Dynamics of a minimal model of interlocked positive and negative feedback loops of transcriptional regulation by cAMP-response element binding proteins.

cAMP-response element binding (CREB) proteins are involved in transcriptional regulation in a number of cellular processes (e.g., neural plasticity and circadian rhythms). The CREB family contains activators and repressors that may interact through positive and negative feedback loops. These loops can be generated by auto- and cross-regulation of expression of CREB proteins, via CRE elements in or near their genes. Experiments suggest that such feedback loops may operate in several systems (e.g., Aplysia and rat). To understand the functional implications of such feedback loops, which are interlocked via cross-regulation of transcription, a minimal model with a positive and negative loop was developed and investigated using bifurcation analysis. Bifurcation analysis revealed diverse nonlinear dynamics (e.g., bistability and oscillations). The stability of steady states or oscillations could be changed by time delays in the synthesis of the activator (CREB1) or the repressor (CREB2). Investigation of stochastic fluctuations due to small numbers of molecules of CREB1 and CREB2 revealed a bimodal distribution of CREB molecules in the bistability region. The robustness of the stable HIGH and LOW states of CREB expression to stochastic noise differs, and a critical number of molecules was required to sustain the HIGH state for days or longer. Increasing positive feedback or decreasing negative feedback also increased the lifetime of the HIGH state, and persistence of this state may correlate with long-term memory formation. A critical number of molecules was also required to sustain robust oscillations of CREB expression. If a steady state was near a deterministic Hopf bifurcation point, stochastic resonance could induce oscillations. This comparative analysis of deterministic and stochastic dynamics not only provides insights into the possible dynamics of CREB regulatory motifs, but also demonstrates a framework for understanding other regulatory processes with similar network architecture.

Dynamics of a minimal model of interlocked positive and negative feedback loops of transcriptional regulation by cAMP-response element binding proteins.

cAMP-response element binding (CREB) proteins are involved in transcriptional regulation in a number of cellular processes (e.g., neural plasticity and circadian rhythms). The CREB family contains activators and repressors that may interact through positive and negative feedback loops. These loops can be generated by auto- and cross-regulation of expression of CREB proteins, via CRE elements in or near their genes. Experiments suggest that such feedback loops may operate in several systems (e.g., Aplysia and rat). To understand the functional implications of such feedback loops, which are interlocked via cross-regulation of transcription, a minimal model with a positive and negative loop was developed and investigated using bifurcation analysis. Bifurcation analysis revealed diverse nonlinear dynamics (e.g., bistability and oscillations). The stability of steady states or oscillations could be changed by time delays in the synthesis of the activator (CREB1) or the repressor (CREB2). Investigation of stochastic fluctuations due to small numbers of molecules of CREB1 and CREB2 revealed a bimodal distribution of CREB molecules in the bistability region. The robustness of the stable HIGH and LOW states of CREB expression to stochastic noise differs, and a critical number of molecules was required to sustain the HIGH state for days or longer. Increasing positive feedback or decreasing negative feedback also increased the lifetime of the HIGH state, and persistence of this state may correlate with long-term memory formation. A critical number of molecules was also required to sustain robust oscillations of CREB expression. If a steady state was near a deterministic Hopf bifurcation point, stochastic resonance could induce oscillations. This comparative analysis of deterministic and stochastic dynamics not only provides insights into the possible dynamics of CREB regulatory motifs, but also demonstrates a framework for understanding other regulatory processes with similar network architecture.

A study in the molecular and cellular functions of GSK3beta in prostate adenocarcinoma

Kinases are part of a complex network of signaling pathways that enable a cell to respond to changes in environmental conditions in a regulated and coordinated way. For example, Glycogen Synthase Kinase 3 beta (GSK3β) modulates conformational changes, protein-protein interaction, protein degradation, and activation of unique domains in proteins that transduce signals from the extracellular milieu to the nucleus. ^ In this project, I investigated the expression and function that GSK3β exhibits in prostate cells. The capacity of GSK3β to regulate two transcription factors (JUN and CREB), which are known to be inversely utilized in prostate tumor cells, was measured. JUN/AP1 is constitutively activated in PC-3 cells; whereas, CREB/CRE activity is ∼20 fold less than the former. GSK3β overexpression obliterates JUN/AP1 activity. With respect to CREB GSK3β increases CREB/CRE activity. Cellular levels of active GSK3β can determine whether JUN or CREB is preferentially active in the PC-3s. Theoretically, in response to a particular cellular context or stimulus, a cell may coordinate JUN and CREB function by regulating GSK3β.^ A comparison of various prostate cell lines showed that active GSK3β is less expressed in normal prostate epithelial cells than in tumor cells. Differentially expressed active (GSK3β) may correlate with progression of prostate carcinoma. If a known marker associated with carcinoma of the prostate could be shown to be regulated by GSK3β then, further study of GSK3β may lead to a better understanding of both possible prevention of the disease and improved therapy for advanced stages. ^ The androgen receptor (AR) is an intriguing phosphoprotein whose regulation is potentially determined by a variety of kinases. One of these is (GSK3β) I found that (GSK3β) is a regulator of the androgen receptor in both the unliganded and liganded states. It can inhibit AR function as measured by reporter assays. Also, GSK3β associates with the AR at the DNA binding domain because deletion constructs expressing either the n-terminus or the c-terminus (both having the DBD in common) immunoprecipitated with GSK3β. Increased understanding of how GSK3β functions in prostate cancer would provide clues into how (1) certain signal pathways are coordinated and (2) the androgen receptor may be regulated. ^

