Optimizing Aromatase Expression and Uncovering Novel Allosteric Inhibitors for Breast Cancer Treatment

Breast cancer occurs in 1 of 8 women while 2,600 new cases of breast cancer are expected in men during 2016 alone1 . Aromatase, a cytochrome P450 enzyme that interconverts androgens into estrogens, is linked to hormonal breast cancer development2 . Aromatase inhibitors are currently used to treat breast cancer, but the mode of binding for some inhibitors remains unknown. The objective of this project is to optimize aromatase recombinant expression in E. coli and discover novel allosteric inhibitors. While screening possible new inhibitory compounds using an activity assay, we identified AR11 and AR13, which produced IC50 values of 25.35 μM and 0.41 μM respectively. We have not yet been successful in increasing recombinant expression of mutant-type aromatase, despite adjusting induction time, incubation temperature, and cell strain. Although optimization of aromatase expression was not achieved, possible inhibitors were uncovered which will be used in future screening of protein crystallization conditions once expression is improved. These crystal screens can then be used to generate new structures of aromatase:inhibitor complexes, leading to improved inhibitor potency and reduced toxicity.Chemistr

Simulation of Sound Absorption by Scattering Bodies Treated with Acoustic Liners Using a Time-Domain Boundary Element Method

Reducing aircraft noise is a major objective in the field of computational aeroacoustics. When designing next generation quiet aircraft, it is important to be able to accurately and efficiently predict the acoustic scattering by an aircraft body from a given noise source. Acoustic liners are an effective tool for aircraft noise reduction, and are characterized by a complex valued frequency-dependent impedance, Z(w). Converted into the time-domain using Fourier transforms, an impedance boundary condition can be used to simulate the acoustic wave scattering of geometric bodies treated with acoustic liners. This work uses an admittance boundary condition where the admittance, Y(w), is defined to be the inverse of impedance, i.e., Y(w) = 1/Z(w). An admittance boundary condition will be derived and coupled with a time domain boundary integral equation. The solution will be obtained iteratively using spatial and temporal basis functions and will allow for acoustic scattering problems to be modeled with geometries consisting of both unlined and soft surfaces. Stability will be demonstrated through eigenvalue analysis

Issues Affecting Medication Use Among Asian Americans, Native Hawaiians, and Pacific Islanders: A Qualitative Study

Background and Purpose: Asian American, Native Hawaiian, and Pacific Islander (AANHPI) populations may have unique issues (e.g., cultural attitudes and language barriers) that impact their relatively low adherence to medication use. Research on the topic is limited because AANHPI populations are generally not included in research studies. We conducted a qualitative investigation to gain insights into low adherence to medication use among AANHPIs and how to address this health disparity. Methods: In-depth individual interviews were conducted with 14 academic pharmacists and four other health care professionals knowledgeable about AANHPI disparities. Results: The majority of participants were either unsure of appropriate medication use by AANHPIs or felt they were used inappropriately. Over half of the participants were involved in or knew of efforts which focused on appropriate medication use. Participants felt that approaches to improving medication adherence included education and counseling, collaboration between providers, and conducting additional research, a role they felt the Daniel K. Inouye College of Pharmacy could fulfill. Conclusion: The appropriate use of medications for AANHPI populations is perceived as a barrier to parity in health care by pharmacists and other health care professionals. While current efforts exist to address appropriate medication use, additional research focusing on potential solutions identified by our participants is required to further assess their effectiveness in helping to close the health care gap

Coexpression of Spectrally Distinct Rhodopsins in Aedes aegypti R7 Photoreceptors

The retina of the mosquito Aedes aegypti can be divided into four regions based on the non-overlapping expression of a UV sensitive Aaop8 rhodopsin and a long wavelength sensitive Aaop2 type rhodopsin in the R7 photoreceptors. We show here that another rhodopsin, Aaop9, is expressed in all R7 photoreceptors and a subset of R8 photoreceptors. In the dorsal region, Aaop9 is expressed in both the cell body and rhabdomere of R7 and R8 cells. In other retinal regions Aaop9 is expressed only in R7 cells, being localized to the R7 rhabdomere in the central and ventral regions and in both the cell body and rhabdomere within the ventral stripe. Within the dorsal-central transition area ommatidia do not show a strict pairing of R7–R8 cell types. Thus, Aaop9 is coexpressed in the two classes of R7 photoreceptors previously distinguished by the non-overlapping expression of Aaop8 and Aaop2 rhodopsins. Electroretinogram analysis of transgenic Drosophila shows that Aaop9 is a short wavelength rhodopsin with an optimal response to 400–450 nm light. The coexpressed Aaop2 rhodopsin has dual wavelength sensitivity of 500–550 nm and near 350 nm in the UV region. As predicted by the spectral properties of each rhodopsin, Drosophila photoreceptors expressing both Aaop9 and Aaop2 rhodopsins exhibit a uniform sensitivity across the broad 350–550 nm light range. We propose that rhodopsin coexpression is an adaptation within the R7 cells to improve visual function in the low-light environments in which Ae. aegypti is active

On a Time Domain Boundary Integral Equation Formulation for Acoustic Scattering by Rigid Bodies in Uniform Mean Flow

