Selective Targeting of CYP3A5 Through Chemical and Genetic Approaches

Cytochrome P450 enzymes function to catalyze a wide range of reactions important for various biological processes. In humans, the CYP3A subfamily is particularly critical for drug response. Within this family are CYP3A4 and CYP3A5, which collectively metabolize greater than half of all currently prescribed drugs. These promiscuous enzymes can bind a broad and structurally diverse array of compounds, in turn leading to an increased risk of their modulation via small molecules. In the case of CYP3A5, which is over-expressed in some cancers, this leads to chemoresistance. Such aberrant expression and corresponding drug resistance merit a need to selectively target CYP3A5. However, the significant overlap in sequence and structural identity with CYP3A4 as well as flexible and dynamic binding modes make development of a selective inhibitor challenging, and no progress has been made thus far. Moreover, the cancer-specific regulation of CYP3A5 remains unknown, removing the possibility of targeting a factor upstream of its transcription. While CYP3A4 regulation in liver is well-documented, these regulators don’t control CYP3A5 in extra-hepatic contexts. This warrants further investigation in order to understand the biological basis of CYP3A5 over-expression in disease models. Here we present discovery of the first isoform-selective CYP3A5 inhibitor. We used high-throughput technology to identify clobetasol propionate as capable of selectively inhibiting CYP3A5 enzymatic activity without conferring CYP3A4 inhibition. We further demonstrate the in vitro ability of the compound using a clinically relevant cell model with CYP3A5 overexpression and CRISPR/Cas9-mediated full genetic deletion. Additionally, we explore the mechanism of selectivity, employing computational and biophysical techniques to illustrate how subtle active site differences allow the compound to adopt a tight heme-ligand coordination exclusively in CYP3A5 and serving as the basis of its selective inhibition

User's manual for the NASA Lewis ice accretion/heat transfer prediction code with electrothermal deicer input

A version of LEWICE has been developed that incorporates a recently developed electrothermal deicer code, developed at the University of Toledo by William B. Wright. This was accomplished, in essence, by replacing a subroutine in LEWICE, called EBAL, which balanced the energies at the ice surface, with a subroutine called UTICE. UTICE performs this same energy balance, as well as handles all the time-timperature transients below the ice surface, for all of the layers of a composite blade as well as the ice layer itself. This new addition is set up in such a fashion that a user may specify any number of heaters, any heater chordwise length, and any heater gap desired. The heaters may be fired in unison, or they may be cycled with periods independent of each other. The heater intensity may also be varied. In addition, the user may specify any number of layers and thicknesses depthwise into the blade. Thus, the new addition has maximum flexibility in modeling virtually any electrothermal deicer installed into any airfoil. It should be noted that the model simulates both shedding and runback. With the runback capability, it can simulate the anti-icing mode of heater performance, as well as detect icing downstream of the heaters due to runback in unprotected portions of the airfoil. This version of LEWICE can be run in three modes. In mode 1, no conduction heat transfer is modeled (which would be equivalent to the original version of LEWICE). In mode 2, all heat transfer is considered due to conduction but no heaters are firing. In mode 3, conduction heat transfer where the heaters are engaged is modeled, with subsequent ice shedding. When run in the first mode, there is virtually identical agreement with the original version of LEWICE in the prediction of accreted ice shapes. The code may be run in the second mode to determine the effects of conduction on the ice accretion process

Partial-Transfer Absorption Imaging: A versatile technique for optimal imaging of ultracold gases

Partial-transfer absorption imaging is a tool that enables optimal imaging of atomic clouds for a wide range of optical depths. In contrast to standard absorption imaging, the technique can be minimally-destructive and can be used to obtain multiple successive images of the same sample. The technique involves transferring a small fraction of the sample from an initial internal atomic state to an auxiliary state and subsequently imaging that fraction absorptively on a cycling transition. The atoms remaining in the initial state are essentially unaffected. We demonstrate the technique, discuss its applicability, and compare its performance as a minimally-destructive technique to that of phase-contrast imaging.Comment: 10 pages, 5 figures, submitted to Review of Scientific Instrument

