• I could take the judgment if you could just provide the service: non-prescription syringe purchase experience at Arizona pharmacies, 2018

      Meyerson, Beth E; Lawrence, Carrie A; Cope, Summer Dawn; Levin, Steven; Thomas, Christopher; Eldridge, Lori Ann; Coles, Haley B; Vadiei, Nina; Kennedy, Amy; Univ Arizona, Southwest Inst Res Women; et al. (BMC, 2019-09-18)
      Background: Community pharmacies are important for health access by rural populations and those who do not have optimum access to the health system, because they provide myriad health services and are found in most communities. This includes the sale of non-prescription syringes, a practice that is legal in the USA in all but two states. However, people who inject drugs (PWID) face significant barriers accessing sterile syringes, particularly in states without laws allowing syringe services programming. To our knowledge, no recent studies of pharmacy-based syringe purchase experience have been conducted in communities that are both rural and urban, and none in the Southwestern US. This study seeks to understand the experience of retail pharmacy syringe purchase in Arizona by PWID. Methods: An interview study was conducted between August and December 2018 with 37 people living in 3 rural and 2 urban Arizona counties who identified as current or former users of injection drugs. Coding was both a priori and emergent, focusing on syringe access through pharmacies, pharmacy experiences generally, experiences of stigma, and recommendations for harm reduction services delivered by pharmacies. Results: All participants reported being refused syringe purchase at pharmacies. Six themes emerged about syringe purchase: (1) experience of stigma and judgment by pharmacy staff, (2) feelings of internalized stigma, (3) inconsistent sales outcomes at the same pharmacy or pharmacy chain, (4) pharmacies as last resort for syringes, (5) fear of arrest for syringe possession, and (6) health risks resulting from syringe refusal. Conclusions: Non-prescription syringe sales in community pharmacies are a missed opportunity to improve the health of PWID by reducing syringe sharing and reuse. Yet, current pharmacy syringe sales refusal and stigmatization by staff suggest that pharmacy-level interventions will be necessary to impact pharmacy practice. Lack of access to sterile syringes reinforces health risk behaviors among PWID. Retail syringe sales at pharmacies remain an important, yet barrier-laden, element of a comprehensive public health response to reduce HIV and hepatitis C among PWID. Future studies should test multilevel evidence-based interventions to decrease staff discrimination and stigma and increase syringe sales.
    • "I'm Scared of the Disappointment": Young Adult Smokers' Relational Identity Gaps and Management Strategies as Sites of Communication Intervention

      Stanley, Samantha J; Pitts, Margaret Jane; Univ Arizona, Dept Commun (ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD, 2019-07-03)
      While cigarette smoking is decreasing among young adults, rates of nicotine consumption through other devices, most notably electronic cigarettes, are on the rise. Framed by communication theory of identity, this study examines young adult smokers' experiences with relational others in regard to their smoking. Focus group discussions and individual interviews convened with 20 young adult cigarette and electronic cigarette smokers revealed identity gaps implicating the relational layer of identity, including personal-relational, enacted-relational, and personal-enacted-relational identity gaps. Participants used communicative and behavioral strategies to manage relational discrepancies. The documented identity gaps and management strategies present opportunities for targeted smoking cessation interventions that amplify dissonance created through identity gaps as a motivational tactic.
    • I/O Aware Power Shifting

      Savoie, Lee; Lowenthal, David K., 1968-; Supinski, Bronis R. de; Islam, Tanzima; Mohror, Kathryn; Rountree, Barry; Schulz, Martin; Dept. of Comput. Sci., Univ. of Arizona (IEEE, 2016-05)
      Power limits on future high-performance computing (HPC) systems will constrain applications. However, HPC applications do not consume constant power over their lifetimes. Thus, applications assigned a fixed power bound may be forced to slow down during high-power computation phases, but may not consume their full power allocation during low-power I/O phases. This paper explores algorithms that leverage application semantics-phase frequency, duration and power needs-to shift unused power from applications in I/O phases to applications in computation phases, thus improving system-wide performance. We design novel techniques that include explicit staggering of applications to improve power shifting. Compared to executing without power shifting, our algorithms can improve average performance by up to 8% or improve performance of a single, high-priority application by up to 32%.
    • Ibuprofen Overuse Leading to Life-threatening Hypokalemia Associated with Renal Tubular Acidosis in Two Patients

