The Most Beautiful Thing in the World : A Rhetorical Analysis of Relational Dialectics and Friendship in the Musical Kinky Boots

In this article, we examine Kinky Boots, a musical that won the Tony Award for Best Musical in 2013 and continues to win over audiences with its positive message about acceptance, as a rhetorical text through William K. Rawlins’ theoretical construct of relational dialectics regarding friendship. Through rhetorical criticism as a research method, we apply Rawlins’ concepts of political and personal friendships, as well as the dialectics of affection and instrumentality, expressiveness and protectiveness, judgment and acceptance, and the ideal and the real to examine notable relationships between characters in the musical. Specifically, we examine the relationships between Charlie and Nicola, Charlie and Lola, and Don and Lola. Through this analysis, we suggest that when participants in the musical’s relationships fail to negotiate dialectic tensions, their relationships can resultantly cease to exist. We also note that the balance of relational dialectics appears to be conducive to healthy relationships. We posit that Kinky Boots provides theatre-goers with life lessons regarding relational dialectics that they can apply to their own real-life relationships, and that Kinky Boots may serve as an effective teaching tool for undergraduate students learning about relational dialectics

MAMMALIAN MSS51 IS A NEWLY DESCRIBED, SKELETAL MUSCLE-SPECIFIC GENE

Skeletal muscle is a complex system with robust ability to repair and regenerate after damage. Modulation of the pathways involved in these processes are very important in the context of muscle disease, where muscle progressively wastes or degenerates and loses its ability to regenerate efficiently. One such pathway relies on nitric oxide (NO) signaling, which we modulated with the phosphodiesterase inhibitor sildenafil and the soluble guanylate cyclase activator BAY 60-2770 in the mouse models of muscle injury and muscular dystrophy, respectively, and showed no benefit from either treatment method. An additional pathway of interest is the myostatin pathway, whose inhibition leads to muscle hypertrophy and altered muscle metabolism. The altered metabolic program includes changes in mRNA levels of many metabolic genes, including the newly-described skeletal muscle-specific gene Mss51, presented here. Expression patterns of Mss51 were described in various tissues of mice and humans, and in muscles of different fiber type distributions. Mss51 was predominantly expressed in glycolytic muscle groups, and in humans, the protein product MSS51 localized to the mitochondria. The effect of ablation of Mss51 was examined in C2C12 immortal myoblasts as well as in mice and primary myoblasts. Decreased Mss51 expression resulted in altered myosin heavy chain expression, increased expression of genes involved in fatty acid oxidation, and altered metabolic function as shown with the Seahorse metabolic flux analyzer in C2C12 myotubes and treadmill endurance in Mss51-/- mice. Overall, Mss51 was shown to be a skeletal muscle-specific gene playing a role in the regulation of metabolic processes specifically in glycolytic muscle groups. Advisor: Dr. Kathryn Wagner Thesis Committee: Dr. Jonathan Pevsner (Chair) Dr. Thomas Clemens (Reader) Dr. Eva Chin (2013-present) Dr. Robert Bloch (2011-2013

Widespread perturbation of ETS factor binding sites in cancer.

Although \u3e90% of somatic mutations reside in non-coding regions, few have been reported as cancer drivers. To predict driver non-coding variants (NCVs), we present a transcription factor (TF)-aware burden test based on a model of coherent TF function in promoters. We apply this test to NCVs from the Pan-Cancer Analysis of Whole Genomes cohort and predict 2555 driver NCVs in the promoters of 813 genes across 20 cancer types. These genes are enriched in cancer-related gene ontologies, essential genes, and genes associated with cancer prognosis. We find that 765 candidate driver NCVs alter transcriptional activity, 510 lead to differential binding of TF-cofactor regulatory complexes, and that they primarily impact the binding of ETS factors. Finally, we show that different NCVs within a promoter often affect transcriptional activity through shared mechanisms. Our integrated computational and experimental approach shows that cancer NCVs are widespread and that ETS factors are commonly disrupted

De novo design of immunoglobulin-like domains

Antibodies, and antibody derivatives such as nanobodies, contain immunoglobulin-like (Ig) β-sandwich scaffolds which anchor the hypervariable antigen-binding loops and constitute the largest growing class of drugs. Current engineering strategies for this class of compounds rely on naturally existing Ig frameworks, which can be hard to modify and have limitations in manufacturability, designability and range of action. Here, we develop design rules for the central feature of the Ig fold architecture—the non-local cross-β structure connecting the two β-sheets—and use these to design highly stable Ig domains de novo, confirm their structures through X-ray crystallography, and show they can correctly scaffold functional loops. Our approach opens the door to the design of antibody-like scaffolds with tailored structures and superior biophysical properties.This research was supported by grants from the Spanish Ministry of Science and Innovation (RYC2018-025295-I, EUR2020-112164, and PID2020-120098GA-I00). This study was also supported in part by grants from Spanish and Catalan public and private bodies (grant/fellowship references MCIN/AEI/10.13039/501100011033/PID2019-107725RG-I00, 2017SGR3 and Fundació “La Marató de TV3” 201815). S.R.M. acknowledges grant BES2016-076877 from the Spanish State Agency for Research (MCIN/AEI/10.13039/501100011033) and the European Social Fund “ESF invests in your future”. U.E. was funded by a Beatriu de Pinós post-doctoral fellowship (AGAUR-MSCA COFUND 2018BP00163. J.R.T. was supported by an EMBO postdoctoral fellowship (under grant agreement ALTF 145-2021). J.C.K. was supported by a National Science Foundation Graduate Research Fellowship (grant DGE-1256082). D.B. and T.M.C. acknowledge the Howard Hughes Medical Institute. We thank the Princess Margaret Cancer Centre for funding of the NMR facility. The Structural Genomics Consortium is a registered charity (no: 1097737) that receives funds from Bayer AG, Boehringer Ingelheim, Bristol Myers Squibb, Genentech, Genome Canada through Ontario Genomics Institute [OGI-196], EU/EFPIA/OICR/McGill/KTH/Diamond Innovative Medicines Initiative 2 Joint Undertaking [EUbOPEN grant 875510], Janssen, Merck KGaA (aka EMD in Canada and US), Pfizer and Takeda

