Showing papers by "Mark O. Cunningham published in 2007"

Impairment of hippocampal gamma (γ)-frequency oscillations in vitro in mice overexpressing human amyloid precursor protein (APP)

Abstract: Alzheimer's disease is associated with a dramatic decline in cognitive performance including hippocampal-dependent memory. We have investigated one feature of hippocampal activity related to memory, the gamma (30-80 Hz)-frequency rhythm. Hippocampal slices from mice overexpressing the human amyloid precursor protein (APP)(SWE) mutation (TAS10) were compared at 8 and 16 months of age with wild-type littermates. In slices obtained from TAS10 mice aged 8 months the gamma-frequency activity evoked with bath application of 200 nm kainate was significantly (P 0.05; n = 11 slices from five animals) between slices from TAS10 and wild-type control mice as the wild-type mice now exhibited a marked age-dependent reduction in gamma-frequency activity (TAS10 area power, 5751 +/- 1573 microV(2); wild-type area power = 5379 +/- 1454 microV(2)). Although no dense-core plaques were evident at 8 months there was detectable amyloid labelling in the TAS10 mice which might account for the deficits in gamma activity observed at this age. Dense plaques were clearly evident in the TAS10, but not wild-type, mice at 16 months of age but no further reductions in gamma-frequency activity were seen in the TAS10 mice. These data suggest that deficits in network function in Alzheimer's disease occur early and are not directly correlated to amyloid load.

Discovery of a small molecule antagonist of the parathyroid hormone receptor by using an N-terminal parathyroid hormone peptide probe

Abstract: Once-daily s.c. administration of either human parathyroid hormone (PTH)-(1-84) or recombinant human PTH-(1-34) provides for dramatic increases in bone mass in women with postmenopausal osteoporosis. We initiated a program to discover orally bioavailable small molecule equivalents of these peptides. A traditional high-throughput screening approach using cAMP activation of the PTH/PTH-related peptide receptor (PPR) as a readout failed to provide any lead compounds. Accordingly, we designed a new screen for this receptor that used a modified N-terminal fragment of PTH as a probe for small molecule binding to the transmembrane region of the PPR, driven by the assumption that the pharmacological properties (agonist/antagonist) of compounds that bound to this putative signaling domain of the PPR could be altered by chemical modification. We developed DPC-AJ1951, a 14 amino acid peptide that acts as a potent agonist of the PPR, and characterized its activity in ex vivo and in vivo assays of bone resorption. In addition, we studied its ability to initiate gene transcription by using microarray technology. Together, these experiments indicated that the highly modified 14 amino acid peptide induces qualitatively similar biological responses to those produced by PTH-(1-34), albeit with lower potency relative to the parent peptide. Encouraged by these data, we performed a screen of a small compound collection by using DPC-AJ1951 as the ligand. These studies led to the identification of the benzoxazepinone SW106, a previously unrecognized small molecule antagonist for the PPR. The binding of SW106 to the PPR was rationalized by using a homology receptor model.

RFID at the Customer Interface: The Issue of Privacy

Abstract: Data capture technologies like Radio Frequency Identification Devices (RFID) can be a double-edged sword. On the one hand they may be viewed positively as the ultimate enabler of customer personalisation or they may be viewed negatively as a 'Big Brother' tool used to unnecessarily monitor consumer purchases and habits (Juban and Wyld, 2004). RFID could ultimately prove to be the defining facilitator of communication between organisations and their customers. However due to the current lack of education as to how RFID may affect consumers, along with the increasing fears over privacy issues, civil liberty and security both the company and the consumer may miss the rewards of RFID. This paper will outline the many benefits and challenges which RFID holds from a consumer perspective. This paper will suggest a research agenda to study the issue of consumer privacy, and promote a better understanding of what exactly RFID means at the customer interface.