essential for the neuroprotective activity including the requirement for a positive charge and an amino acid in the L-configuration. Relatively minor alterations to both the terminal arginine and polyamine moieties significantly attenuated neuroprotective efficacy. Our data implies that these compounds are neuroprotective through a currently undefined mechanism rather than non-specific ionic interactions described previously for other polyamine-containing compounds
Lactate and glucose as energy substrates during, and after, oxygen deprivation in rat hippocampal acute and cultured slices
No full textThe effects of raised brain lactate levels on neuronal survival following hypoxia or ischemia is still a source of controversy among basic and clinical scientists. We have sought to address this controversy by studying the effects of glucose and lactate on neuronal survival in acute and cultured hippocampal slices. Following a 1-h hypoxic episode, neuronal survival in cultured hippocampal slices was significantly higher if glucose was present in the medium compared with lactate. However, when the energy substrate during the hypoxic period was glucose and then switched to lactate during the normoxic recovery period, the level of cell damage in the CA1 region of organotypic cultures was significantly improved from 64.3 +/- 2.1 to 74.6 +/- 2.1% compared with cultures receiving glucose during and after hypoxia. Extracellular field potentials recorded from the CA1 region of acute slices were abolished during oxygen deprivation for 20 min, but recovered almost fully to baseline levels with either glucose (82.6 +/- 10.0%) or lactate present in the reperfusion medium (108.1 +/- 8.3%). These results suggest that lactate alone cannot support neuronal survival during oxygen deprivation, but a combination of glucose followed by lactate provides for better neuroprotection than either substrate alone
Stretch-induced injury in organotypic hippocampal slice cultures reproduces in vivo post-traumatic neurodegeneration: role of glutamate receptors and voltage-dependent calcium channels
No full textThe relationship between an initial mechanical event causing brain tissue deformation and delayed neurodegeneration in vivo is complex because of the multiplicity of factors involved. We have used a simplified brain surrogate based on rat hippocampal slices grown on deformable silicone membranes to study stretch-induced traumatic brain injury. Traumatic injury was induced by stretching the culture substrate, and the biological response characterized after 4 days. Morphological abnormalities consistent with traumatic injury in humans were widely observed in injured cultures. Synaptic function was significantly reduced after a severe injury. The N-methyl-D-aspartate (NMDA) receptor antagonist MK-801 attenuated neuronal damage, prevented loss of microtubule-associated protein 2 immunoreactivity and attenuated reduction of synaptic function. In contrast, the NMDA receptor antagonists 3-[(R)-2-carboxypiperazin-4-yl]-propyl-1-phosphonic acid (CPP) and GYKI53655, were neuroprotective in a moderate but not a severe injury paradigm. Nifedipine, an L-type voltage-dependent calcium channel antagonist was protective only after a moderate injury, whereas omega-conotoxin attenuated damage following severe injury. These results indicate that the mechanism of damage following stretch injury is complex and varies depending on the severity of the insult. In conclusion, the pharmacological, morphological and electrophysiological responses of organotypic hippocampal slice cultures to stretch injury were similar to those observed in vivo. Our model provides an alternative to animal testing for understanding the mechanisms of post-traumatic delayed cell death and could be used as a high-content screen to discover neuroprotective compounds before advancing to in vivo models
Progress: An Experiment in Historiography and Environmental Theater
No full textiii, 73 p.The author presents two essays: "Women's Reproductive Rights in Nazi Germany : Mothers, 'Degenerates' and the State," and "Designing 'Progress' : Hitting the Books, Dipping the Brushes, Screwing the Bolts." The first essay describes the dramatic impact that the rise of Hitler and the Nazi party had on German feminism and reproductive rights. The author analyzes the legislation and propganda of the era. The second essay describes the process of conceptualizing and designing the sets for a short theater piece based on the author's history research. A 1930s era German doctor meets a series of female patients receiving pre-natal care, a post-surgey check-up, and sterilization
"Indignation Can Move Mountains": Women in the French Resistance, 1940-1944
No full textiii, 83 p.The author discusses the role of women in French society in the years before World War II, traces the rise of the Vichy Regime, noting the ways in which the regime sought to reorganize French society in the wake of defeat, and then gives an overview of the French Resistance, highlighting the participation of French women. Though the Resistance work of women has not been remembered in the same quantities as men, their efforts were equally vital to the functioning of the Resistance. While resistance work required women to take on a political role, their work was often an extension of traditional female spaces. In this way, the Resistance was both liberating and repressive. The remarkable women of the French Resistance took a courageous stand against what they considered a threat to their identity. Says Germaine Tillion, "Faced with crime and cruelty, something wells up within you. I call it indignation.
