Inhibition of arterial KDR channels by DPO-1 and activation of cloned human BK channels by BPA-MS

The following documents our attempt at answering a fundamental question in vascular smooth muscle: Which K+ channels control membrane potential, and thus, vascular tone? A number of groups have approached this question and great strides have been made; however, uncertainty remains as to which specific K+ channel(s) underlies this physiologically important current. Previous studies using nonselective pharmacological inhibitors of voltage-dependent K+ (KV) channels, particularly delayed rectifier K+ (KDR) channels, indicate membrane depolarization, Ca2+ influx, and vasoconstriction. Importantly, however, there are more than 40 genes known to encode KV channel subunits. We hypothesize that KDR channels composed of KV 1 subunits are responsible for the polarizing current of arterial smooth muscle. Recently, diphenyl phosphine oxide-1 (DPO-1) has been suggested as a specific KV1.5 inhibitor. Therefore, we used DPO-1 as a pharmacological tool to investigate the role of KV1.5 subunits in the KDR channels of arterial smooth muscle. In Chapter 2, we tested the specificity of DPO-1 for KV1.5 using KV1.5 knockout (KO) mice. Whole-cell patch clamp recordings revealed reduced current and less percent block by DPO-1 in aortic smooth muscle cells from KO mice. Additionally, in Chapter 2, we determined that resistance vessels from rat brain and skeletal muscle contain a DPO-1-sensitive KDR current, constrict in response to DPO-1, and these KDR channels control reactivity. In Chapter 3, we investigated the mechanism of block by DPO-1 of KDR channels in porcine coronary smooth muscle cells and found that it was largely similar to that known for cloned KV1.5 channels. Together this work suggests that KV1.5 is a major contributor to the KDR current observed in arterial smooth muscle across a number of species and in a variety of arterial vessel types. Furthermore, these DPO-1-sensitive KDR channels regulate vascular tone, buffer vasoconstriction, and control reactivity. An additional interest of our group, and incorporated into the body of this document as Chapter 4, is the effects of the xenoestrogenic endocrine disruptor bisphenol A (BPA). We have previously shown that BPA activates large conductance voltage- and Ca2+-activated K+ (BK) channels and here we build on this knowledge by examining which side of the cell membrane BPA mediates the activity of BK. This was done by formation of a membrane impermeable BPA-monosulfate (BPA-MS) and subsequent electrophysiological experiments determined that BPA may have both intracellular and extracellular binding sites on the beta1 auxiliary subunit. Collectively, this dissertation is an investigation of the physiology and pharmacology of K+ channels with respect to an underlying interest in vascular smooth muscle physiology

Generic data for representing truck tire characteristics in simulations of braking and braking-in-a-turn maneuvers. Final report

Navistar International Transportation Corporation, Fort Wayne, Ind.Great Lakes Center for Truck and Transit Research, Ann Arbor, Mich.Transportation Department, University Transportation Centers Program, Washington, D.C.http://deepblue.lib.umich.edu/bitstream/2027.42/1133/2/88023.0001.001.pd

Tracking and stability of multi-unit truck combinations. Final report

Notes: Report covers the period 30 June 1984-30 April 1984Motor Vehicle Manufacturers Association, Detroit, Mich.http://deepblue.lib.umich.edu/bitstream/2027.42/182/2/71545.0001.001.pd

Evaluation of criteria for truck air brake adjustment. Interim report. Volume 1

Notes: Report covers the period Nov 1989 - March 1991Federal Highway Administration, Office of Motor Carrier Safety, Washington, D.C.http://deepblue.lib.umich.edu/bitstream/2027.42/921/2/81825.0001.001.pd

A test procedure for evaluating the obstacle evasion performance of heavy trucks. Final report

Notes: Report covers the period July 1990 - Sept 1991Motor Vehicle Manufacturers Association, Detroit, Mich.http://deepblue.lib.umich.edu/bitstream/2027.42/938/2/82061.0001.001.pd

Development of microcomputer models of truck braking and handling. Final report

Notes: Report covers the period 1 July 1986 - 30 June 1987Motor Vehicle Manufacturers Association, Detroit, Mich.http://deepblue.lib.umich.edu/bitstream/2027.42/9/2/76419.0001.001.pd

Subsequent Ultrasonographic Non-Visualization of the Ovaries Is Hastened in Women with Only One Ovary Visualized Initially

Because the effects of age, menopausal status, weight and body mass index (BMI) on ovarian detectability by transvaginal ultrasound (TVS) have not been established, we determined their contributions to TVS visualization of the ovaries when one or both ovaries are visualized on the first ultrasound exam. A total of 29,877 women that had both ovaries visualized on their first exam were followed over 202,639 prospective TVS exams and 9703 women that had only one ovary visualized on their first exam were followed over 63,702 ultrasonography exams. All images were reviewed by a physician. While non-visualization of both ovaries increased with age in women selected on the basis of the visualization of only one ovary on their first ultrasound exam, one or both ovaries could be visualized in two out of every three women at 80 years of age and more than 50% of women over 80 years of age. At each age, more non-visualizations were associated with women that had only one ovary visualized on their first visit. Having only one ovary visualized on the first exam advanced non-visualizations by an average of ~10 years across all ages and by \u3e20 years in women under 40 years of age. Conclusions: Having only one ovary visualized on an initial ultrasound exam considerably hastens complete non-visualization for this population; however, in these women, ovaries can still be visualized well past menopause, and body habitus is not limiting to TVS ovarian imaging, thus TVS should be considered capable of capturing an ovarian image in two out of every three women at 80 years of age

Tracking Medical Students and Graduates from Hometown to Practice using Geographic Information Systems, 2011-2017

Background: Indiana University School of Medicine (IUSM) through its statewide system provides medical education and clinical experiences across Indiana for more than 1,450 medical students in nine regions, including Indianapolis and eight regional medical campuses (RMCs). The majority of medical students begin their education distributed among the RMCs, and some students continue clinical experiences at the RMCs for their third and fourth years. Methods: We used a Geographic Information System (GIS) to visualize and document the contribution of our RMCs in Indiana to the physician workforce pipeline. Using data from the 2011-2017 graduating classes, we created a geospatial database that linked key information from student records and public domain sources (e.g., hometown, campus assignment, PGY1 specialty, and practice) with their corresponding locational information. ArcGIS 10.5 GIS software was used to produce a series of maps to visualize patterns in student outcomes among the RMCs over time. Results: By using GIS to track medical trainees from hometown to practice, we can provide accurate visualization of extensive geographic data. The maps revealed similarities and differences among the RMCs not fully appreciated until visually mapped, including the specialty choice of students from different campuses and the proportion of graduates practicing in medically underserved areas of the state. Conclusions: GIS maps and their analyses can identify strengths and distinctions among the RMCs while providing accurate descriptions of the role of geography in the professional development journey of the physician workforce. This ongoing project is a major step toward integrating GIS as a familiar tool in academic administration and health workforce research to assist future decision-making by the school leadership

The Effect of Low-Density Lipoprotein Cholesterol on T-Cell Mitochondrial Respiration

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