Policy implications of public health workforce development for disaster preparedness in the United States

Public health efforts were initiated in the United States with legislative actions for enhancing food safety and ensuring pure drinking water. Some additional policy initiatives during the early 20th century helped organize and coordinate relief efforts for victims of natural disasters. By 1950's the federal government expanded its role for providing better health and safety to the communities, and its disaster relief activities became more structured. A rise in terrorism related incidents during the late 1990's prompted new proactive policy directions. The traditional policy and program efforts for rescue, recovery, and relief measures changed focus to include disaster preparedness and countermeasures against terrorism.^ The study took a holistic approach by analyzing all major disaster related policies and programs, in regard to their structure, process, and outcome. Study determined that United States has a strong disaster preparedness agenda and appropriate programs are in place with adequate policy support, and the country is prepared to meet all possible security challenges that may arise in the future. The man-made disaster of September 11th gave a major thrust to improve security and enhance preparedness of the country. These new efforts required large additional funding from the federal government. Most existing preparedness programs at the local and national levels are run with federal funds which is insufficient in some cases. This discrepancy arises from the fact that federal funding for disaster preparedness programs at present are not allocated by the level of risks to individual states or according to the risks that can be assigned to critical infrastructures across the country. However, the increased role of the federal government in public health affairs of the states is unusual, and opposed to the spirit of our constitution where sovereignty is equally divided between the federal government and the states. There is also shortage of manpower in public health to engage in disaster preparedness activities, despite some remarkable progress following the September 11th disaster.^ Study found that there was a significant improvement in knowledge and limited number of studies showed improvement of skills, increase in confidence and improvement in message-mapping. Among healthcare and allied healthcare professionals, short-term training on disaster preparedness increased knowledge and improved personal protective equipment use with some limited improvement in confidence and skills. However, due to the heterogeneity of these studies, the results and interpretation of this systematic review may be interpreted with caution.^

When Policy Opportunity is not Enough: College Access and Enrollment Patterns among Texas Percent Plan Eligible Students

In 1998, Texas initiated a bold new statewide university admission policy aimed at increasing college access for traditionally underserved students in the state. House Bill 588 (known as the Texas Top 10 Percent Plan (TTPP)) guaranteed automatic admission to the college or university of their choice for all top performing students in Texas public high schools. Fourteen years after the plan’s implementation, we see great strides and complexities in understanding student outcomes as a result of the percent plan. However, the legal controversy over the percent plan both in Texas and other states incorporating similar yet distinctly motivated alternative admissions plans continues to play out from institutional decision boards to the highest court in the nation. This study seeks to add to that discussion by exploring two questions. Descriptively, what are the admission and enrollment patterns within racial/ethnic groups of percent plan eligible students, over time, for Texas elite, emergent elite, and remaining public institutions? Given that all eligible percent plan students may enter the institution of choice in Texas, does which type of institution a TTPP student chooses relate to their race/ethnicity? The descriptive story told by the admission and enrollment distributions of equally eligible TTPP students is a complex but compelling one. Fundamentally, it identifies that statistically different application and enrollment patterns exist for Hispanic and especially African American TTPP beneficiaries relative to their White and Asian American counterparts.

An evaluation of the centers for Medicare & Medicaid Services' Hospital Acquired Conditions and Present on Admission Indicator Reporting program

Objective: This dissertation evaluated three aspects of the Centers for Medicare and Medicaid Services' Hospital Acquired Conditions and Present on Admission Indicator Reporting program (HACPOA program) to produce three journal articles for publication. ^ Methods: All payer admission records from state inpatient databases from Arizona, New Jersey and Washington states were analyzed for the year 2008. However some analyses required a sample of adult only Medicare patients in the first two studies. California's inpatient data (2004 – 2010) was also analyzed in the third study to examine the reporting and non-payment program elements' impact on the incidence of hospital acquired conditions. ^ Results: Majority diagnoses reported in inpatient prospective payment systems hospitals were present on admission. However, some diagnoses are still coded as "not present on admission" and "insufficient documentation to determine whether or not conditions are present on admission or not". This is important because it reveals that hospital complications still occur in hospitals. Hospital fall and trauma injuries were the most common hospital acquired conditions observed in this study. Predictors of hospital fall injuries include age, gender, number of diagnoses, number of procedures, number of chronic conditions while predictors of hospital trauma injuries include number of e-codes, number of diagnoses and the presence of chronic conditions on a patient's admission records. Finally, the implementation of the present on admission reporting requirement increased reports of certain hospital acquired conditions while the non-payment policy element in the Hospital Acquired Conditions program reduced the incidence of hospital fall and trauma injuries in particular. ^ Conclusion: The implementation of the Hospital Acquired Conditions and Present on Admission Indicator Reporting program has made the state inpatient database a more useful source of data capable of now identifying hospital complications. The reporting and nonpayment program elements in the HACPOA program have also impacted the incidence of hospital acquired conditions. ^