      Thammineni, Nikhila; Kathi, Pradeep R; Sharma, Aditi; Jawed, Areeba; Univ Arizona, Internal Med Gastroenterol (CUREUS INC, 2019-12-17)
      Ibuprofen is a commonly used medication in the United States and is used both by prescription and over the counter, while hypokalemia is a life-threatening condition caused by various etiologies, one of which is the side effect of medications. Ibuprofen is well-known for its various nephrotoxic side effects, including hyperkalemia as a common electrolyte abnormality, however, renal tubular acidosis leading to hypokalemia with the use of ibuprofen has been reported rarely. We present here two cases of life-threatening hypokalemia due to over-thecounter use of large doses of ibuprofen and describe its management.
    • Ice Ice Baby: Are Librarian Stereotypes Freezing Us Out of Instruction?

      Pagowsky, Nicole; DeFrain, Erica; University of Arizona Libraries (2014-06-03)
      Why do librarians struggle so much with instruction? Part of the problem is that we have so many facets to consider: pedagogy, campus culture, relationships with faculty, and effectiveness with students. Research on student and faculty perceptions of librarians combined with sociological and psychological research on the magnitude of impression effects prompted us to more thoroughly examine how perceptions of instruction librarians impact successful teaching and learning. In this article, we look at theories of impression formation, the historical feminization of librarianship, and suggestions for next steps that we should take in order to take charge of our image and our instruction.
    • Ideas and perspectives: Tracing terrestrial ecosystem water fluxes using hydrogen and oxygen stable isotopes – challenges and opportunities from an interdisciplinary perspective

      Penna, Daniele; Hopp, Luisa; Scandellari, Francesca; Allen, Scott T.; Benettin, Paolo; Beyer, Matthias; Geris, Josie; Klaus, Julian; Marshall, John D.; Schwendenmann, Luitgard; et al. (COPERNICUS GESELLSCHAFT MBH, 2018-10-30)
      In this commentary, we summarize and build upon discussions that emerged during the workshop "Isotope-based studies of water partitioning and plant-soil interactions in forested and agricultural environments" held in San Casciano in Val di Pesa, Italy, in September 2017. Quantifying and understanding how water cycles through the Earth's critical zone is important to provide society and policymakers with the scientific background to manage water resources sustainably, especially considering the ever-increasing worldwide concern about water scarcity. Stable isotopes of hydrogen and oxygen in water have proven to be a powerful tool for tracking water fluxes in the critical zone. However, both mechanistic complexities (e.g. mixing and fractionation processes, heterogeneity of natural systems) and methodological issues (e.g. lack of standard protocols to sample specific compartments, such as soil water and xylem water) limit the application of stable water isotopes in critical-zone science. In this commentary, we examine some of the opportunities and critical challenges of isotope-based ecohydrological applications and outline new perspectives focused on interdisciplinary research opportunities for this important tool in water and environmental science.
    • Identifiability of parameters of three-phase oil relative permeability models under simultaneous water and gas (SWAG) injection