It has been well-known that under the assumption of a uniform mean flow, the acoustic wave propagation equation can be formulated as a boundary integral equation. However, the constant mean flow assumption, while convenient for formulating the integral equation, does not satisfy the solid wall boundary condition wherever the body surface is not aligned with the assumed uniform flow. A customary boundary condition for rigid surfaces is that the normal acoustic velocity be zero. In this paper, a careful study of the acoustic energy conservation equation is presented that shows such a boundary condition would in fact lead to source or sink points on solid surfaces. An alternative solid wall boundary condition, termed zero energy flux boundary condition, is proposed that conserves the acoustic energy and a time domain boundary integral equation is derived. Furthermore, stabilization of the integral equation by BurtonMiller type reformulation is presented. The stability is studied theoretically as well as numerically by an eigenvalue analysis. Numerical solutions are also presented that demonstrate the stability of the current formulation

Investigating the Numerical Stability of Using an Impedance Boundary Condition to Model Broadband Noise Scattering With Acoustic Liners

Reducing aircraft noise is a major objective in the field of computational aeroacoustics. When designing next generation quiet aircraft, it is important to be able to accurately and efficiently predict the acoustic scattering by an aircraft body from a given noise source. Acoustic liners are an effective tool for achieving aircraft noise reduction and are characterized by a frequency-dependent impedance value. Converted into the time-domain using Fourier transforms, an impedance boundary condition can be used to simulate the acoustic wave scattering by geometric bodies treated with acoustic liners. A Broadband Impedance Model will be discussed in which the liner impedance is specified along a wide range of frequencies. The liner impedance boundary condition will be derived and coupled with a time-domain boundary integral equation to model acoustic scattering by a flat plate consisting of both un-lined and lined surfaces. The scattering solution will be obtained iteratively using both spatial and temporal basis functions and the stability will be demonstrated through eigenvalue analysis. Stability will be assessed for its dependence on time step, spatial discretization, as well as temporal basis function order. Both second- and third-order backward difference Lagrange temporal basis functions are considered

On a Time Domain Boundary Integral Equation Formulation for Acoustic Scattering by Rigid Bodies in Uniform Mean Flow

It has been well-known that under the assumption of a uniform mean flow, the acoustic wave propagation equation can be formulated as a boundary integral equation. However, the constant mean flow assumption, while convenient for formulating the integral equation, does not satisfy the solid wall boundary condition wherever the body surface is not aligned with the assumed uniform flow. A customary boundary condition for rigid surfaces is that the normal acoustic velocity be zero. In this paper, a careful study of the acoustic energy conservation equation is presented that shows such a boundary condition would in fact lead to source or sink points on solid surfaces. An alternative solid wall boundary condition, termed zero energy flux boundary condition, is proposed that conserves the acoustic energy and a time domain boundary integral equation is derived. Furthermore, stabilization of the integral equation by Burton-Miller type reformulation is presented. The stability is studied theoretically as well as numerically by an eigenvalue analysis. Numerical solutions are also presented that demonstrate the stability of the current formulation. (C) 2017 Acoustical Society of America

A New Formulation of Time Domain Boundary Integral Equation for Acoustic Wave Scattering in the Presence of a Uniform Mean Flow

It has been well-known that under the assumption of a constant uniform mean flow, the acoustic wave propagation equation can be formulated as a boundary integral equation, in both the time domain and the frequency domain. Compared with solving partial differential equations, numerical methods based on the boundary integral equation have the advantage of a reduced spatial dimension and, hence, requiring only a surface mesh. However, the constant uniform mean flow assumption, while convenient for formulating the integral equation, does not satisfy the solid wall boundary condition wherever the body surface is not aligned with the uniform mean flow. In this paper, we argue that the proper boundary condition for the acoustic wave should not have its normal velocity be zero everywhere on the solid surfaces, as has been applied in the literature. A careful study of the acoustic energy conservation equation is presented that shows such a boundary condition in fact leads to erroneous source or sink points on solid surfaces not aligned with the mean flow. A new solid wall boundary condition is proposed that conserves the acoustic energy and a new time domain boundary integral equation is derived. In addition to conserving the acoustic energy, another significant advantage of the new equation is that it is considerably simpler than previous formulations. In particular, tangential derivatives of the solution on the solid surfaces are no longer needed in the new formulation, which greatly simplifies numerical implementation. Furthermore, stabilization of the new integral equation by Burton-Miller type reformulation is presented. The stability of the new formulation is studied theoretically as well as numerically by an eigenvalue analysis. Numerical solutions are also presented that demonstrate the stability of the new formulation

The Employment Non-Discrimination Act: Its Scope, History, and Prospects

The Employment Non-Discrimination Act (ENDA) is a proposed federal bill that would prohibit discrimination in hiring and employment based on an individual’s actual or perceived sexual orientation or gender identity by civilian, nonreligious employers who employ at least 15 employees. Advocates for lesbian, gay, bisexual, and transgender (LGBT) people and their congressional allies have fought for the passage of some form of ENDA for more than four decades, including the 113th Congress, which commenced in January 2013. Although ENDA’s passage is still far from certain, this chapter will discuss in greater detail the impact ENDA would have on both employers and their employees if—and perhaps when—it becomes law. • The chapter begins by analyzing the specific terms of the bill, with a particular focus on the employers ENDA covers, what exactly is prohibited, and what exemptions exist. • The chapter next provides a brief legislative history of ENDA, including a summary of congressional hearings, to give the reader a sense of how the legislation has evolved and been shaped by the political process. As of April 30, 2014, Congress had held 11 hearings and issued three reports regarding ENDA. The full Senate had voted twice on ENDA, and the full House of Representatives had voted once on the legislation. • Finally, the chapter examines the past and present controversies and challenges facing ENDA, as a means of providing insight into ENDA’s prospects for passage and potential changes in future drafts of the bill. Given that ENDA’s history has roots going back 40 years, this chapter can provide only a broad overview of its history, but through this history, it also aims to offer enough details to provide insight into its future