PMID: 16496370;Abstract:
Cell transplantation offers a potential new treatment for stroke. Animal studies using models that produce ischemic damage in both the striatum and the frontal cortex have shown beneficial effects when hNT cells (postmitotic immature neurons) were transplanted into the ischemic striatum. In this study, we investigated the effect of hNT cells in a model of stroke in which the striatum remains intact and damage is restricted to the cortex. hNT cells were transplanted into the ischemic cortex 1 week after stroke induced by distal middle cerebral artery occlusion (dMCAo). The cells exhibited robust survival at 4 weeks posttransplant even at the lesion border. hNT cells did not migrate, but they did extend long neurites into the surrounding parenchyma mainly through the white matter. Neurite extension was predominantly toward the lesion in ischemic animals but was bidirectional in uninjured animals. Extension of neurites through the cortex toward the lesion was also seen when there was some surviving cortical tissue between the graft and the infarct. Prolonged deficits were obtained in four tests of sensory-motor function. hNT-transplanted animals showed a significant improvement in functional recovery on one motor test, but there was no effect on the other three tests relative to control animals. Thus, despite clear evidence of graft survival and neurite extension, the functional benefit of hNT cells after ischemia is not guaranteed. Functional benefit could depend on other variables, such as infarct location, whether the cells mature, the behavioral tests employed, rehabilitation training, or as yet unidentified factors. © 2006 Wiley-Liss, Inc.
PMID: 10535107;PMCID: PMC1690213;Abstract:
Transmissible spongiform encephalopathies such as scrapie are caused by a protein-only infectious agent, known as a prion. It is not clear how a protein can be capable of replicating itself, and the mechanism remains controversial. One influential model hypothesizes that prions are nucleated, macroscopically linear polymers. We investigated the theoretical kinetics of this model and derived predictions which could be used to test the model. In the model, the polymerization and depolymerization rates are independent of polymer size. This leads to an exponential size distribution at equilibrium. In agreement with a prediction stemming from this size distribution, the average size of PrP-res polymers was proportional to the square root of the concentration of PrP-res in a published study of in vitro conversion. Prion digestion by proteinase K (PK) is predicted to be biphasic. The second phase of digestion should be virtually independent of the PK concentration and should depend on the initial size distribution of prion polymers. For initially equilibrated polymers with an exponential size distribution, phase two digestion is exponential at a predicted rate. This rate varies in a defined way with the concentration used for equilibration and with other parameters which affect the average polymer size.
PMID: 19486147;PMCID: PMC2770902;Abstract:
Reversible phenotypic switching can be caused by a number of different mechanisms including epigenetic inheritance systems and DNA-based contingency loci. Previous work has shown that reversible switching systems may be favored by natural selection. Many switches can be characterized as "on/off" where the "off" state constitutes a temporary and reversible loss of function. Loss-of-function phenotypes corresponding to the "off" state can be produced in many different ways, all yielding identical fitness in the short term. In the long term, however, a switch-induced loss of function can be reversed, whereas many loss-of-function mutations, especially deletions, cannot. We refer to these loss-of-function mutations as "irreversible mimics" of the reversible switch. Here, we develop a model in which a reversible switch evolves in the presence of both irreversible mimics and metapopulation structure. We calculate that when the rate of appearance of irreversible mimics exceeds the migration rate, the evolved reversible switching rate will exceed the bet-hedging rate predicted by panmictic models. © 2009 The Society for the Study of Evolution.