      Ranaee, Ehsan; Moghadasi, Leili; Inzoli, Fabio; Riva, Monica; Guadagnini, Alberto; Univ Arizona, Dept Hydrol & Atmospher Sci (ELSEVIER SCIENCE BV, 2017-11)
      We assess the relative performance of a suite of selected models to interpret three-phase oil relative permeability data and provide a procedure to determine identifiability of the model parameters. We ground our analysis on observations of Steady-State two-and three-phase relative permeabilities we collect on a water-wet Sand-Pack sample through series of core-flooding experiments. Three-phase experiments are characterized by simultaneous injection of water and gas into the core sample initiated at irreducible water saturation, a scenario which is relevant for modern enhanced oil recovery techniques. The selected oil relative permeability models include classical and recent formulations and we consider their performance when (i) solely two-phase data are employed and/or (ii) two-and three-phase data are jointly used to render predictions of three-phase oil relative permeability, kro. We assess identifiability of model parameters through the Profile Likelihood (PL) technique. We rely on formal model discrimination criteria for a quantitative evaluation of the interpretive skill of each of the candidate models tested. We also evaluate the relative degree of likelihood associated with the competing models through a posterior probability weight and use Maximum Likelihood Bayesian model averaging to provide modelaveraged estimate of kro and the associated uncertainty bounds. Results show that assessing identifiability of uncertain model parameters on the basis of the available dataset can provide valuable information about the quality of the parameter estimates and can reduce computational costs by selecting solely identifiable models among available candidates.
    • Identification and characterization of a mosquito-specific eggshell organizing factor in Aedes aegypti mosquitoes

      Isoe, Jun; Koch, Lauren E; Isoe, Yurika E; Rascón, Alberto A; Brown, Heidi E; Massani, Brooke B; Miesfeld, Roger L; Univ Arizona, Dept Chem & Biochem; Univ Arizona, Mel & Enid Zuckerman Coll Publ Hlth (PUBLIC LIBRARY SCIENCE, 2019-01-01)
      Mosquito-borne diseases are responsible for several million human deaths annually around the world. One approach to controlling mosquito populations is to disrupt molecular processes or antagonize novel metabolic targets required for the production of viable eggs. To this end, we focused our efforts on identifying proteins required for completion of embryonic development that are mosquito selective and represent potential targets for vector control. We performed bioinformatic analyses to identify putative protein-coding sequences that are specific to mosquito genomes. Systematic RNA interference (RNAi) screening of 40 mosquito- specific genes was performed by injecting double-stranded RNA (dsRNA) into female Aedes aegypti mosquitoes. This experimental approach led to the identification of eggshell organizing factor 1 (EOF1, AAEL012336), which plays an essential role in the formation and melanization of the eggshell. Eggs deposited by EOF1-deficient mosquitoes have nonmelanized fragile eggshells, and all embryos are nonviable. Scanning electron microscopy (SEM) analysis identified that exochorionic eggshell structures are strongly affected in EOF1-deficient mosquitoes. EOF1 is a potential novel target, to our knowledge, for exploring the identification and development of mosquito-selective and biosafe small-molecule inhibitors.
    • Identification and characterization of lysine-rich proteins and starch biosynthesis genes in the opaque2 mutant by transcriptional and proteomic analysis

      Jia, Mo; Wu, Hao; Clay, Kasi; Jung, Rudolf; Larkins, Brian; Gibbon, Bryan; Department of Biology, Baylor University, One Bear place #97388, Waco, TX 76798, USA; Pioneer Hi-Bred International, Inc., Johnston, IA 50131, USA; Department of Plant Sciences, University of Arizona, Tucson, AZ 85721, USA (BioMed Central, 2013)
      BACKGROUND:The opaque2 mutant is valuable for producing maize varieties with enhanced nutritional value. However, the exact mechanisms by which it improves protein quality and creates a soft endosperm texture are unclear. Given the importance of improving nutritional quality in grain crops, a better understanding of the physiological basis for these traits is necessary.RESULTS:In this study, we combined transcript profiling and proteomic analysis to better understand which genes and proteins are altered by opaque2 in the W64A inbred line. These analyses showed that the accumulation of some lysine-rich proteins, such as sorbitol dehydrogenase and glyceraldehyde3-phosphate dehydrogenase, was increased in mature kernels and may contribute substantially to the lysine content of opaque2 endosperm. Some defense proteins such as beta-glucosidase aggregating factor were strongly down regulated and may be regulated directly by opaque2. The mutant also had altered expression of a number of starch biosynthesis genes and this was associated with a more highly crystalline starch.CONCLUSIONS:The results of these studies revealed specific target genes that can be investigated to further improve nutritional quality and agronomic performance of high lysine maize lines, particularly those based on the presence of the opaque2 mutation. Alteration of amylopectin branching patterns in opaque2 starch could contribute to generation of the soft, starchy endosperm.
    • Identification and quantitation of clinically relevant microbes in patient samples: Comparison of three k-mer based classifiers for speed, accuracy, and sensitivity

