Review of "Writing Program and Writing Center Collaborations," edited by Alice Johnston Myatt and Lynee Lewis Gaillet

University Writing Cente

Post-translational Modifications of Pregnant X Receptor

Pregnane X Receptor (PXR, NR1I2) is a member of the nuclear receptor (NR) superfamily of ligand-activated transcription factors. Expression levels of PXR are highest in the liver and intestine. The activation of PXR can be achieved by exposure to a myriad of xenobiotic compounds and prescription drugs to regulate the expression of genes that encode key enzymes and membrane transporter proteins. Collectively, these PXR-target genes encode gene products that function in a coordinate manner and comprise a vital xenobiotic detoxification pathway in these tissues. In this way, PXR activation by these compounds functions as a ‘xeno-sensor’ of foreign substances in our body to positively regulate the transcription of genes such as cytochrome P450 (CYP) 3A4, and the drug efflux transporter multiple drug resistant protein 1 (MDR1/P-gp), as well as other drug metabolizing enzymes and drug transporter proteins. Xenobiotic-mediated activation of PXR in humans also represents the molecular mechanism of CYP3A4-triggered adverse drug-drug interactions in which the induction of the expression of this broadly selective drug-metabolizing enzyme increases the metabolism of many other co-administered substrates. Activation of PXR also appears to be involved at some level in the MDR1-mediated acquired resistance to chemotherapeutic agents in multiple cancer types. Beyond the canonical physiology of ligand-mediated PXR activation in the regulation of drug metabolism, accumulating evidence clearly indicates that PXR exerts a trans-repressive activity towards the inflammatory response in both the liver and intestine in humans. A broad spectrum of evidence suggests the involvement of post-translational modifications (PTMs) in the regulation of the trans-repressive transcriptional effects of many liver-enriched NR proteins. Previous studies in our laboratory have revealed that PXR is the molecular target of several PTMs including phosphorylation, ubiquitination, and SUMO- (small ubiquitin-like modifier) modification (SUMOylation). Moreover, our research shows that PTMs that target PXR likely regulate its biological activity through sophisticated system of networking or ‘crosstalk’. Crosstalk in this sense is defined as how various PTMs interact with each other on a given protein target to produce a specific biological outcome. The current study is focused on the mechanism of crosstalk between the PTMs and their effect upon the regulation of PXR-mediated trans-repression phenomenon. In the first chapter of this dissertation I provide an introduction to the topic of NR signaling in general, followed by an explanation of canonical PXR signaling in detail. In Chapter 2, the role of crosstalk between the SUMOylation and ubiquitination pathways is examined and its effect upon the regulation of PXR biology in primary hepatocytes is discussed. Tumor necrosis factor-alpha (TNFα)-triggered SUMO(1)ylation of PXR is well-known to inhibit the expression of inflammatory genes in liver and intestine. I show in this dissertation that treatment with the PXR activators, such as Rifampicin (Rif), promotes the SUMO3-modification of PXR. Further, I show that the SUMO(3)ylation of PXR subsequently increases the ubiquitination of PXR, likely to promote proteasomal degradation of this important transcription factor. In Chapter 3, the crosstalk between SUMOylation and acetylation was investigated. I found that pharmacological inhibition of histone deacetylase 3 (HDAC3) activity in cell line-based assays significantly promotes the SUMOylation of PXR, which subsequently impairs the ability of PXR to interact with its canonical corepressor multi-protein complex HDAC3/SMRT (silencing mediator for retinoid or thyroid–hormone receptor). Taken together, the results presented in this dissertation provide novel insight into the likely molecular mechanisms that regulate the clinically observed PXR-mediated trans-repression phenomenon. Specifically, my results suggest that this phenomenon is controlled by an SUMO-acetyl ‘functional switch’ in which PXR acetylation marks PXR as competent for its subsequent SUMOylation, given the correct physiological extracellular condition, namely inflammation. In Chapter 4, the molecular details of the role of phosphorylation in the regulation of PXR-initiated transcription, and its effect upon the interaction with PXR accessory proteins were examined. Utilizing a liquid chromatography tandem mass spectrometry (LC-MS/MS)-based proteomic approach, two phosphorylation sites (T135 and S221) in PXR were identified in primary mouse hepatocytes. Phosphorylation at identified sites inhibits the trans-activation capacity of PXR through interrupting PXR-RXRα hetero-dimerization and PXR association with coactivator proteins. In conclusion, PTMs modulate different aspects of PXR biological activity in the liver and is especially essential for PXR-originated trans-repression of the inflammatory response in liver and intestine. Collectively, the data presented in this dissertation sheds new light upon the molecular mechanisms governing PXR-mediated suppression of inflammation, and could be expected to provide innovative strategies to target the PXR protein for the treatment of inflammatory diseases

Graduate Writing Groups: Evidence-Based Practices for Advanced Graduate Writing Support