doi:10.1016/S1359-6446(05)03502-6
No full textA major challenge for the pharmaceutical industry is the development of relevant model systems in which knowledge gained from high-throughput, genomic and proteomic approaches can be integrated to study function. Animal models are still the main choice for such studies but over the past few years powerful new in vitro systems have begun to emerge as useful tools to study function. Organotypic cultures made from slices of explanted tissue represent a complex multi-cellular in vitro environment with the potential to assess biological function and are uniquely placed to act as an important link between high-throughput approaches and animal models
Dynamic, regional mechanical properties of the porcine brain: Indentation in the coronal plane,"
No full textStress relaxation tests using a custom designed microindentation device were performed on ten anatomic regions of fresh porcine brain (postmortem time <3 h). Using linear viscoelastic theory, a Prony series representation was used to describe the shear relaxation modulus for each anatomic region tested. Prony series parameters fit to load data from indentations performed to $10% strain differed significantly by anatomic region. The gray and white matter of the cerebellum along with corpus callosum and brainstem were the softest regions measured. The cortex and hippocampal CA1/CA3 were found to be the stiffest. To examine the large strain behavior of the tissue, multistep indentations were performed in the corona radiata to strains of 10%, 20%, and 30%. Reduced relaxation functions were not significantly different for each step, suggesting that quasi-linear viscoelastic theory may be appropriate for representing the nonlinear behavior of this anatomic region of porcine brain tissue. These data, for the first time, describe the dynamic and short time scale behavior of multiple anatomic regions of the porcine brain which will be useful for understanding porcine brain injury biomechanics at a finer spatial resolution than previously possible
Science Fiction as Social Commentary: The Galactic Empire and the Third Reich
No full textiii, 64 p.Why is it that historians are interested in science fiction to the extent that they are? What does the genre provide us with that is so fascinating and thought-provoking that it has caused historians to want to study, analyze and dissect science fiction works? The answer is quite simple; science fiction essentially is history in itself. It is very common for authors of science fiction works to use their writing as outlets expressing their personalized views. As historians, we should be very interested in science fiction as a means of understanding, for example, political, social and/or military backdrops of the time in which the author was writing. Science fiction as both literature and film, presents us with not only opportunities to "escape reality," but also to criticize those realities
thorough "metaphoric mirrors." The futuristic scenarios that science fiction authors present us with are essentially different takes on the past and present; by viewing the past and in fact, even the present from a different perspective, historians may be able to imagine alternate circumstances as possibilities for the world they are currently living, or have lived in. Since science fiction allows us to study the role the individual plays in society,2 this might further allow historians to consider the role of accident or contingency in human affairs; just how much effect do individual humans have on the greater history? Take, for example, Isaac Asimov's Foundation; a scientist and his team of psycho historians manage to alter the decline and re-ascent of an entire empire based on calculations. Asimov's book, then, would be a trigger to historians to consider the roles of humans in such large events.
calculations. Asimov's book, then, would be a trigger to historians to consider the
roles of humans in such large events
The role of brain-derived neurotrophic factor in the regulation of dendritic arbor morphology, neuronal network activity, and neuroprotection
No full textThe dendritic architecture of a neuron determines how it receives inputs, and thus, changes in dendrite morphology will affect connectivity among neurons. Aberrant changes in the development of the arbor, or after the arbor has formed, can disrupt the functioning of neural circuits, causing severe brain dysfunction and leading to pathologies seen in cognitive disorders, neurological diseases, and trauma. Brain-derived neurotrophic factor (BDNF) is one of the most well-studied regulators of dendritic and synaptic plasticity. It is also known to be a pro-survival factor and is overexpressed in neurons that survive injuries, such as ischemia. This dissertation explores how BDNF shapes the dendritic arbor of single hippocampal neurons and the dynamics of in vitro hippocampal networks. Previous work in our laboratory has shown that BDNF significantly increases proximal dendrite branching in hippocampal neurons after 72 hours of bath application. Building on this work, we show that local application of BDNF via microbeads increases both proximal and distal dendrite branching in a shorter time than does bath application. We also show that overexpression of BDNF shapes the dendritic arbor differently depending on the intracellular targeting of BDNF transcripts. To understand how BDNF affects the development of hippocampal neuronal networks, we use microelectrode arrays (MEAs) to record the spontaneous activity of these networks before and after bath application of BDNF. Our results suggest a role for BDNF in the long-term development of neuronal network dynamics, as changes in network parameters were only observed at one week after treatment. Finally, we explore whether BDNF exerts neuroprotective effects following excitotoxic injury. Global activity parameters decrease following injury with excess glutamate with no benefit from BDNF treatment, but BDNF does protect connections with distinct baseline synchronizations from injury-induced decreases. Taken together, our results indicate that BDNF is involved in the development of the dendritic arbor, the maturation of neuronal networks, and the protection of distinct connections after excitotoxic injury.Ph.D.Includes bibliographical referencesby Kate M. O’Neil
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