      Watts, George S; Thornton, James E; Youens-Clark, Ken; Ponsero, Alise J; Slepian, Marvin J; Menashi, Emmanuel; Hu, Charles; Deng, Wuquan; Armstrong, David G; Reed, Spenser; et al. (PUBLIC LIBRARY SCIENCE, 2019-11-22)
      Infections are a serious health concern worldwide, particularly in vulnerable populations such as the immunocompromised, elderly, and young. Advances in metagenomic sequencing availability, speed, and decreased cost offer the opportunity to supplement or even replace culture-based identification of pathogens with DNA sequence-based diagnostics. Adopting metagenomic analysis for clinical use requires that all aspects of the workflow are optimized and tested, including data analysis and computational time and resources. We tested the accuracy, sensitivity, and resource requirements of three top metagenomic taxonomic classifiers that use fast k-mer based algorithms: Centrifuge, CLARK, and KrakenUniq. Binary mixtures of bacteria showed all three reliably identified organisms down to 1% relative abundance, while only the relative abundance estimates of Centrifuge and CLARK were accurate. All three classifiers identified the organisms present in their default databases from a mock bacterial community of 20 organisms, but only Centrifuge had no false positives. In addition, Centrifuge required far less computational resources and time for analysis. Centrifuge analysis of metagenomes obtained from samples of VAP, infected DFUs, and FN showed Centrifuge identified pathogenic bacteria and one virus that were corroborated by culture or a clinical PCR assay. Importantly, in both diabetic foot ulcer patients, metagenomic sequencing identified pathogens 4–6 weeks before culture. Finally, we show that Centrifuge results were minimally affected by elimination of time-consuming read quality control and host screening steps.
    • Identification of Actionable Fusions as an Anti-EGFR Resistance Mechanism Using a Circulating Tumor DNA Assay

      Clifton, Katherine; Rich, Thereasa A.; Parseghian, Christine; Raymond, Victoria M.; Dasari, Arvind; Pereira, Allan Andresson Lima; Willis, Jason; Loree, Jonathan M.; Bauer, Todd M.; Chae, Young Kwang; et al. (AMER SOC CLINICAL ONCOLOGY, 2019-10-03)
      PURPOSE: Gene fusions are established oncogenic drivers and emerging therapeutic targets in advanced colorectal cancer. This study aimed to detail the frequencies and clinicopathological features of gene fusions in colorectal cancer using a circulating tumor DNA assay. METHODS: Circulating tumor DNA samples in patients with advanced colorectal cancer were analyzed at 4,581 unique time points using a validated plasma-based multigene assay that includes assessment of fusions in FGFR2, FGFR3, RET, ALK, NTRK1, and ROS1. Associations between fusions and clinicopathological features were measured using Fisher's exact test. Relative frequencies of genomic alterations were compared between fusion-present and fusion-absent cases using an unpaired t test. RESULTS: Forty-four unique fusions were identified in 40 (1.1%) of the 3,808 patients with circulating tumor DNA detected: RET(n = 6; 36% of all fusions detected), FGFR3 (n = 2; 27%), ALK(n = 10, 23%), NTRK1 (n = 3; 7%), ROS1 (n = 2; 5%), and FGFR2 (n = 1; 2%). Relative to nonfusion variants detected, fusions were more likely to be subclonal (odds ratio, 8.2; 95% CI, 2.94 to 23.00; P < .001). Mutations associated with a previously reported anti-epidermal growth factor receptor (anti-EGFR) therapy resistance signature (subclonal RAS and EGFR mutations) were found with fusions in FGFR3 (10 of 12 patients), RET(nine of 16 patients), and ALK(seven of 10 patients). For the 27 patients with available clinical histories, 21 (78%) had EGFR monoclonal antibody treatment before fusion detection. CONCLUSION: Diverse and potentially actionable fusions can be detected using a circulating tumor DNA assay in patients with advanced colorectal cancer. Distribution of coexisting subclonal mutations in EGFR, KRAS, and NRAS in a subset of the patients with fusion-present colorectal cancer suggests that these fusions may arise as a novel mechanism of resistance to anti-EGFR therapies in patients with metastatic colorectal cancer.
    • Identification of boosted Higgs bosons decaying into b-quark pairs with the ATLAS detector at 13 TeV