Simulating Ice Accretion Effects on Engine Performance

Develop a modeling tool that can be used to predict the onset of engine icing due to ice crystal ingestion. The tool will be capable of modeling the effects of ice build up as well as its effect on engine performance. Perform a parametric study of an engine with simulated ice blockage effects at altitude conditions. Using the tool, estimate the effect of blockage in the low pressure compressor due to ice buildup (accretion), and its effects on engine performance

Examining Mechanisms for Voltage-Sensitive Calcium Channel-Mediated Secretion Events in Bone Cells

In addition to their well-described functions in cell excitability, voltage-sensitive calcium channels (VSCCs) serve a critical role in calcium (Ca2+)-mediated secretion of pleiotropic paracrine and endocrine factors, including those produced in bone. Influx of Ca2+ through VSCCs activates intracellular signaling pathways to modulate a variety of cellular processes that include cell proliferation, differentiation, and bone adaptation in response to mechanical stimuli. Less well understood is the role of VSCCs in the control of bone and calcium homeostasis mediated through secreted factors. In this review, we discuss the various functions of VSCCs in skeletal cells as regulators of Ca2+ dynamics and detail how these channels might control the release of bioactive factors from bone cells. Because VSCCs are druggable, a better understanding of the multiple functions of these channels in the skeleton offers the opportunity for developing new therapies to enhance and maintain bone and to improve systemic health

7075-T6 and 2024-T351 Aluminum Alloy Fatigue Crack Growth Rate Data

Experimental test procedures for the development of fatigue crack growth rate data has been standardized by the American Society for Testing and Materials. Over the past 30 years several gradual changes have been made to the standard without rigorous assessment of the affect these changes have on the precision or variability of the data generated. Therefore, the ASTM committee on fatigue crack growth has initiated an international round robin test program to assess the precision and variability of test results generated using the standard E647-00. Crack growth rate data presented in this report, in support of the ASTM roundrobin, shows excellent precision and repeatability

Mixed Phase Modeling in GlennICE with Application to Engine Icing

A capability for modeling ice crystals and mixed phase icing has been added to GlennICE. Modifications have been made to the particle trajectory algorithm and energy balance to model this behavior. This capability has been added as part of a larger effort to model ice crystal ingestion in aircraft engines. Comparisons have been made to four mixed phase ice accretions performed in the Cox icing tunnel in order to calibrate an ice erosion model. A sample ice ingestion case was performed using the Energy Efficient Engine (E3) model in order to illustrate current capabilities. Engine performance characteristics were supplied using the Numerical Propulsion System Simulation (NPSS) model for this test case

The impact of cafeteria feeding during lactation in the rat on novel object discrimination in the offspring

There is increasing evidence that hyperenergetic diets impact on memory in rodents. However, it is largely unknown how diets, such as a cafeteria diet (CD), that mimic a Western diet act on learning and memory, in particular when fed during early stages of development. Here, we fed lactating dams a cafeteria diet and exposed both male and female offspring to a novel object discrimination (NOD) task, a two-trial test of recognition memory in which rats exposed to two identical objects during a training/familiarisation trial can discriminate a novel from a familiar object during the subsequent choice trial. The choice trial was performed following inter-trial interval (ITI) delays of up to 4 h. Maternal diet did not impact on exploration of the objects by either sex during the familiarisation trial. Control males discriminated the novel from the familiar object indicating intact memory with an ITI of 1h, but not 2 or 4h. CD delayed this natural forgetting in male rats such that discrimination was also evident after a 2h ITI. In contrast, control females exhibited discrimination following both 1 and 2h ITIs, but CD impaired performance. In summary, the present study shows that maternal exposure to CD programmes NOD in the adult. In better performing females dietary programming interferes with NOD whereas NOD was improved in males after lactational CD feeding

Detroit Journal March

Title only.https://scholarsjunction.msstate.edu/cht-sheet-music/1598/thumbnail.jp