Exploring electronic effects on the partitioning of actinides(III) from lanthanides(III) using functionalised bis-triazinyl phenanthroline ligands

The first examples of 4,7-disubstituted 2,9-bis(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-1,2,4-benzo-triazin-3-yl)-1,10- phenanthroline (CyMe4 -BTPhen) ligands are reported herein. Evaluating the kinetics, selectivity and stoichiometry of actinide(III) and lanthanide(III) radiotracer extractions has provided a mechanistic insight into the extraction process. For the first time, it has been demonstrated that metal ion extraction kinetics can be modulated by backbone functionalisation and a promising new CHON compliant candidate ligand with enhanced metal ion extraction kinetics has been identified. The effects of 4,7- functionalisation on the equilibrium metal ion distribution ratios are far more pronounced than those of 5,6-functionalisation. The complexation of Cm(III) with two of the functionalised ligands was investigated by TRLFS and, at equilibrium, species of 1:2 [M:L] stoichiometry were observed exclusively. A direct correlation between the ELUMO-EHOMO energy gap and metal ion extraction potential is reported, with DFT studies reaffirming experimental findings

Scientific Opportunities to Reduce Risk in Nuclear Process Science

Cleaning up the nation’s nuclear weapons complex remains as one of the most technologically challenging and financially costly problems facing the U.S. Department of Energy (DOE). Safety, cost, and technological challenges have often delayed progress in retrieval, processing, and final disposition of high-level waste, spent nuclear fuel, and challenging materials. Some of the issues result from the difficulty and complexity of the technological issues; others have programmatic bases, such as contracting strategies that may provide undue focus on near-term, specific clean-up goals or difficulty in developing and maintaining stakeholder confidence in the proposed solutions. We propose that independent basic fundamental science research focused on the full cleanup life-cycle offers an opportunity to help address these challenges by providing 1) scientific insight into the fundamental mechanisms involved in currently selected processing and disposal options, 2) a rational path to the development of alternative technologies should the primary options fail, 3) confidence that models that predict long-term performance of different disposal options are based upon the best available science, 4) fundamental science discovery that enables transformational solutions to revolutionize the current baseline processes

Pan-Cancer Analysis of lncRNA Regulation Supports Their Targeting of Cancer Genes in Each Tumor Context

Long noncoding RNAs (lncRNAs) are commonly dys-regulated in tumors, but only a handful are known toplay pathophysiological roles in cancer. We inferredlncRNAs that dysregulate cancer pathways, onco-genes, and tumor suppressors (cancer genes) bymodeling their effects on the activity of transcriptionfactors, RNA-binding proteins, and microRNAs in5,185 TCGA tumors and 1,019 ENCODE assays.Our predictions included hundreds of candidateonco- and tumor-suppressor lncRNAs (cancerlncRNAs) whose somatic alterations account for thedysregulation of dozens of cancer genes and path-ways in each of 14 tumor contexts. To demonstrateproof of concept, we showed that perturbations tar-geting OIP5-AS1 (an inferred tumor suppressor) andTUG1 and WT1-AS (inferred onco-lncRNAs) dysre-gulated cancer genes and altered proliferation ofbreast and gynecologic cancer cells. Our analysis in-dicates that, although most lncRNAs are dysregu-lated in a tumor-specific manner, some, includingOIP5-AS1, TUG1, NEAT1, MEG3, and TSIX, synergis-tically dysregulate cancer pathways in multiple tumorcontexts

Understanding the Role of Past Health Care Discrimination in Help-Seeking and Shared Decision-Making for Depression Treatment Preferences

As a part of a larger, mixed-methods research study, we conducted semi-structured interviews with 21 adults with depressive symptoms to understand the role that past health care discrimination plays in shaping help-seeking for depression treatment and receiving preferred treatment modalities. We recruited to achieve heterogeneity of racial/ethnic backgrounds and history of health care discrimination in our participant sample. Participants were Hispanic/Latino (n = 4), non-Hispanic/Latino Black (n = 8), or non-Hispanic/Latino White (n = 9). Twelve reported health care discrimination due to race/ethnicity, language, perceived social class, and/or mental health diagnosis. Health care discrimination exacerbated barriers to initiating and continuing depression treatment among patients from diverse backgrounds or with stigmatized mental health conditions. Treatment preferences emerged as fluid and shaped by shared decisions made within a trustworthy patient–provider relationship. However, patients who had experienced health care discrimination faced greater challenges to forming trusting relationships with providers and thus engaging in shared decision-making processes