      Berlendis, S.; Cheu, E.; Delitzsch, C.M.; Johns, K.A.; Jones, S.; Lampl, W.; LeBlanc, M.; Leone, R.; Loch, P.; Rutherfoord, J.P.; et al. (SPRINGER, 2019-10)
      This paper describes a study of techniques for identifying Higgs bosons at high transverse momenta decaying into bottom-quark pairs, H -> b (b) over bar, for proton-proton collision data collected by the ATLAS detector at the Large Hadron Collider at a centre-of-mass energy root s = 13 TeV. These decays are reconstructed from calorimeter jets found with the anti-k(t) R = 1.0 jet algorithm. To tag Higgs bosons, a combination of requirements is used: b-tagging of R = 0.2 track-jets matched to the large-R calorimeter jet, and requirements on the jet mass and other jet substructure variables. The Higgs boson tagging efficiency and corresponding multijet and hadronic top-quark background rejections are evaluated using Monte Carlo simulation. Several benchmark tagging selections are defined for different signal efficiency targets. The modelling of the relevant input distributions used to tag Higgs bosons is studied in 36 fb(-1) of data collected in 2015 and 2016 using g -> b (b) over bar and Z(-> b (b) over bar)gamma event selections in data. Both processes are found to be well modelled within the statistical and systematic uncertainties.
    • Identification of Channeling in Pore‐Scale Flows

      Siena, Martina; Iliev, Oleg; Prill, Torben; Riva, Monica; Guadagnini, Alberto; Univ Arizona, Dept Hydrol & Atmospher Sci (AMER GEOPHYSICAL UNION, 2019-03-29)
      We quantify flow channeling at the microscale in three-dimensional porous media. The study is motivated by the recognition that heterogeneity and connectivity of porous media are key drivers of channeling. While efforts in the characterization of this phenomenon mostly address processes at the continuum scale, it is recognized that pore-scale preferential flow may affect the behavior at larger scales. We consider synthetically generated pore structures and rely on geometrical/topological features of subregions of the pore space where clusters of velocity outliers are found. We relate quantitatively the size of such fast channels, formed by pore bodies and pore throats, to key indicators of preferential flow and anomalous transport. Pore-space spatial correlation provides information beyond just pore size distribution and drives the occurrence of these velocity structures. The latter occupy a larger fraction of the pore-space volume in pore throats than in pore bodies and shrink with increasing flow Reynolds number. Plain Language Summary The movement of fluids and dissolved chemicals through porous media is massively affected by the heterogeneous nature of these systems. The presence of "fast channels," that is, preferential flow paths characterized by large velocities persisting over long distances, gives rise to very short solute travel times, with key implications in, for example, environmental risk assessment. While efforts in the characterization of this phenomenon mostly address processes at the continuum (laboratory or field) scale, it is recognized that pore-scale channeling of flow may affect the system behavior at larger scales. Here we provide criteria for the identification of fast channels at the pore scale, addressing feedback between channeling and geometrical/topological features of the investigated porous structures. Our results clearly evidence the major role of well-defined regions in the pore space, termed pore throats, in driving flow channeling. We also find that the strength of channeling is controlled by the characteristic Reynolds number of the flow field.
    • Identification of ejaculated proteins in the house mouse (Mus domesticus) via isotopic labeling