Writing centers seek to expand their services beyond tutoring and develop evidence-based practices. Continuing and expanding the existing practices, the authors have adopted graduate writing groups (GWGs) to support graduate writers, especially those working on independent writing projects like a dissertation or article for publication. This article provides an effective model on how to develop and assess virtual graduate writing groups (VGWGs). This replicable, aggregable, and data-supported (RAD) research applied a mixed-methods design with pre- and postsurveys over the three semesters of running the VGWG. It found that the VGWG offered a full range of writing support that met graduate writers’ needs for time-based, skill-based, draft-based, and emotion-based support. Specifically, the VGWG significantly improved students’ approaches to writing in five key areas—goal setting, focusing on dissertation writing, generating plans for writing sessions, writing productivity, and writing progress. Therefore, this study contributes robust empirical validation of this model, suggesting that VGWG is an effective method to sup-port graduate writers and expand writing center services. Also, the authors provide a useful model on how writing centers can effectively assess through pre- and postsurveys in a straightforward manner, an assessment model that has both internal and external benefits

Structured Neural-PI Control with End-to-End Stability and Output Tracking Guarantees

We study the optimal control of multiple-input and multiple-output dynamical systems via the design of neural network-based controllers with stability and output tracking guarantees. While neural network-based nonlinear controllers have shown superior performance in various applications, their lack of provable guarantees has restricted their adoption in high-stake real-world applications. This paper bridges the gap between neural network-based controllers and the need for stabilization guarantees. Using equilibrium-independent passivity, a property present in a wide range of physical systems, we propose neural Proportional-Integral (PI) controllers that have provable guarantees of stability and zero steady-state output tracking error. The key structure is the strict monotonicity on proportional and integral terms, which is parameterized as gradients of strictly convex neural networks (SCNN). We construct SCNN with tunable softplus-$\beta$ activations, which yields universal approximation capability and is also useful in incorporating communication constraints. In addition, the SCNNs serve as Lyapunov functions, giving us end-to-end performance guarantees. Experiments on traffic and power networks demonstrate that the proposed approach improves both transient and steady-state performances, while unstructured neural networks lead to unstable behaviors.Comment: arXiv admin note: text overlap with arXiv:2206.0026

Bridging Transient and Steady-State Performance in Voltage Control: A Reinforcement Learning Approach with Safe Gradient Flow

Deep reinforcement learning approaches are becoming appealing for the design of nonlinear controllers for voltage control problems, but the lack of stability guarantees hinders their deployment in real-world scenarios. This paper constructs a decentralized RL-based controller featuring two components: a transient control policy and a steady-state performance optimizer. The transient policy is parameterized as a neural network, and the steady-state optimizer represents the gradient of the long-term operating cost function. The two parts are synthesized through a safe gradient flow framework, which prevents the violation of reactive power capacity constraints. We prove that if the output of the transient controller is bounded and monotonically decreasing with respect to its input, then the closed-loop system is asymptotically stable and converges to the optimal steady-state solution. We demonstrate the effectiveness of our method by conducting experiments with IEEE 13-bus and 123-bus distribution system test feeders.Comment: Published in IEEE Control Systems Letters, vol. 7, pp. 2845-2850, 2023 with CDC presentatio

Nuclear-receptor–mediated regulation of drug– and bile-acid–transporter proteins in gut and liver

This is an Accepted Manuscript of an article published by Taylor & Francis in Drug Metabolism Reviews on 2015 Sep 2, available online: http://www.tandfonline.com/10.3109/03602532.2012.748793.Adverse drug events (ADEs) are a common cause of patient morbidity and mortality and are classically thought to result, in part, from variation in expression and activity of hepatic enzymes of drug metabolism. It is now known that alterations in the expression of genes that encode drug- and bile-acid–transporter proteins in both the gut and liver play a previously unrecognized role in determining patient drug response and eventual clinical outcome. Four nuclear receptor (NR) superfamily members, including pregnane X receptor (PXR, NR1I2), constitutive androstane receptor (NR1I3), farnesoid X receptor (NR1H4), and vitamin D receptor (NR1I1), play pivotal roles in drug- and bile-acid– activated programs of gene expression to coordinately regulate drug- and bile-acid transport activity in the intestine and liver. This review focuses on the NR-mediated gene activation of drug and bile-acid transporters in these tissues as well as the possible underlying molecular mechanisms

Experimental study on water evaporation from sand using environmental chamber

International audienceLarge-scale evaporation experiments were conducted on bare sand using an environmental chamber. Four different atmospheric conditions and various drying durations were imposed to soil sample. Both the atmospheric parameters (air flow rate, relative humidity and temperature) and the response of soil (volumetric water content, temperature and soil suction) were monitored simultaneously. Notably, the temperature and matric suction at soil surface were monitored using infrared thermometer and high-capacity tensiometer, respectively. The results show that the air and soil temperatures depend on the evaporation process and atmospheric conditions. In addition, volumetric water content in the near-surface zone is strongly affected by the evaporation process and changes linearly over depth. The evaporation rate is strongly dependent on the air conditions