Bifurcation and singularity analysis of a molecular network for the induction of long-term memory.

Withdrawal reflexes of the mollusk Aplysia exhibit sensitization, a simple form of long-term memory (LTM). Sensitization is due, in part, to long-term facilitation (LTF) of sensorimotor neuron synapses. LTF is induced by the modulatory actions of serotonin (5-HT). Pettigrew et al. developed a computational model of the nonlinear intracellular signaling and gene network that underlies the induction of 5-HT-induced LTF. The model simulated empirical observations that repeated applications of 5-HT induce persistent activation of protein kinase A (PKA) and that this persistent activation requires a suprathreshold exposure of 5-HT. This study extends the analysis of the Pettigrew model by applying bifurcation analysis, singularity theory, and numerical simulation. Using singularity theory, classification diagrams of parameter space were constructed, identifying regions with qualitatively different steady-state behaviors. The graphical representation of these regions illustrates the robustness of these regions to changes in model parameters. Because persistent protein kinase A (PKA) activity correlates with Aplysia LTM, the analysis focuses on a positive feedback loop in the model that tends to maintain PKA activity. In this loop, PKA phosphorylates a transcription factor (TF-1), thereby increasing the expression of an ubiquitin hydrolase (Ap-Uch). Ap-Uch then acts to increase PKA activity, closing the loop. This positive feedback loop manifests multiple, coexisting steady states, or multiplicity, which provides a mechanism for a bistable switch in PKA activity. After the removal of 5-HT, the PKA activity either returns to its basal level (reversible switch) or remains at a high level (irreversible switch). Such an irreversible switch might be a mechanism that contributes to the persistence of LTM. The classification diagrams also identify parameters and processes that might be manipulated, perhaps pharmacologically, to enhance the induction of memory. Rational drug design, to affect complex processes such as memory formation, can benefit from this type of analysis.

Convergent etiology of Eker rat and human uterine leiomyoma

The Eker rat model has allowed researchers the unique opportunity to study the tumorigenesis of spontaneously occurring uterine leiomyoma. Animals in this line harbor a germline mutation in the tuberous sclerosis complex-2 (Tsc-2) tumor suppressor gene and develop uterine leiomyomas at a rate of ∼65%. Primary leiomyomas obtained from humans and Eker rats along with Eker-derived leiomyoma cell lines were used in studies described herein to determine the effect of PPARγ ligand treatment on the proliferation of this cell type and to determine the role of tuberin and p27Kip1 in the etiology of this tumor type. Treatment of leiomyoma cells of human and rat origin with PPARγ-activating compounds resulted in decreased proliferation. Additionally, PPARγ ligands inhibited estrogen-dependent gene transactivation in Eker-derived leiomyoma cells suggesting that nuclear receptor cross-talk may exist between PPAR and the ER and may be responsible for the inhibition of proliferation in this cell type. Loss of tuberin, the product of the TSC-2 gene, is associated with Eker rat leiomyoma development while the role of this tumor suppressor in human leiomyoma development is unknown. Data herein show that tuberin expression is diminished in 25% of human leiomyomas tested. Additionally, we observed diminished p27 Kip1 expression in 80% of human uterine leiomyomas compared to normal myometrium. Interestingly, the loss of tuberin expression in human leiomyoma was associated with cytoplasmic p27Kip1 accumulation in this cell type. Furthermore, tuberin-null Eker rat leiomyomas and derived cell lines had predominantly cytoplasmic p27Kip1 compared to tuberin-expressing normal myometrium. Taken together, our data show that human and Eker rat leiomyoma proliferation is inhibited upon PPARγ treatment and that the etiology of human and Eker rat leiomyoma converge at loss of p27Kip1 function. Furthermore, our data indicate that the loss of p27 Kip1 function is mediated by loss of expression (in 80% of human leiomyoma) or cytoplasmic localization potentially resulting from the loss of tuberin. ^

Follow-up care after a health fair screening in three Houston neighborhoods in 2008

Background. Each year thousands of people participate in mass health screenings for diabetes and hypertension, but little is known about whether or not those who receive higher than normal screening results obtain the recommended follow-up medical care, or what barriers they perceive to doing so. ^ Methods. Study participants were recruited from attendees at three health fairs in low-income neighborhoods in Houston, Texas Potential participants had higher than normal blood pressure (> 90/140 mgHg) or blood glucose readings (100 mm/dL fasting or 140 mm/dL random). Study participants were called at one, two, and three months and asked if they had obtained follow-up medical care; those who had not yet obtained follow-up care were asked to identify barriers. Using a modified Aday-Andersen model of health service access, the independent variables were individual and community characteristics and self-perceived need. The dependent variable was obtaining follow-up care, with barriers to care a secondary outcome. ^ Results. Eighty-two study participants completed the initial questionnaire and 59 participants completed the study protocol. Forty-eight participants (59% under an intent to treat analysis, 81% of those completing the study protocol) obtained follow-up care. Those who completed the initial questionnaire and who reported a regular source of care were significantly more likely to obtain follow-up care. For those who completed the study protocol the relationship between having a regular source of care and obtaining follow-up care approached but did not reach significance. For those who completed the initial questionnaire, self-described health status, when examined as a binary variable (good, very good, excellent, or poor, fair, not sure) was associated with obtaining follow-up care for those who rated their health as poor, fair, or not sure. While the group who completed the study protocol did not reach statistical significance, the same relationship between self-described health status of poor, fair, or not sure and obtaining follow-up care was present. The participants who completed the study protocol and described their blood pressure as OK or a little high were statistically more likely to get follow-up care than those who described it as high or very high. All those on oral medications for hypertension (12/12) and diabetes (4/4) who were told to obtain follow-up care did so; however, the small sample size allows this correlation to be of statistical significance only for those treating hypertension. ^ The variables significantly associated with obtaining follow-up care were having a regular source of care, self-described health status of poor, fair, or not sure, self-described blood pressure of OK or a little high, and taking medication for blood pressure. ^ At the follow-up telephone calls, 34 participants identified barriers to care; cost was a significant barrier reported by 16 participants, and 10 reported that they didn’t have time because they were working long hours after Hurricane Ike. ^ The study included the offer of access assistance: information about nearby safety-net providers, a visit to or information from the Health Information Center at their Neighborhood Center location, or information from Project Safety Net (a searchable web site for safety net providers). Access assistance was offered at the health fairs and then again at follow-up telephone calls to those who had not yet obtained follow-up care. Of the 48 participants who reported obtaining follow-up care, 26 said they had made use of the access assistance to do so. The use of access assistance was associated with being Hispanic, not having health insurance or a regular source of care, and speaking Spanish. It was also associated with being worried about blood glucose. ^ Conclusion. Access assistance, as a community enabling characteristic, may be useful in aiding low-income people in obtaining medical care. ^