      Dean, Matthew; Findlay, Geoffrey; Hoopmann, Michael; Wu, Christine; MacCoss, Michael; Swanson, Willie; Nachman, Michael; Molecular and Computational Biology, University of Southern California, 1050 Childs Way, Los Angeles, CA, USA; Ecology and Evolutionary Biology, University of Arizona, Tucson, AZ, USA; Department of Genome Sciences, University of Washington, Seattle, WA, USA; et al. (BioMed Central, 2011)
      BACKGROUND:Seminal fluid plays an important role in successful fertilization, but knowledge of the full suite of proteins transferred from males to females during copulation is incomplete. The list of ejaculated proteins remains particularly scant in one of the best-studied mammalian systems, the house mouse (Mus domesticus), where artificial ejaculation techniques have proven inadequate. Here we investigate an alternative method for identifying ejaculated proteins, by isotopically labeling females with 15N and then mating them to unlabeled, vasectomized males. Proteins were then isolated from mated females and identified using mass spectrometry. In addition to gaining insights into possible functions and fates of ejaculated proteins, our study serves as proof of concept that isotopic labeling is a powerful means to study reproductive proteins.RESULTS:We identified 69 male-derived proteins from the female reproductive tract following copulation. More than a third of all spectra detected mapped to just seven genes known to be structurally important in the formation of the copulatory plug, a hard coagulum that forms shortly after mating. Seminal fluid is significantly enriched for proteins that function in protection from oxidative stress and endopeptidase inhibition. Females, on the other hand, produce endopeptidases in response to mating. The 69 ejaculated proteins evolve significantly more rapidly than other proteins that we previously identified directly from dissection of the male reproductive tract.CONCLUSION:Our study attempts to comprehensively identify the proteins transferred from males to females during mating, expanding the application of isotopic labeling to mammalian reproductive genomics. This technique opens the way to the targeted monitoring of the fate of ejaculated proteins as they incubate in the female reproductive tract.
    • Identification of G-quadruplexes in long functional RNAs using 7-deazaguanine RNA

      Weldon, Carika; Behm-Ansmant, Isabelle; Hurley, Laurence H; Burley, Glenn A; Branlant, Christiane; Eperon, Ian C; Dominguez, Cyril; College of Pharmacy and BIO5 Institute, University of Arizona; University of Arizona Cancer Center (NATURE PUBLISHING GROUP, 2016-11-07)
      RNA G-quadruplex (G4) structures are thought to affect biological processes, including translation and pre-mRNA splicing, but it is not possible at present to demonstrate that they form naturally at specific sequences in long functional RNA molecules. We developed a new strategy, footprinting of long 7-deazaguanine-substituted RNAs (FOLDeR), that allows the formation of G4s to be confirmed in long RNAs and under functional conditions.
    • Identification of gender differences in ultrasound milestone assessments during emergency medicine residency training: a pilot study

      Acuña, Josie; Situ-LaCasse, Elaine H; Patanwala, Asad E; Stolz, Lori A; Amini, Richard; Friedman, Lucas; Adhikari, Srikar; Univ Arizona, Dept Emergency Med (Dove Medical Press Ltd., 2019-03)
      Objectives: Prior literature suggests that incongruities between male and female resident's procedural competency may be explained by gender bias during the evaluation process. There are no known studies investigating gender differences in the assessment of ultrasound-based procedural skills among emergency medicine (EM) residents. The purpose of this study was to evaluate for gender differences in ultrasound milestone assessments among EM residents. Methods: This is a retrospective study including EM residents. Milestone assessment data were collected from a total of 3 Accreditation Council for Graduate Medical Education (ACGME) EM residency programs representing a 3-year period The outcome measures included mean milestone levels, milestone levels at baseline and graduation and differences in milestone achievement between female and male EM residents. An unpaired Student's t-test was used to compare milestone scores between female and male residents. Results: A total of 456 ultrasound milestone evaluations were collected from 91 EM residents (34 females [37%] and 57 males [63%]). No significant differences were noted in the overall mean milestone level between females (2.3 +/- 0.6) and males (2.2 +/- 0.6) (P=0.387). There were no significant differences noted in the ultrasound milestone level between females (0.8 +/- 0.6) and males (0.7 +/- 0.7) at baseline (P=0.754). Although it did not reach statistical significance (P=0.197), the increase in the mean ultrasound milestone level from baseline to graduation was greater in males (3.4 +/- 0.7) compared to females (3.1 +/- 0.7). Conclusion: Overall, there were no statistically significant differences in the mean ultrasound milestone levels between females and males. The rate of ultrasound milestone level achievement during EM residency training at our institution had a slight tendency to be higher for males than females in the observed residency programs; however, this also did not reach statistical significance. Possible gender bias while evaluating ultrasound milestone levels needs to be further studied on a larger scale.
    • Identification of novel DNA methylation inhibitors via a two-component reporter gene system

      Lin, Yi-Shiuan; Shaw, Arthur; Wang, Shi-Gang; Hsu, Chia-Chen; Teng, I-W; Tseng, Min-Jen; Huang, Tim; Chen, Ching-Shih; Leu, Yu-Wei; Hsiao, Shu-Huei; et al. (BioMed Central, 2011)
      BACKGROUND:Targeting abnormal DNA methylation represents a therapeutically relevant strategy for cancer treatment as demonstrated by the US Food and Drug Administration approval of the DNA methyltransferase inhibitors azacytidine and 5-aza-2'-deoxycytidine for the treatment of myelodysplastic syndromes. But their use is associated with increased incidences of bone marrow suppression. Alternatively, procainamide has emerged as a potential DNA demethylating agent for clinical translation. While procainamide is much safer than 5-aza-2'-deoxycytidine, it requires high concentrations to be effective in DNA demethylation in suppressing cancer cell growth. Thus, our laboratories have embarked on the pharmacological exploitation of procainamide to develop potent DNA methylation inhibitors through lead optimization.METHODS:We report the use of a DNA methylation two-component enhanced green fluorescent protein reporter system as a screening platform to identify novel DNA methylation inhibitors from a compound library containing procainamide derivatives.RESULTS:A lead agent IM25, which exhibits substantially higher potency in GSTp1 DNA demethylation with lower cytotoxicity in MCF7 cells relative to procainamide and 5-aza-2'-deoxycytidine, was identified by the screening platform.CONCLUSIONS:Our data provide a proof-of-concept that procainamide could be pharmacologically exploited to develop novel DNA methylation inhibitors, of which the translational potential in cancer therapy/prevention is currently under investigation.
    • Identification of the Hard X-Ray Source Dominating the E > 25 keV Emission of the Nearby Galaxy M31

      Yukita, M.; Ptak, A.; Hornschemeier, A. E.; Wik, D.; Maccarone, T. J.; Pottschmidt, K.; Zezas, A.; Antoniou, V.; Ballhausen, R.; Lehmer, B. D.; et al. (IOP PUBLISHING LTD, 2017-03-22)
      We report the identification of a bright hard X-ray source dominating the M31 bulge above 25 keV from a simultaneous NuSTAR-Swift observation. We find that this source is the counterpart to Swift J0042.6+4112, which was previously detected in the Swift BAT All-sky Hard X-ray Survey. This Swift BAT source had been suggested to be the combined emission from a number of point sources; our new observations have identified a single X-ray source from 0.5 to 50 keV as the counterpart for the first time. In the 0.5-10 keV band, the source had been classified as an X-ray Binary candidate in various Chandra and XMM-Newton studies; however, since it was not clearly associated with Swift J0042.6+4112, the previous E < 10 keV observations did not generate much attention. This source has a spectrum with a soft X-ray excess (kT similar to 0.2 keV) plus a hard spectrum with a power law of Gamma similar to 1 and a cutoff around 15-20 keV, typical of the spectral characteristics of accreting pulsars. Unfortunately, any potential pulsation was undetected in the NuSTAR data, possibly due to insufficient photon statistics. The existing deep HST images exclude high-mass (> 3 M-circle dot) donors at the location of this source. The best interpretation for the nature of this source is an X-ray pulsar with an intermediate-mass (< 3 M-circle dot) companion or a symbiotic X-ray binary. We discuss other possibilities in more detail.
    • Identification of the substrate recruitment mechanism of the muscle glycogen protein phosphatase 1 holoenzyme

      Kumar, Ganesan Senthil; Choy, Meng S; Koveal, Dorothy M; Lorinsky, Michael K; Lyons, Scott P; Kettenbach, Arminja N; Page, Rebecca; Peti, Wolfgang; Univ Arizona, Dept Chem & Biochem (AMER ASSOC ADVANCEMENT SCIENCE, 2018-11-01)
      Glycogen is the primary storage form of glucose. Glycogen synthesis and breakdown are tightly controlled by glycogen synthase (GYS) and phosphorylase, respectively. The enzyme responsible for dephosphorylating GYS and phosphorylase, which results in their activation (GYS) or inactivation (phosphorylase) to robustly stimulate glycogen synthesis, is protein phosphatase 1 (PP1). However, our understanding of how PP1 recruits these substrates is limited. Here, we show how PP1, together with its muscle glycogen-targeting (GM) regulatory subunit, recruits and selectively dephosphorylates its substrates. Our molecular data reveal that the GM carbohydrate binding module (GMCBM21), which is amino-terminal to the GM PP1 binding domain, has a dual function in directing PP1 substrate specificity: It either directly recruits substrates (i.e., GYS) or recruits them indirectly by localization (via glycogen for phosphorylase). Our data provide the molecular basis for PP1 regulation by GM and reveal how PP1-mediated dephosphorylation is driven by scaffolding-based substrate recruitment.
    • Identification of transcription-factor genes expressed in the Arabidopsis female gametophyte

      Wang, Dongfang; Zhang, Changqing; Hearn, David; Kang, Il-Ho; Punwani, Jayson; Skaggs, Megan; Drews, Gary; Schumaker, Karen; Yadegari, Ramin; School of Plant Sciences, University of Arizona, Tucson, Arizona 85721-0036, USA; et al. (BioMed Central, 2010)
      BACKGROUND:In flowering plants, the female gametophyte is typically a seven-celled structure with four cell types: the egg cell, the central cell, the synergid cells, and the antipodal cells. These cells perform essential functions required for double fertilization and early seed development. Differentiation of these distinct cell types likely involves coordinated changes in gene expression regulated by transcription factors. Therefore, understanding female gametophyte cell differentiation and function will require dissection of the gene regulatory networks operating in each of the cell types. These efforts have been hampered because few transcription factor genes expressed in the female gametophyte have been identified. To identify such genes, we undertook a large-scale differential expression screen followed by promoter-fusion analysis to detect transcription-factor genes transcribed in the Arabidopsis female gametophyte.RESULTS:Using quantitative reverse-transcriptase PCR, we analyzed 1,482 Arabidopsis transcription-factor genes and identified 26 genes exhibiting reduced mRNA levels in determinate infertile 1 mutant ovaries, which lack female gametophytes, relative to ovaries containing female gametophytes. Spatial patterns of gene transcription within the mature female gametophyte were identified for 17 transcription-factor genes using promoter-fusion analysis. Of these, ten genes were predominantly expressed in a single cell type of the female gametophyte including the egg cell, central cell and the antipodal cells whereas the remaining seven genes were expressed in two or more cell types. After fertilization, 12 genes were transcriptionally active in the developing embryo and/or endosperm.CONCLUSIONS:We have shown that our quantitative reverse-transcriptase PCR differential-expression screen is sufficiently sensitive to detect transcription-factor genes transcribed in the female gametophyte. Most of the genes identified in this study have not been reported previously as being expressed in the female gametophyte. Therefore, they might represent novel regulators and provide entry points for reverse genetic and molecular approaches to uncover the gene regulatory networks underlying female gametophyte development.